Abstract Number: 279

Sequence-based artificial intelligence-guided inhibitory peptides to counteract AAV neutralizing antibodies in gene therapy

Presenter: Bingqi Xu
Session: 803. Emerging Tools, Techniques, and Artificial Intelligence in Hematology: MRD Assays and Novel Drug Discovery Pipelines

Abstract: Background: Gene therapy using adeno-associated virus (AAV) as a vector has been successfully applied in treating various monogenic diseases with significant efficacy. However, the presence of neutralizing antibodies (Nab) against AAV in patients’ plasma hinders the delivery of AAV to the target tissue. Thereby monogenic diseases like hemophilia A/B, Glycogen Storage Disease Type Ia, and Duchenne muscular dystrophy, requiring systemic administration, are more significantly affected by Nab. In contrast, monogenic diseases suitable for local AAV administration such as eye and ear diseases minimize the impact of Nab. All patients undergoing gene therapy developed Nab, persisting at elevated levels even multiple years, which becomes the main obstacle limiting patients from receiving repeated dosing. Nab bind exclusively to the accessible surface regions of AAV capsid proteins, disrupting viral infection. These antigenic targets are classified as either linear epitopes or conformational epitopes. Importantly, certain antibodies recognizing conformational epitopes may also bind corresponding linear peptide fragments, enabling short peptides to act as effective decoys against Nab binding. This reciprocal recognition provides a mechanistic rationale for using short peptides as decoys to effectively block Nab binding to AAV. Natural Language Processing (NLP) techniques have been successfully applied to protein sequence research, which correspond to the structural, functional, and biochemical properties of proteins. According to prior studies, taking amino acid (aa) sequences as input, transformer-based models or pre-trained models frequently demonstrate excellent performance across various tasks, including contact prediction, structure prediction, generation models, and feature extraction. Immunogenicity is also a critical attribute of protein-based drugs, gene therapy vectors, and vaccines. The immunogenicity classification model trained on millions of aa sequences, leveraging the principle that the human immune system tolerates self-proteins but reacts to pathogen-derived proteins enables rapid identification and optimization of immunogenic regions in therapeutic candidates. Method Using a curated dataset of human- and virus-derived amino acid sequences, we trained peptide classification models based on modified BERT (Bidirectional Encoder Representations from Transformers) architectures with bidirectional Transformer encoders and the pretrained evolutionary-scale model ESM- 2. After validating model performance, “virus-polarized” sequences within AAV2 and AAV843 capsids were identified to guide peptide selection. The antibody-blocking efficacy of these AI-predicted decoy peptides was confirmed using a leave-one-out (LOO) strategy and peptide-antibody binding assays. A similar AI- guided decoy development strategy proved effective in Nab in severe hemophilia A with inhibitors (HAI). Finally, the ability of decoy peptides to enhance AAV gene therapy was validated across one primary and two secondary in vivo models, alongside assessment of potential immune responses. To generate novel decoys, we developed a contrastive loss-trained variational autoencoder (VAE) with a BERT encoder to design and validate AI-generated peptide candidates. Results We compare two fine-tuning strategies: full-parameter tuning and low-rank adaptation (LoRA). Across multiple BERT-based encoders, the models achieve over 84% classification accuracy at the optimal aa length. Using these models, we identify short virus-polarized peptides from AAV capsids. A Leave-One- Out strategy validates the importance of these peptides in blocking preexisting and therapy-induced Nab, and in mediating direct or competitive binding to specific antibodies. This decoy strategy proves effective in patients with severe hemophilia A with inhibitors, demonstrating cross-disease potential. We confirm the peptides’ inhibitory effects in one primary and two secondary AAV dosing models, and sequential administration of IgG-degrading enzymes (Ides) and decoy peptides blocks high-titer Nab without inducing inflammatory responses or immunogenicity in vivo. Furthermore, a contrastive loss-optimized variational autoencoder (VAE) with a BERT-based encoder designs peptides that effectively block Nab of AAVs. These findings highlight the potential of sequence-based AI algorithms to overcome high-titer Nab barriers in AAV gene therapies.

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Abstract Number: 301

Musculoskeletal ultrasound evaluation of joint health status and bleeding phenotype in severe and non-severe hemophilia (A and B)

Presenter: Jonathan Roberts
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Prophylaxis Across the Age Spectrum

Abstract: Introduction: People with hemophilia (PwH) A and B are known to have variable bleeding phenotypes, may have joint bleeding that is less clinically apparent, and musculoskeletal ultrasound (MSKUS) has become an established modality for evaluating joint status. Evaluation of individual bleeding phenotype can be challenging, however clinical tools including the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT), self-BAT, and the Beighton Hypermobility Score (BHS) are useful, validated tools for evaluation of joint health status, in addition to MSKUS. We hypothesize that presence and degree of joint disease, evaluated with MSKUS and physical assessment scoring, will correlate with severity of bleeding phenotype as characterized through clinical history, BAT assessment, and presence of joint hypermobility in PwH A and B. Methods: We assessed baseline joint status of elbows, knees, and ankles, and disease progression over one year with MSKUS, ISTH-BAT, self-BAT, and assessment of hypermobility with the BHS. PwH with severe, moderate, or mild hemophilia A or B were assessed at baseline and one year later during their comprehensive clinic visit at our institution. Clinical bleeding phenotype was evaluated with BHS and BAT scores, and joint health was evaluated with MSKUS. Joint health outcomes were reviewed comparing baseline to year 1 metrics. Analysis of joints with arthropathy included determination for improvement, maintenance and worsening of joint health in terms of hemophilia severity and ABR. Results: 101 PwH were enrolled. Of the 101 total enrolled, the majority were PwH A (n=75) severe (43), moderate (7), mild (25). The remaining patients (n=26) were PwH B severe (7), moderate (13), mild (6). Many patients were regularly treated with prophylaxis at baseline (55/100), with 10 having a history of inhibitors, 9 PwH A and 1 PwH B. 28 patients enrolled with target joints mild (2); moderate (1); severe (25). MSKUS measurements were completed using the JADE protocol 1 . Baseline clinical bleeding data showed ISTH-BAT mean 13 (SD 13) and median 7 (IQR 7.6 – 18), self-BAT mean 13 (SD 13) and median 8 (IQR 6- 18.5), BHS mean 2 (SD 1) and median 1.9 (IQR 0-2), annualized bleed rate (ABR) mean 2.7 (SD 1) and median 4.5 (IQR 0-3.3). Seventy-five PwH completed follow-up MSKUS. Joints with arthropathy showed improvement in 13 elbow (PwH A: mild 4, moderate 1, severe 4), stable elbow in 5 (PwH A: mild 1, moderate 2, severe 1), worsened elbow in 17 (PwH A: mild 4, moderate 1, severe 6; PwH B: mild 1, moderate 1); improved ankle in 30 (PwH A: mild 3, moderate 2, severe 12; PwH B: mild 2, moderate 1), stable ankle in 24 (PwH A: mild 3, severe 10; PwH B: mild 1, moderate 1), worsened ankle in 27 (PwH A: mild 6, moderate 1, severe 8; PwH B: mild 2, moderate 3); improved knee in 25 (PwH A: mild 5, moderate 1, severe 8; PwH B: mild 1, moderate 1), stable knee in 17 (PwH A: mild 2, severe 6; PwH B: mild 3, moderate 4), worsened knee in 40 (PwH A: mild 8, moderate 1, severe 13; PwH B: mild 3, moderate 3). PwH and ABR of 0 showed (improvement in elbow 1, stable 2, worsened 5), (improvement in ankle 9, stable 7 worsened 9), (improvement in knee 0, stable 10, worsened 15); ABR 1-3 showed (improvement in elbow 6, stable 2, worsened 4), (improvement in ankle 9, stable 6, worsened 8), (improvement knee in 6, stable 5, worsened 11). Surprisingly, 12 PwH with reported historical zero ABR demonstrated worse joint health status with follow-up MSKUS (10 worse elbow, 7 knee, 5 ankle). Discussion: Knowledge pertaining to joint health status and bleeding phenotype is PwH A and B is limited. We assessed the presence and degree of joint disease, evaluated with MSKUS and physical assessment scoring, and severity of bleeding phenotype as characterized through clinical history, BAT assessment, and presence of joint hypermobility in PwH hemophilia A and B. Some PwH demonstrated worsening joint status despite historical zero ABR, which suggests MSKUS utility in evaluation of the effect of sub- clinical bleeding. These results suggest a needed large, multicenter study to expand understanding of joint status and bleeding phenotype in PwH. References 1. Volland, L.M., et al., Development and Reliability of the Joint Tissue Activity and Damage Examination for Quantitation of Structural Abnormalities by Musculoskeletal Ultrasound in Hemophilic Joints. J Ultrasound Med, 2019. 38(6): p. 1569-1581.

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Abstract Number: 302

NXT007 prophylaxis in people with hemophilia A with or without FVIII inhibitors: A global Phase I/II multiple-ascending-dose study

Presenter: Maria Elisa Mancuso
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Prophylaxis Across the Age Spectrum

Abstract: Background: NXT007 is a next-generation bispecific antibody, based on emicizumab, that mimics the cofactor function of activated factor (F)VIII to restore intrinsic tenase activity in people with hemophilia A (PwHA). In comparison with emicizumab, NXT007 has demonstrated greater potency and higher maximum effect in thrombin generation (TG) analysis, and has a longer half-life. NXT007 was first investigated in PwHA in the multiple-ascending-dose (MAD) part of the Phase I/II NXTAGE study (Shima et al. OC 20. ISTH 2025); after a median of 68.4 weeks of follow-up, there were no safety concerns at any dose and the two highest dose cohorts had zero treated bleeds. Here, we report on the first three cohorts of the Phase I/II global MAD study of NXT007 in PwHA.

Methods: The global MAD study of NXT007 (NCT05987449) is an open-label, non-randomized, multicenter trial. Eligible participants (pts) are males aged 12–59 years with a diagnosis of severe (FVIII activity <1 IU/dL) or moderate (FVIII activity 1–5 IU/dL) congenital HA with/without FVIII inhibitors. The primary treatment phase was 24 weeks. Each cohort received two loading doses of subcutaneous NXT007 at Days 1 and 15, followed by maintenance doses every 4 weeks from Day 29. The loading doses for cohorts 1, 2, and 3, were 0.42mg/kg, 1.05mg/kg, and 1.62mg/kg, respectively. Maintenance doses were 0.28mg/kg, 0.70mg/kg, and 1.08mg/kg, respectively; these were the same doses given to NXTAGE cohorts B2–B4, to be comparable at steady state. Pts may continue their NXT007 maintenance dose for up to 7 years in the extension phase. The primary objective is to investigate the safety of NXT007, including incidence of adverse events (AEs) and serious AEs (SAEs). Secondary and exploratory objectives include efficacy (annualized bleeding rate [ABR] using the ISTH-SSC 72-hour rule and a negative binomial regression model), pharmacokinetics (PK), pharmacodynamics (including TG), D-dimer measurement, and immunogenicity (incidence of anti-drug antibodies [ADA]).

Results: At data cut-off (April 21, 2025), 22 pts had been treated with NXT007: seven in cohort 1, nine in cohort 2, and six in cohort 3. One pt left the study prior to any NXT007 administration due to meeting an exclusion criterion. No pt discontinued NXT007 treatment. At enrollment, the median (range) age of pts was 36 (15–49) years. Twenty (90.9%) pts had severe HA and 2 (9.1%) had moderate HA. Nineteen (86.4%) pts had no history of FVIII inhibitors, 2 (9.1%) had previous and 1 (4.5%) had current FVIII inhibitors. Median (range) observation period in cohorts 1, 2, and 3 was 68.9 (61.1–80.0), 44.1 (42.1–46.1), and 21.6 (20.1–24.1) weeks, respectively. At data cut-off, 6/7 (85.7%) pts in cohort 1 had experienced a total of 47 AEs; 8/9 (88.9%) pts in cohort 2 had 26 AEs; and 5/6 (83.3%) pts in cohort 3 had 23 AEs. Of 285 NXT007 administrations, 29 (10.2%) in five pts were associated with an injection-site reaction, all of which were Grade 1 and resolved by data cut-off. One other pt, in cohort 2, experienced AEs considered to be related to NXT007: transient Grade 2 aspartate aminotransferase increase and Grade 1 alanine aminotransferase increase. Two pts experienced SAEs, both of which resolved and were considered unrelated to NXT007: a pt in cohort 2 had Grade 3 adjustment disorder and a pt in cohort 3 had a Grade 3 fall. There were no thrombotic events or thrombotic microangiopathies. ABRs (95% confidence intervals) for treated bleeds in the maintenance period were 0.11 (0.02–0.81) for cohort 1, 0.15 (0.02–1.04) for cohort 2, and 1.94 (0.73–5.16) for cohort 3. During the maintenance period, 6/7 (85.7%) pts in cohort 1, 8/9 (88.9%) in cohort 2, and 5/6 (83.3%) in cohort 3 had zero treated bleeds. NXT007 plasma concentrations increased dose dependently and in line with population PK simulations. Activated FXI-triggered TG peak height increased from baseline and with increasing NXT007 plasma concentrations, into the non-hemophilic range. D-dimer levels were unaffected by NXT007. ADA were detected in most pts, but had no impact on PK, safety, or efficacy, and no cross-reactivity with emicizumab.

Conclusions: NXT007 was well tolerated, with a tolerable safety profile in all dose cohorts. Treated bleed ABRs were low; one pt per cohort experienced a treated bleed in the maintenance period, except for one notable outlier in cohort 3 with multiple bleeds. Presence of ADA had no impact on PK. These data support progression to Phase III trials.

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Abstract Number: 303

AKATSUKI third interim analysis: Safety of emicizumab during and after immune tolerance induction implementation

Presenter: Keiji Nogami
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Prophylaxis Across the Age Spectrum

Abstract: Background: Immune tolerance induction (ITI) therapy is recommended to eradicate factor (F)VIII inhibitors in people with hemophilia A (PwHA). There are limited safety data available on emicizumab in combination with ITI, particularly concerning thrombotic events (TEs), with ITI efficacy also a subject of interest. This study presents the safety of emicizumab during and directly following ITI.

Methods: AKATSUKI (jRCTs041200037) is a Phase IV, prospective, open-label, multicenter study. Eligible PwHA had a positive FVIII inhibitor titer (≥0.6 BU/mL) and would begin ITI therapy after study enrollment, or were undergoing ITI therapy but had not met the criteria for partial ITI success. PwHA with FVIII inhibitors received an approved emicizumab dosing regimen and ITI therapy. ITI dosing regimens included 50 IU/kg standard half-life (SHL) or extended half-life (EHL) FVIII concentrate administered three times a week; for EHL FVIII, a dosing frequency of twice per week was permitted. Further details, including post-ITI maintenance dosing regimens, have been published (Matsushita, BMJ Open 2022). The primary endpoint was evaluation of adverse events (AEs), including TEs, and abnormal clinical laboratory values during and immediately after ITI. Secondary endpoints included number of treated bleeds, number of participants who started ITI after study entry who achieved ITI partial success, and changes in FVIII inhibitor titer during ITI and after achieving partial success. Partial success was defined as a negative FVIII inhibitor test result combined with a normal FVIII recovery value in the participant’s blood sample.

Results: Twelve male participants (median [range] age at entry: 2.5 [1–54] years) enrolled. Participants received emicizumab (n=11), ITI (n=9), or both (n=7) before enrollment; one participant received emicizumab and ITI separately, with no treatment overlap. The median (range) duration of ITI before enrollment was 536 (12–1,734) days. Three participants began ITI after enrollment, all aged <2 years. This interim analysis was performed 144 weeks after the first study dose of emicizumab in the last enrolled participant (evaluation period, median [range]: 1079.5 [224–1,342] days; data cut-off: October 31, 2024). Three participants used SHL FVIII and nine participants used EHL FVIII for ITI therapy. Overall, 90 AEs were reported and there were no TEs. One Grade 1 event of swelling was considered emicizumab-related, but this resolved the same day it occurred. Three participants experienced a serious AE (SAE), all of which resolved and were considered unrelated to emicizumab or FVIII concentrate. There was one abnormal laboratory value: a Grade 1 prolonged activated partial thromboplastin time influenced by heparin administration. In total, 22 treated bleeds were reported in seven participants: one spontaneous, two surgical and 19 traumatic . Of these, 16 were managed with recombinant activated FVII, six were managed with EHL FVIII and none treated with activated prothrombin complex concentrate. Median annualized bleeding rate during the study period was 0.44 (range: 0.00–2.09). By data cut-off, six participants, all with a history of ITI before study entry, achieved negative FVIII inhibitor status. Median (range) duration of ITI at study entry for these participants was 381 (12–1,734) days and median (range) duration of ITI during the study, up to the point at which a negative FVIII inhibitor status was achieved, was 93 (5–137) weeks. Of these six participants, three maintained continuous FVIII inhibitor negativity during the observation period. Three participants had achieved partial ITI success by data cut-off, though recurrence of FVIII inhibitors occurred in two participants. Of these, one participant experienced FVIII inhibitor recurrence 12 days after partial ITI success was achieved (FVIII inhibitor level = 0.97 BU/mL), the other experienced recurrence 16 days after partial ITI success was achieved (FVIII inhibitor level = 1.82 BU/mL).

Conclusions: At this 144-week interim analysis, no new safety concerns or TEs were reported. Effective bleed control was confirmed with a combination of emicizumab and ITI. Of the 12 participants enrolled, three achieved partial ITI success, though two participants had recurrence of FVIII inhibitors. Negative inhibitor status was reported in six participants. AKATSUKI continues to evaluate the safety of emicizumab during, and following, ITI therapy in PwHA with FVIII inhibitors.

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Abstract Number: 306

Marstacimab prophylaxis in participants with Hemophilia A or B with inhibitors: Results from the Phase 3 BASIS trial

Presenter: Davide Matino
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Prophylaxis Across the Age Spectrum

Abstract: Background: Background: Marstacimab is a monoclonal antibody that inhibits tissue factor pathway inhibitor to enhance thrombin generation and restore hemostasis in participants (pts) with hemophilia A (HA) or hemophilia B (HB). The phase 3 BASIS study (NCT03938792) evaluated the safety and efficacy of marstacimab in adults and adolescents with severe HA (factor VIII <1%) or moderately severe to severe HB (factor IX ≤2%), with or without inhibitors. Marstacimab was approved for prophylactic use in individuals with HA or HB without inhibitors. Here, we present results of the BASIS study in pts with inhibitors.

Methods: This open-label, single-arm study enrolled males aged ≥12 to <75 years with current or historical high-titer inhibitors (≥5 BU/mL). After a 6-month observational phase (OP) on bypassing agents (on-demand [OD] or routine prophylaxis [RP]), pts received a subcutaneous loading dose of marstacimab 300 mg followed by 150 mg once weekly (QW) during the 12-month active treatment phase (ATP). The primary endpoint was annualized bleeding rate (ABR) for treated bleeds during marstacimab prophylaxis vs prior OD therapy with bypassing agents. Secondary endpoints included ABR for specific bleed types and patient-reported health-related quality of life (HRQoL). Safety, including the incidence and severity of adverse events (AEs) and immunogenicity, was evaluated in all dosed pts.

Results: Sixty pts (44 adults, 16 adolescents) with HA (n=47) or HB (n=13) with inhibitors entered the OP (OD: n=57; RP: n=3), with 51 transitioning to the ATP (OD: n=48; RP: n=3). Median age was 23 (range 12– 75) years. Most pts were Asian (53.3%) or White (31.7%). At baseline, 71.9% of OD pts and 66.7% of RP pts had ≥1 target joint. Median marstacimab treatment duration was 364 (range, 259–406) days. Marstacimab reduced the mean ABR for treated bleeds from 19.78 (95% CI: 16.12, 24.27) in the OP to 1.39 (95% CI: 0.85, 2.29) in the ATP, demonstrating superiority of marstacimab over OD therapy (estimated ABR ratio, 0.07 [95% CI: 0.042, 0.118]; 2-sided P<0.0001). Results were consistent by hemophilia type, age, and geographic subgroup. For all bleed types, mean ABR was consistently superior with marstacimab vs OD in the OP (joint: 1.10 vs 15.15; spontaneous: 0.87 vs 15.27; target joint: 0.79 vs 6.42; total [treated and untreated]: 4.36 vs 27.29; estimated ABR ratio, ≤0.16; 2-sided P≤0.0001 for all bleed types). Marstacimab also demonstrated superiority vs OD therapy in all patient-reported HRQoL endpoints, except EQ-visual analog scale (VAS). After 6 months in the ATP, pts reported significantly greater improvements in Haem-A-QoL Physical Health domain (estimated median difference vs OP, −25.9 [95% CI: −37.5, −14.2]; 2-sided P<0.0001), Haem-A-QoL total score (estimated median difference, −13.5 [95% CI: −19.8, −7.2]; 2-sided P<0.0001), and EQ-5D-5L index score (estimated median difference, 0.1043 [95% CI: 0.0060, 0.2027]; 2-sided P=0.0377). During the ATP, 38 (74.5%) pts reported AEs, mostly mild or moderate; the most frequent were COVID-19 (21.6%), upper respiratory tract infection (15.7%), fibrin D- dimer increased (9.8%), and headache (9.8%). A total of 5 pts reported serious AEs (SAEs) during the OP. One pt reported an SAE (treatment-related skin rash [grade 3], resolved at follow-up) during the ATP, which led to study discontinuation. Ten pts had their marstacimab dose temporarily discontinued or reduced due to an AE, most commonly COVID-19 (7 pts). Antidrug antibodies (ADAs) were detected in 10/51 (19.6%) pts; titers were low and 9/10 cases resolved by end of study. ADA status had no impact on efficacy or safety endpoints. Neutralizing antibodies were detected in 2 pts; titers were low and antibodies were transient and resolved by end of study. No deaths or thrombotic events were reported.

Conclusion: In pts with HA or HB and inhibitors, subcutaneous marstacimab QW significantly reduced ABR for all bleeding related endpoints vs prior OD therapy and improved HRQoL. Marstacimab demonstrated a favorable safety profile, consistent with the noninhibitor cohort and earlier studies.

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Abstract Number: 537

Mim8 prophylaxis in adults and adolescents with hemophilia A: 52-week efficacy and safety outcomes from the phase 3 FRONTIER2 study

Presenter: Steven Lentz
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Innovations Shaping the Future of Hemophilia Care

Abstract: Introduction: Mim8 (denecimig) is a new-generation, bispecific antibody, activated factor VIII mimetic in clinical development for subcutaneous prophylaxis (PPX) for hemophilia A (HA) with or without inhibitors. The 26-week main phase of the phase 3 FRONTIER2 study (NCT05053139) demonstrated superiority of once- every-week (QW) and once-every-month (QM) Mim8 PPX in reducing annualized bleeding rates (ABRs) for treated bleeds versus on ‑ demand therapy or prior clotting factor concentrate (CFC) PPX. Aim To assess 52-week efficacy and safety of Mim8 PPX in adults and adolescents (aged ≥12 years) with HA with or without inhibitors from the FRONTIER2 extension phase. Methods In the 26-week main phase, participants were randomized to Mim8 QW or QM, or continued on-demand standard-of-care treatment. Participants were grouped by prior treatment regimen: on ‑ demand or CFC PPX. In the 26-week extension, all on-demand participants switched to Mim8 PPX (QW or QM); others continued their assigned regimen. Mim8 was administered using a tiered-dosing approach. Primary endpoint: number of treated bleeds; selected secondary endpoints: number of injection-site reactions (ISRs) and anti-Mim8 antibodies. ABR was estimated using a negative binomial regression model. Safety and immunogenicity were assessed. Ethics approval and informed consent were obtained. Results Of 281 randomized participants, 97% completed the main phase and 96% the extension. Mean (min; max) age at baseline was 32 (13;64) years for the pre-study on-demand group (n=61) and 31 (12;69) years for the pre-study CFC PPX group (n=220). In the pre-study CFC PPX group vs the pre-study on-demand group, there was a higher proportion of patients with severe HA (86% vs 77%) and lower proportion with inhibitors (2% vs 44%). This analysis includes 27 newly reported participants from China. In the main phase, all participants who continued on-demand treatment (n=18) experienced treated bleeds. Estimated mean ABR (95% confidence interval [CI]) was 16.09 (11.21;23.09). All participants entered the extension, during which 88% (Mim8 QW, n=7/8) and 70% (Mim8 QM, n=7/10) had zero treated bleeds. Estimated mean ABRs (95% CI) were 0.67 (0.13;3.61) and 0.79 (0.19;3.33), respectively. For participants previously treated on-demand: of those randomized to Mim8 QW, 86% (n=19/22) had zero treated bleeds in the main phase and 91% (n=19/21) in the extension, with estimated mean ABRs (95% CI) of 0.43 (0.17;1.07) and 0.45 (0.19;1.08), respectively; of those randomized to Mim8 QM, 91% (n=19/21) had zero treated bleeds in the main phase and 86% (n=18/21) in the extension, with estimated mean ABRs (95% CI) of 0.25 (0.08;0.76) and 0.25 (0.08;0.77), respectively. For participants previously on CFC PPX: of those randomized to Mim8 QW, 67% (n=74/111) had zero treated bleeds in the main phase and 70% (n=73/104) in the extension, with estimated mean ABRs (95% CI) of 2.32 (1.35;3.99) and 1.28 (0.78;2.08), respectively; of those randomized to Mim8 QM, 63% (n=69/109) had zero treated bleeds in the main phase and 69% (n=74/108) in the extension, with estimated mean ABRs (95% CI) of 1.79 (1.22;2.63) and 1.54 (0.92;2.59), respectively. Across main and extension phases, median ABR was 0 in all Mim8-treated arms. Adverse events (AEs) were reported in 74% (n=104) of Mim8 QW and 71% (n=100) of Mim8 QM participants. Most AEs were mild: 84% (399/475) of events with Mim8 QW and 82% (321/390) with Mim8 QM. Overall, ISRs occurred in 12% (n=17) of QW and 9% (n=12) of QM participants, accounting for 1.81% and 1.34% of injections, respectively. Overall, anti-Mim8 antibodies were detected in 21 (7%) recipients without clinical evidence of neutralizing activity; all were low (95%) or medium (5%) titer. No thromboembolic events, hypersensitivity reactions, or clinically relevant laboratory abnormalities were observed, including coagulation parameters. Conclusion Over 52 weeks, Mim8 QW and QM PPX provided sustained bleed protection in adults and adolescents with HA, with or without inhibitors, supporting its use as a long-term prophylactic option. During the extension, Mim8 was well tolerated, with infrequent ISRs, few serious AEs, no thromboembolic events or hypersensitivity reactions, and no anti-Mim8 antibodies with clinical impact. Participants completing FRONTIER2 are eligible for the open-label extension, FRONTIER4 (NCT05685238). Mim8 may offer an effective and convenient approach to reducing disease and treatment burden in this population.

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Abstract Number: 539

Clinical outcomes up to 4 years of once-weekly efanesoctocog alfa prophylaxis in previously treated adults, adolescents, and children with severe hemophilia A: Interim analysis of the Phase 3 XTEND-ed long-term extension study

Presenter: Lynn Malec
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Innovations Shaping the Future of Hemophilia Care

Abstract: Introduction: Efanesoctocog alfa is a first-in-class high-sustained factor VIII (FVIII) replacement therapy designed to decouple recombinant FVIII from endogenous von Willebrand factor. In the Phase 3 XTEND-1 (NCT04161495) and XTEND-Kids (NCT04759131) studies, once-weekly efanesoctocog alfa exhibited effective bleed protection, was well tolerated, providing FVIII activity within the normal to near-normal (>40%) range for 4 and 3 days, respectively, at steady state. We present the third interim analysis of the XTEND-ed (NCT04644575) long-term extension study examining the safety and efficacy of efanesoctocog alfa prophylaxis in patients with severe hemophilia A.

Methods: Participants who completed XTEND-1 (≥12 years) and XTEND-Kids (<12 years), could continue once- weekly 50 IU/kg efanesoctocog alfa prophylaxis in the ongoing, multicenter, open-label, long-term XTEND-ed study. The primary endpoint was the incidence of FVIII inhibitor development and secondary endpoints included annualized bleed rates (ABRs), efficacy for bleed treatment, and safety. Data cut: February 21, 2025.

Results: Among adults and adolescents, 146 participants rolled over from XTEND-1 to XTEND-ed baseline with a median (range) age of 37.0 (13.0–74.0) years. The median (range) treatment duration in XTEND-ed was 166.0 (14.1–192.7) weeks, comprising a median (range) of 167.0 (14.0–200.0) exposure days (EDs). The median (range) cumulative treatment duration from XTEND-1 baseline until XTEND-ed data cut was 212.2 (46.3–244.8) weeks, comprising a median (range) of 216.5 (47.0–254.0) EDs. No FVIII inhibitor development was observed. During XTEND-ed, the mean (SD) ABR for Day 1–Month 12 (n=146) was 0.70 (1.31), Months 12–24 (n=141) was 0.62 (1.23) and Months 24–36 (n=132) was 0.45 (1.24), with 96/146 (65.8%), 96/141 (68.1%), and 103/132 (78.0%) participants with zero bleeds, respectively. The mean (95% CI) model-based ABR for the efficacy period was 0.60 (0.47; 0.76) for overall treated bleeds, and 0.20 (0.15; 0.28) and 0.29 (0.22; 0.39) for spontaneous and traumatic bleeds, respectively. Of 252 treated bleeding episodes, 94.0% (237) were resolved with 1 efanesoctocog alfa injection; participants rated the response excellent/good for 87.8% (173/197) bleeds. The median (range) weekly efanesoctocog alfa consumption was 51.6 (39.4–58.9) IU/kg. In total, 126 participants (86.3%) experienced ≥1 treatment- emergent adverse event (TEAE), most commonly COVID-19 (26.7%), arthralgia (17.1%), influenza (15.1%), and nasopharyngitis (15.1%). Two participants had ≥1 treatment-related TEAE (facial paralysis and reduced FVIII levels); no treatment-related serious TEAEs were reported. TEAEs unrelated to study drug led to the death of 2 participants and treatment discontinuation in 3 participants. Among children, 71 participants (<6 years, n=35; 6–<12 years, n=36) rolled over from XTEND-Kids to XTEND-ed, with the median (range) treatment duration of 116.7 (36.3–152.6) weeks, comprising a median (range) of 116.0 (11.0–153.0) EDs. The median (range) cumulative treatment duration from XTEND-Kids baseline until XTEND-ed data cut was 169.8 (88.2–204.7) weeks , with a median (range) of 171.0 (65.0– 207.0) EDs. No FVIII inhibitors were observed. During XTEND-ed, the mean (SD) ABR evaluated for Day 1– Month 12 (n=71) was 0.68 (1.13) and Months 12–24 (n=62) was 0.49 (0.82), with 46/71 (64.8%) and 41/62 (66.1%) participants with zero bleeds, respectively. The mean (95% CI) model-based ABR was 0.64 (0.48; 0.85) for overall treated bleeds, and 0.08 (0.04; 0.15) and 0.44 (0.31; 0.62) for spontaneous and traumatic bleeds, respectively. Of 89 treated bleeding episodes, 91.0% (81) were resolved with 1 efanesoctocog alfa injection; participants rated the response excellent/good for 94.1% (64/68) bleeds. The median (range) weekly efanesoctocog alfa consumption was 54.0 (46.2–73.1) IU/kg. Overall, 60 (84.5%) participants experienced ≥1 TEAE; most commonly pyrexia (18.3%), upper respiratory tract infection (16.9%), arthralgia (15.5%), and cough (15.5%). Two participants had ≥1 treatment-related TEAE (asthma and post infusion pain and headache); no treatment-related serious TEAEs or treatment discontinuations were reported.

Conclusion: Results from up to 4 years of the XTEND-ed study demonstrate that once-weekly efanesoctocog alfa continues to be well tolerated, providing highly effective bleed protection with no inhibitor development in adults, adolescents, and children with severe hemophilia A.

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Abstract Number: 540

From efficacy to experience: 52-week patient-reported outcomes with Mim8 in adolescents and adults with hemophilia A with or without inhibitors (FRONTIER2)

Presenter: Cedric Hermans
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Innovations Shaping the Future of Hemophilia Care

Abstract: Introduction: Mim8 is a new-generation, bispecific antibody, activated factor VIII mimetic in clinical development for subcutaneous prophylaxis (PPX) in hemophilia A (HA) with or without factor VIII inhibitors. The phase 3 FRONTIER2 study (NCT05053139) demonstrated that Mim8 once every week (QW) or once every month (QM) significantly reduced the annualized bleeding rate for treated bleeds compared with continued on- demand treatment or previous clotting factor concentrate (CFC) PPX. Improvements in patient-reported outcomes (PROs) were observed during the 26-week main phase. Objective Objective Assess PROs with Mim8 PPX over 52 weeks.

Methods: FRONTIER2 is an open-label, randomized trial in patients aged ≥12 years with HA, with or without inhibitors. Participants receiving on-demand treatment before the study were randomized to Mim8 PPX QW (Arm 2a) or QM (Arm 2b) for 52 weeks (main + extension), or to continue on-demand treatment (Arm 1) for 26 weeks (main) then switch to Mim8 QW or QM for another 26 weeks (extension). Participants on prior CFC PPX were randomized to Mim8 QW (Arm 3) or QM (Arm 4) for 52 weeks (main + extension). PROs were assessed at baseline, Week 26, and Week 52 using three instruments: the Hemophilia Treatment Experience Measure (Hemo-TEM; range 0–100; lower scores indicate lower burden, ≥8-point reduction defined as clinically meaningful improvement), the physical functioning domain of the Pediatric Quality of Life Inventory (PedsQL; range 0–100; higher scores indicate better functioning), and the Joint Pain Rating Scale (JPRS; range 0–10; lower scores indicate less pain). Additionally, the Patient Global Impression of Change (PGI-C) for pain and physical function and the Hemophilia Patient Preference Questionnaire (HPPQ) were assessed at Week 26 and Week 52. Changes were calculated from the start of Mim8 PPX (Week 0 for Arms 2a/2b/3/4; Week 26 for Arm 1).

Results: Comparable PRO results were observed across QW and QM dosing; therefore, results were pooled by previous treatment (Arm 1, Arms 2a/2b, Arms 3/4). A total of 281 participants were included in the full analysis set. Mean age was 32 (Arm 1), 32 (Arm 2a/2b), and 31 years (Arms 3/4). Most participants were male (99%) and weighed ≥45 kg (94%). This report includes 27 patients from China (Arm 1, n=1; Arms 2a/2b, n=2; Arms 3/4, n=24) absent from the prior 26- week abstract (Mancuso et al. ISTH 2024; LB01.5). At Week 52, mean changes in Hemo-TEM total scores from baseline were –16.0 in Arm 1 (n=13), –12.7 in Arms 2a/2b (n=29), and –9.7 in Arms 3/4 (n=182). Clinically meaningful improvement was achieved by 8/13 (62%), 16/29 (55%), and 84/182 (46%) respectively. At Week 52, a fairly strong or very strong preference for Mim8 over previous treatment was reported by 15/17 (88%) of participants in Arm 1, 39/40 (98%) in Arms 2a/2b, and 175/192 (91%) in Arms 3/4 as assessed by HPPQ. Mean changes in PedsQL physical function scores were +13.0 in Arm 1 (n=13), +17.6 in Arms 2a/2b (n=29), and +4.0 in Arms 3/4 (n=167). Improvements in PGI-C physical function were reported by 17/17 (100%) of participants in Arm 1, 36/40 (90%) in Arms 2a/2b, and 138/192 (72%) in Arms 3/4. Mean changes in JPRS joint pain scores were –1.8 in Arm 1 (n=13), –1.5 in Arms 2a/2b (n=29), and –0.4 in Arms 3/4 (n=184). Improvements in PGI-C pain intensity were reported by 15/17 (88%) of participants in Arm 1, 38/40 (95%) in Arms 2a/2b, and 115/192 (60%) in Arms 3/4. Discussion/Conclusion Discussion/Conclusion Mim8 PPX was associated with improvements across all assessed PROs over 52 weeks, including reduced treatment burden, improved physical function, decreased joint pain, and strong treatment preference. These findings are consistent with Week 26 results, indicating sustained patient-perceived benefits with continued Mim8 use. PROs were comparable between QW and QM dosing, supporting the flexibility of Mim8 tiered dosing. In Arms 3/4, the smaller magnitude of change may reflect a ceiling effect among participants on PPX at baseline. Patient preference data were highly favorable, including among participants already receiving PPX. These results support the long-term benefit of Mim8 in HA treatment, extending beyond bleed control. Consistent PRO improvements and strong patient preference highlight the potential for Mim8 to enhance the treatment experience and quality of life.

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Abstract Number: 1285

Evolution of joint health and physical activity in people with hemophilia A without factor VIII inhibitors switching to emicizumab prophylaxis: A second interim analysis of the BEYOND ABR study

Presenter: Rebecca Kruse-Jarres
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster I

Abstract: Background: Advances in hemophilia A (HA) treatment have led to lower bleeding rates (Srivastava et al. Haemophilia 2020), shifting focus toward functional endpoints such as joint health. Despite treatment with factor (F)VIII prophylaxis, joint health has been observed to deteriorate over time (Arvanitakis et al. Haemophilia 2024). BEYOND ABR (NCT05181618) aims to evaluate joint health and physical activity outcomes in people with HA (PwHA) switching from FVIII prophylaxis to emicizumab. This second interim analysis reports data analyzed after 12 months of treatment with emicizumab.

Methods: BEYOND ABR is a Phase IV, multicenter, open-label study in PwHA aged 13–69 years with moderate/severe HA without FVIII inhibitors. Joint health for ankles, knees, and elbows is evaluated in participants’ joints without pre-study surgery/procedures using the Hemophilia Joint Health Score (HJHS) 2.1. Numerical changes in problem joint counts (defined as per Chowdary et al. Haemophilia 2023) from baseline are captured by both participants and investigators. Target joint resolution is assessed in participants with ≥52 weeks of follow-up. Physical activity is measured using the International Physical Activity Questionnaire (IPAQ). The number of participants with zero treated bleeds is determined using data from a Bleeds and Medication Questionnaire. The Emicizumab Preference Survey was carried out following 6 months of emicizumab treatment.

Results: Overall, 136 PwHA were enrolled, all male with varying levels of joint status/impairment. At the single joint level, mean (standard deviation [SD]) HJHS total score was 2.3 (3.5) at baseline and improved by -0.3 (1.7) at Month 6 and -0.5 (1.9) at Month 12. At Month 6, 93/726 (12.8%) joints showed an improvement of ≥2 points, increasing to 119/696 (17.1%) at Month 12; 41/726 (5.6%) joints and 42/696 (6.0%) joints showed a worsening of ≥2 points at Month 6 and Month 12, respectively. At the participant level, the mean (SD) HJHS sum of joints (excluding Global Gait Score; maximum score: 120, calculated as 6 joints x 10 points each) was 10.1 (13.2) at baseline and improved by -2.0 (6.4) at Month 6 and -2.8 (7.9) at Month 12. In total, 23/88 (26.1%) participants reported an improvement of ≥4 points in HJHS sum of joints from baseline to Month 12 and 5/88 (5.7%) reported worsening of ≥4 points at Month 12. At Month 12, the number of participant-reported problem joints had decreased from baseline in 35/117 (29.9%) participants, including resolution of ≥2 problem joints in 16 (13.7%) participants. Conversely, 16/117 (13.7%) participants reported an increase in the number of problem joints from baseline, including an increase of ≥2 problem joints in 8 participants (6.8%). The number of investigator-reported problem joints reduced in 33/131 (25.2%) participants at Month 12; 13 (9.9%) participants had ≥2 resolved problem joints. Overall, 19/131 (14.5%) participants had an increase in investigator-reported problem joints, including 14 (10.7%) with an increase of ≥2 problem joints. In participants who remained in the study for at least one year, 27/27 (100%) baseline target joints in 15 participants had resolved at Month 12. In participants with valid IPAQ data at baseline and/or 3 months and/or 12 months after switching to emicizumab, the proportion of participants in the low physical activity category decreased from 30.8% (32/104) at baseline to 22.3% (23/103) at Month 3, and remained stable at Month 12 (23.4% [22/94]). The proportion of participants in the high physical activity category increased from 44.2% (46/104) to 52.4% (54/103) at Month 3, and was 50.0% (47/94) at Month 12. Zero treated bleeds were reported by 110/136 (80.9%) participants between Weeks 1 and 24, and 105/134 (78.4%) between Weeks 25 and 48. At Month 6, 125/130 (96.2%) participants preferred emicizumab to their previous FVIII prophylaxis, while only 1/130 (0.8%) preferred their previous treatment; 4/130 (3.1%) had no preference.

Conclusions: In the first 12 months after switching from FVIII prophylaxis to emicizumab, participants had low bleeding rates associated with numerical improvements in joint health, as measured with HJHS, plus a reduction in the number of problem and target joints. Overall, physical activity levels assessed with IPAQ were stable or showed a shift towards higher activity levels, and most participants preferred emicizumab compared with their previous treatment. Follow-up will continue for 3 years.

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Abstract Number: 1286

Real-world experience of efanesoctocog alfa in Hemophilia A patients in the US: A retrospective analysis

Presenter: Sibgha Zaheer
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster I

Abstract: Introduction: Efanesoctocog alfa is a first-in-class, high-sustained factor VIII (FVIII) replacement therapy designed to overcome the half-life limitations imposed by von Willebrand factor (VWF). In pivotal Phase 3 trials, XTEND-1 (NCT04161495) and XTEND-Kids (NCT04759131), once-weekly efanesoctocog alfa (50 IU/kg) was well tolerated and provided highly effective bleed protection in adults and children with severe hemophilia A. Real-world data on efanesoctocog alfa in routine U.S. clinical practice remain limited. The aim of this retrospective chart review was to investigate treatment patterns and outcomes associated with efanesoctocog alfa used for prophylaxis, on-demand, or perioperative management of bleeds in adults and children with hemophilia A who switched from previous standard-of-care therapies in the United States.

Methods: This was a multicenter, retrospective, observational chart review conducted across four clinical sites in the United States. The study included adult and pediatric patients with a diagnosis of hemophilia A who switched from a prior therapy (standard half-life FVIII [SHL]; extended half-life FVIII [EHL] or non-factor therapy [emicizumab]) to efanesoctocog alfa in routine clinical practice. Data was extracted from medical records, and patients were stratified into three cohorts based on treatment approach: prophylaxis, on- demand, and perioperative management. Patient identification period was February 23, 2023, to December 1, 2024, for the prophylaxis and on-demand cohorts, and to October 31, 2024, for the perioperative cohort.

Results: The retrospective chart review included 41 hemophilia A patients, with a median (interquartile range [IQR]) age of 21 (13–32) years and most patients were male (39 [95.1%]). Of these patients, 31 (75.6%) had severe hemophilia A, and 5 (12.2%) each had moderate or mild forms. Patients were stratified into prophylaxis (n=34), on-demand (n=5), and perioperative (n=3) cohorts; one patient enrolled in the prophylaxis cohort was also concurrently included in the perioperative cohort. The overall median (IQR) duration of efanesoctocog alfa treatment was 14.0 (10.7–15.1) months, with a median (IQR) dose per injection of 50 (49.0–50.0) IU/kg. Most patients (35 [89.7%]) received efanesoctocog alfa as a once-weekly injection. Among the prophylaxis and on-demand cohorts, 12 patients previously on SHL and 12 on EHL FVIII products switched to efanesoctocog alfa, primarily due to its longer half-life, which resulted in reduced injection frequency and better protection from joint bleeds. In the prophylaxis cohort, mean (SD) annualized bleeding rates (ABRs) decreased from 1.5 (1.57) to 1.2 (1.95) in the SHL group and from 2.2 (2.44) to 0.6 (1.07) in the EHL group following the switch to efanesoctocog alfa. Additionally, 13 patients who switched from emicizumab to efanesoctocog alfa reported improved bleed protection during physical activity and better control of joint bleeds as the main reasons for the switch. After switching from emicizumab to efanesoctocog alfa prophylaxis, mean (SD) ABRs declined from 1.6 (1.5) to 0.7 (0.7). In the perioperative cohort, four surgical procedures were documented in three patients: osteotomy of the right thumb, tooth extraction, knee replacement, and vasectomy. No unexpected bleeding events occurred, and no patients required blood transfusions. The primary reason for selecting efanesoctocog alfa in the perioperative setting was improved bleed protection with fewer injections. Due to the retrospective nature of this chart review, adverse event data were not collected.

Conclusion: This retrospective chart review provides real-world evidence that efanesoctocog alfa is a safe and highly effective treatment for hemophilia A across all severities in the pediatric and adult population. Patients experienced improved bleed protection, especially joint bleeds, and required fewer injections compared to SHL/EHL. Comparisons before and after the switch to efanesoctocog alfa showed a meaningful reduction in ABRs, highlighting that clinical outcomes in real world use were consistent with those observed in the clinical trial program.

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Abstract Number: 1287

Long-term outcomes with emicizumab prophylaxis in patients with hemophilia a in China

Presenter: Yuan Xu
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster I

Abstract: Introduction: Emicizumab, a bispecific monoclonal antibody that bridges activated factor IX and factor X, has emerged as an effective prophylactic treatment for patients with hemophilia A ( PwHAs). However, real-world responses are heterogeneous, long-term data remain limited, and the determinants of long- term efficacy are unclear.

Methods: Data from 132 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who received emicizumab prophylaxis for more than one year from 25 centers in China were pooled to establish a long-term efficacy and safety profile. Annualized bleed rate (ABR) and Annualized joint bleed rate (AJBR) were estimated using the negative binomial regression model. Machine learning models—including the Feature Tokenizer Transformer, random forest, XGBoost, LightGBM, ResNet, and CatBoost—were applied to predict post-emicizumab ABR.

Results: A total of 132 patients were enrolled in our study. All patients were followed up for a median of 26.0 months (interquartile range [IQR], 16.0–40.0). Across a median efficacy period of 25.5 months (IQR, 16.0–40.0; data cutoff: May 25, 2025), the model-based ABR (for all bleeds) and treated ABR were 0.81 (95% confidence interval [CI], 0.62–1.07) and 0.30 (0.21-0.42), respectively. ABR declined compared to baseline and then stabilized at <1 in analyses based on 12-month treatment intervals. During months 1 to 12 (n=132), 62.9% of participants had 0 bleeds, 82.6% had no treated bleeds, 90.9% reported no joint bleeds, and 94.7% reported no treated joint bleeds. To determine the factors associated with long-term efficacy, we applied machine learning models. Among them, the Feature Tokenizer Transformer model yielded the best performance (AUC=0.905±0.012). Feature importance was ranked by mean absolute SHapley Additive exPlanations (SHAP) values. The top three predictors of post-emicizumab ABR > 1 were: historical inhibitor status, whether standard loading dose (3 mg/kg for 4 weeks) was administered, and baseline ABR. Injection site reactions were reported in 10 out of 132 patients (7.6%). No deaths, thromboembolic events, or thrombotic microangiopathies were reported during the study period.

Conclusions: In this multicenter real-world study, we indicated that emicizumab prophylaxis maintained low bleeding rates in PwHAs of all ages and remains well tolerated. Historical inhibitor status, whether standard loading dose was administered, and baseline ABR were the most informative variables for predicting post-emicizumab ABR > 1.

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Abstract Number: 1288

Concizumab efficacy in patients with Hemophilia A/B without inhibitors from the Phase 3 explorer8 study: A post-hoc sensitivity analysis for the intra-patient comparison of concizumab with previous prophylaxis

Presenter: Anthony Chan
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster I

Abstract: Background: Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody indicated for hemophilia A/B with/without inhibitors, approved in US, Europe and other countries for once-daily, subcutaneous prophylaxis in hemophilia A/B with inhibitors. During the prospective, multicenter, open- label, phase 3 explorer8 study (NCT04082429), superiority was confirmed for concizumab compared with on-demand treatment in patients with hemophilia A/B without inhibitors (HA/HB). Furthermore, a subset of patients was included in an intra-patient comparison of concizumab to previous prophylaxis. The estimated annualized bleeding rate (ABR) ratio between concizumab and previous prophylaxis was 1.39 (95% confidence interval [CI]: 0.73; 2.63) for HA and 1.75 (0.81; 3.78) for HB. The upper limit of the 95% CI was above 2 (pre-defined non-inferiority margin), meaning that non-inferiority of concizumab to previous prophylaxis was not confirmed. The median ABRs for the intra-patient analysis group were numerically similar for HA (concizumab: 2.3 [interquartile range, IQR: 0.0–4.7]; previous prophylaxis: 2.2 [0.8–6.2]) and decreased in HB with concizumab (concizumab: 1.4 [0.0–8.1]; previous prophylaxis: 2.1 [0.9–4.2]). A review of the data showed that extreme ABRs in three patients (HA n=2; HB n=1) influenced the mean ABR. However, no common risk factors or characteristics were identified and neutralizing anti- concizumab antibodies were not reported. Aim The impact of the extreme ABRs on the intra-patient comparison of concizumab to previous prophylaxis was investigated with a post-hoc sensitivity analysis. Methods Male patients (≥12 years) were assigned to one of four arms in explorer8. A subset of patients receiving concizumab in a non-randomized arm were included in the intra-patient analysis. Patients received a 1.0 mg/kg concizumab loading dose (Day 1), followed by 0.20 mg/kg daily starting from Day 2+, with potential dose adjustment (5–8 weeks) to 0.15 or 0.25 mg/kg based on concizumab plasma concentration measured after week 4. Informed consent/ethics committee approval were obtained. Sensitivity analyses using imputation were performed to investigate the impact of the extreme ABRs at the 32-week cut-off (defined as when patients receiving concizumab prophylaxis had completed the visit after 32 weeks, or permanently discontinued treatment). Here, treated spontaneous and traumatic bleeding episodes for the three patients with extreme ABRs were replaced by imputed values computed from the remaining patients with HA/HB. The sensitivity analyses were conducted using parametric (negative binomial regression models) and non-parametric (Wilcoxon signed-rank test) approaches. Results The sensitivity analyses included all patients in the intra-patient analysis set (HA n=29; HB n=22). Among these patients, 38 (74.5%) were White, 12 (23.5%) were Asian, and 1 (2.0%) was Black/African American. For HA, the post-hoc sensitivity analysis using imputed values for the three patients with extreme ABRs showed that the estimated mean ABR (95% CI) for concizumab decreased from 5.1 (2.71; 9.65) to 2.8 (1.76;4.57) upon analysis after imputation using the negative binomial regression. The ABR ratio (95% CI) of concizumab vs previous prophylaxis reduced from 1.39 (0.73; 2.63) to 0.75 (0.40; 1.42). For HB, the estimated mean ABR for concizumab decreased from 5.4 (2.27; 12.91) to 3.1 (1.80; 5.37) and the ABR ratio (95% CI) of concizumab vs previous prophylaxis reduced from 1.75 (0.81; 3.78) to 1.00 (0.58; 1.73). For both HA/HB, the upper limits of the 95% CIs were below the non-inferiority margin of 2.0. Wilcoxon signed-rank tests showed that ‘no difference’ could not be rejected between median ABRs for concizumab and previous prophylaxis with imputed data for both HA/HB. Conclusion Post-hoc sensitivity analyses using imputed data for the three patients in the explorer8 intra-patient comparison subset who had extreme ABRs showed that the upper limit of the 95% CI of the ABR ratios decreased below the non-inferiority margin of 2.0 when comparing concizumab to previous prophylaxis. This indicates that for the majority of patients, ABRs during concizumab demonstrated non-inferiority when compared to prior prophylaxis regimens. As with any therapy, there may be some variability in individual responses to treatment. Overall, the phase 3 explorer8 study showed that once-daily, subcutaneous concizumab prophylaxis was efficacious and well-tolerated.

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Abstract Number: 1290

Patient characteristics, treatment patterns, and bleeding in people with Hemophilia A without inhibitors initiating efanesoctocog alfa in the US: An administrative claims analysis

Presenter: Jennifer Dumont
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster I

Abstract: Background: Hemophilia A is a rare genetic disorder causing spontaneous bleeding and joint damage. Efanesoctocog alfa (Efa) is a first-in-class high-sustained recombinant factor VIII (FVIII) replacement therapy approved in the United States (US) in February 2023 for prophylaxis, perioperative management, and on-demand treatment of bleeds in adults and children with hemophilia A. However, real-world data on the use of Efa are limited. Aim: Aim: To describe patient characteristics, treatment patterns, and annualized bleed rates (ABRs) among people with hemophilia (PwHA) without inhibitors receiving prophylactic Efa in routine clinical practice.

Methods: This retrospective observational cohort study used US administrative closed claims to identify PwHA without inhibitors initiating prophylactic Efa. Index date was the first claim for Efa between February 22, 2023, and January 01, 2024, that met the criteria for prophylactic use. Patients were required to have ≥180 days of continuous health plan enrollment prior and post index date. A 180-day pre-index washout period was applied to exclude patients with prior Efa use who did not meet the criteria for prophylactic use of Efa. Demographics were assessed at index; clinical comorbidities, prior hemophilia therapies, and bleeds were evaluated during the 180-day pre-index period. Treatment patterns were assessed from index through the end of follow-up and ABRs were assessed from 1 day after index through the end of the follow-up period, death, disenrollment, or end of Efa therapy, whichever occurred first. Treatment patterns were described for all patients, and bleed rates were assessed for those with continuous Efa use for ≥180 days post-index.

Results: Eighty PwHA initiated prophylactic Efa. The mean (SD) age of the study population (N=80) was 26.6 (14.7) years, with 43.8% of patients aged 18–39 years. Patients were predominantly male (96.3%), White (46.3%), and had Medicaid coverage (61.3%). Geographical distribution of the patients was comparable across the South (31.3%), Midwest (28.8%), and West (28.8%) regions of the US. Demographics were similar across 47 patients who had ≥180 days of continuous Efa therapy post index. The top comorbidities were pain (33.8%), arthritis (30.0%), obesity (11.3%), anxiety (11.3%), and hypertension (8.8%). The mean (SD) Charlson Comorbidity Index score among all patients was 0.49 (1.28). Within the 180-day pre-index period, 81.3% of patients received any prophylaxis (FVIII or emicizumab), 5% used on-demand FVIII therapy only, and 13.7% patients were not treated with FVIII or emicizumab. The most commonly used products as on-demand or prophylactic prior to index were efmoroctocog alfa (30.0%), octocog alfa (17.5%), emicizumab (15.0%), and rurioctocog alfa pegol (11.3%). The most common last prophylactic treatment product classes used prior to index were extended half-life (EHL) (46.3%), followed by standard half-life (SHL) (18.8%), and emicizumab (10%). Among the 80 patients followed up for an average of 255 days, the average proportion of days covered by Efa therapy was 80%. On average, each patient had 10 (4.7) claims for Efa, with an average duration of treatment of 205 (83) days. Fifteen patients discontinued Efa, of whom 9 ended treatment, 3 re-initiated Efa (defined as a new claim for Efa after a gap of >60 days), and 3 switched to another hemophilia A therapy. In the 180-day baseline period prior to index, 6 out of 47 patients receiving Efa continuously for ≥180 days post-index had a total of 8 bleeds (7 non-traumatic and 1 traumatic). The mean (SD) baseline ABR among these 47 patients was 0.35 (1.06) for all bleeds including traumatic bleeds, 0.30 (1.03) for non-traumatic bleeds, and 0.04 (0.30) for traumatic bleeds. Two of 8 bleed events were joint bleeds, with a mean (SD) ABR of 0.09 (0.41). Over an average (SD) follow-up period of 272 (64) days, 3 out of 47 (6.4%) patients had a total of 3 non-traumatic bleeds, with a mean (SD) ABR of 0.09 (0.35). Of these, 2 bleeds were joint-related (mean [SD] ABR=0.06 [0.29]), and 1 was a gastrointestinal bleed (mean [SD] ABR=0.03 [0.21]).

Conclusions: This retrospective claims analysis showed that bleed rates among PwHA receiving Efa were low, consistent with outcomes observed in clinical trials. Most patients transitioning to Efa were previously treated with EHLs. Majority of patients continued treatment during the follow-up period, with relatively low switching or discontinuation of treatment.

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Abstract Number: 1292

A low-cost Clinical Prediction model for identifying female hemophilia carriers and women and girls with hemophilia (WGH) in central China

Presenter: Li Zhou
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster I

Abstract: Background: Background: While hemophilia is traditionally considered an X-linked recessive disorder mainly affecting males, female hemophilia carriers (FHCs), are increasingly recognized to experience abnormal bleeding, especially when factor VIII (FVIII) or factor IX (FIX) levels below 50 IU/dL. These individuals are now classified as women and girls with hemophilia (WGH) by the ISTH/SSC. However, in China, clinical recognition and testing for FHCs and WGH remain limited due to the high cost and inaccessibility of genetic testing. There is an unmet need for affordable, accessible screening tools to identify high-risk women, guide further diagnosis, and enable timely prevention and management in resource-limited regions. Objectives Objectives To develop and validate a low-cost prediction model incorporating ISTH bleeding assessment tool (ISTH- BAT) scores, FVIII:C or FIX:C levels, and age, aiming to identify FHCs and classify WGH among females from families affected by hemophilia A and B.

Methods: We prospectively enrolled 318 females aged 5–80 years from families with hemophilia A or B in central China, primarily from Jiangxi Province. and categorized them into three groups: Group A: confirmed carriers (n=129; 100 with hemophilia A, 29 with hemophilia B) Group B: femaleswith a family history of hemophilia but unknown carrier status (n=104) Group C: healthy non-carrier controls (n=85) All participants completed the ISTH-BAT, and coagulation factor VIII (FVIII:C) or IX (FIX:C) activity was measured using standard one-stage clotting assays. Age, family history, and other clinical data were collected via structured questionnaires. A multivariable logistic regression model was constructed using 80% of the dataset for training and 20% for testing, with 5-fold cross-validation. Predictor variables included clotting factor level (FVIII:C or FIX:C), total BAT score, and age. Model discrimination was assessed using area under the ROC curve (AUC), and performance metrics included sensitivity, specificity, and overall accuracy. Calibration was evaluated using calibration plots and Hosmer–Lemeshow tests.

Results: The final model achieved an AUC of 0.94 (95% CI: 0.89–0.98) in the test dataset, with an overall accuracy of 94.7%, sensitivity of 94.4%, and specificity of 100%. Factor activity was the strongest independent predictor (OR per 10 IU/dL = 0.32; 95% CI: 0.18–0.55; p<0.001), followed by BAT score (OR per point = 1.41; 95% CI: 1.18–1.68; p=0.002) and younger age (OR per 10-year increase = 0.77; 95% CI: 0.61–0.96; p=0.021). The tool requires only basic clinical data and inexpensive lab tests, offering a practical screening method before genetic testing. Conclusions Conclusions We developed a low-cost prediction model combining BAT scores, age and coagulation factor levels for identifying FHCs and WGH in central China. The tool helps identify at-risk women, supports shared decision-making, facilitates early identification and encourages appropriate genetic testing, particularly in under-resourced areas. To our knowledge, this represents the first prediction model specifically tailored for female hemophilia screening in a Chinese population. This study offers a scalable framework for broader clinical implementation and may support the development of national strategies for carrier screening and counseling. Future work will focus on multi-centre validation and development of a digital tool for clinical implementation. Disclosures Disclosures Topics: Topics: Hemophilia, Female Carriers, BAT Score, Coagulation Factors, Screening Tool, Bleeding Risk, Prediction Model Author notes Author notes *Asterisk with author names denotes non-ASH members.

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Abstract Number: 1295

In vitro comparison of eptacog beta and eptacog alfa with antithrombin lowering (simulated fitusiran) using thrombin generation assay

Presenter: Sibgha Zaheer
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster I

Abstract: Introduction: Eptacog beta, an FDA approved bypassing agent for the treatment of bleeds in patients with hemophilia A and B with inhibitors differs from eptacog alfa in its glycosylation profiles and platelet binding properties. Fitusiran, a non-factor therapy that suppresses antithrombin (AT) production was recently approved for prophylaxis in hemophilia A and B, with or without inhibitors. For persons with hemophilia and inhibitors, breakthrough bleeds on fitusiran prophylaxis would require treatment with a bypassing agent. In fitusiran clinic trials, eptacog alfa was used at reduced dosing (45µg/kg) for bleed management. To date, the combined effect of eptacog beta and fitusiran on in vitro thrombin generation (TG) has not been described. Our study aims to characterize the impact of eptacog beta (eB) and AT lowering (to mimic fitusiran) on TG parameters and compare to that of eptacog alfa (eA).

Methods: Thrombin generation assay with a tissue factor trigger was used to evaluate peak (nM) and endogenous thrombin potential (ETP (nM*min)) in pooled FVIII deficient plasma spiked with concentrations of eA ranging from 0-2 µg/mL (0-120 µg/kg), or eB ranging from 0-3.22 µg/mL (0-300 µg/kg). AT levels (15 - 92%) were achieved via an anti-human AT antibody. AT activity was measured by a chromogenic assay. Pooled normal plasma (PNP) was used as control.

Results: TG parameters of PNP were peak (71.2-154.8) and ETP (879.08 -1472.43). TG parameters that exceeded the upper limit of the assay were noted at the following combinations: 15% AT with > 0.17µg/mL (25 µg/kg) eB; > 0.25µg/mL (15 µg/kg) of eA 20% AT with > 0.45 µg/mL (50 µg/kg) eB; > 0.25 µg/mL (15 µg/kg) eA 25% AT with > 1.28 µg/mL (125 µg/kg) eB; > 0.75 µg/mL (45 µg/kg) eA 30% AT with > 2.44 µg/mL (225 µg/kg) eB; > 1.0 µg/mL (60 µg/kg) eA 35% AT with > 2 µg/mL (120 µg/kg) eA High TG parameters were noted at the following combinations: 20% AT with eB: 0.17µg/mL (25 µg/kg) [peak 174, ETP 3383] and 0.28µg/mL (35 µg/kg) [peak 181, ETP 3567] 25% AT with eB: 0.17µg/mL (25 µg/kg) [peak 164, ETP 3331]; 0.28 µg/mL (35µg/kg) [peak 174, ETP 3461]; 0.45 µg/mL (50 µg/kg) [peak of 177.9, ETP of 3545]; 0.57 µg/mL (75 µg/kg) [peak 177.37, ETP of 3705]; 25% AT with eA: 0.25 µg/mL (15 µg/kg) [peak 176.85, ETP 3357]; 0.5 µg/mL (30 µg/kg) [peak 177.27, ETP 3961]; 30% AT with eB: 0.28 µg/mL (35µg/kg) [peak 165, ETP 3280]; 0.45 µg/mL (50 µg/kg) [peak 166.14, ETP 3417]; 0.57 µg/mL (75 µg/kg) [peak 175.24, ETP 3616]; 1.28 µg/mL (125 µg/kg) [peak 179, ETP 3651]; 1.56 µg/mL (150 µg/kg) [peak 181, of 3715] 30% with eA: 0.25 µg/mL (15 µg/kg) [peak 165, ETP 3265]; 0.5µg/mL (30 µg/kg) [peak 178.34, ETP 3795]; 0.75 µg/mL (45 µg/kg) [peak 179, ETP 4010] 35 % AT with eB: 0.45 µg/mL (50 µg/kg) [peak 158, ETP 3286]; 0.57 µg/mL (75 µg/kg) [peak 159, ETP 3523]; 1.28 µg/mL (125 µg/kg) [peak 168, ETP of 3625]; 1.56 µg/mL (150 µg/kg) [peak 167, ETP 3672]; 2.44 µg/mL (225 µg/kg) [peak 171, ETP 3788]; 3.22 µg/mL (300 µg/kg) [peak 176, ETP 3908] 35% with eA: 0.25 µg/mL (15 µg/kg) [peak 155, ETP of 3173]; 0.5µg/mL (30 µg/kg) [peak 166, ETP 3704]; 0.75 µg/mL (45 µg/kg) [peak 175, ETP 3823]; 1.0 µg/mL (60 µg/kg) [peak 177, ETP 4077]; 1.5 µg/mL (90 µg/kg) [peak 181, ETP 4249] Normal TG were seen at the following combinations: 30% AT with: 0.17 µg/mL (25 µg/kg) eB [peak 153, ETP 3184] 35 % AT with: 0.17 µg/mL (25 µg/kg) eB [peak 146, ETP 3045]; 0.28 µg/mL (35µg/kg) eB [peak 149, ETP 3120] AT levels > 40 % with all doses of eA and eB resulted in normal or slightly above normal TG parameters.

Conclusions: These results demonstrate that in vitro both eptacog beta and eptacog alfa similarly increase TG when AT levels are reduced to fitusiran target ranges. Eptacog alfa doses of 45µg/kg, used to treat bleeds in patients on fitusiran, had similar TG parameters to the 75µg/kg and 125µg/kg doses of eptacog beta. This data provides in vitro proof of concept supporting the use of eptacog beta for the treatment of breakthrough bleeds of patients on fitusiran prophylaxis. The clinical implications of the amplified in vitro TG remain to be seen, and human in vivo studies are needed to support patient bleed management guidelines.

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Abstract Number: 1297

First report of high-titer FVIII inhibitor development following AAV-mediated gene therapy in Hemophilia A

Presenter: Davide Matino
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster I

Abstract: Over the past decade, adeno-associated virus (AAV) vector–based gene therapy (GT) has emerged as a major advance in hemophilia A (HA). To date, over 280 patients have received HA gene therapy, and no confirmed cases of FVIII inhibitor development following GT have been reported. We report the case of a 47 yo male patient (pt) with severe HA (intron 22 inversion) who developed FVIII inhibitors following a single 3x10 13 vg/kg dose of giroctocogene fitelparvovec in the ongoing phase 3 AFFINE study. Prior to enrollment, he was on damoctocog alfa pegol prophylaxis (>150 ED). Medical history included HCV and HIV infection, as well as immune thrombocytopenia (ITP) from 1987 to 2007 that was treated with IV gammaglobulin, RH immune globulin and prednisolone, splenectomy in 1995 and IVIG until 2000, with stable platelet counts since then. The pt has no personal or family history of inhibitors. HLA typing revealed no haplotypes associated with increased inhibitor risk. Following gene therapy, FVIII activity peaked above the normal range within the first 3 months (4.42 IU/mL by chromogenic substrate assay). The pt experienced recurrent episodes of mild transaminitis, triggering 3 tapering courses of corticosteroids (CS) of several months in the first year, initiated on Day (D) 25 post infusion. On these occasions when CS were tapered and discontinued a decline in FVIII:C was observed, partially reversed with the reIntroduction: of CS. After the 3rd CS course discontinuation (D335), FVIII:C continued to decrease (1.1 to 0.2 IU/mL) leading to the initiation of mycophenolate mofetil (MMF) and CS were reintroduced. During the planned W52 visit (D369), a low-titer FVIII inhibitor of 2.7 BU was detected (FVIII:C: 0.016 IU/mL). Subsequent retrospective testing of stored samples allowed the detection of a first positive measurement at D334 (0.6 BU). The pt then developed a high-titer inhibitor of 5.3 BU on D453 (FVIII:C: 0.062 IU/mL). Although no bleeding episodes were observed since screening, the pt reported new, recurrent joint aches suggestive of possible microbleeds, not confirmed by imaging. In response, MMF was increased to 1 g twice daily on D455 to support inhibitor eradication, and emicizumab prophylaxis was initiated on D460 (225 mg QW). Inhibitor titers continued to rise, peaking at 647.9 BU on D592, then declining to 416.9BU on D690. Throughout this period, FVIII:C and FVIII antigen levels were below limit of detection, and liver enzymes remained within normal limits. FVIII:C inhibition kinetic was evaluated using a Nijmegen-modified Bethesda assay. Serial dilutions of plasma were incubated with pooled normal plasma and assayed for residual FVIII activity using a bovine chromogenic substrate assay. The data were plotted and analyzed using Hill slope fitting to characterize the steepness and pattern of FVIII recovery, exhibiting a prolonged low-residual plateau, followed by a gradual increase in FVIII activity with increasing dilution. This was followed by a threshold point beyond which an accelerated recovery phase emerged, modestly approaching the activity levels observed in inhibitor-free control plasma. These results are consistent with a Type 2 inhibitor, exhibiting a characteristic two-phase inhibition profile. Total anti-FVIII antibodies were measured using a modified FVIII IgG-specific enzyme immunoassay (EIA). A positive cutoff was established using the mean and 2 standard deviations above a healthy control population (n=24) for anti-FVIII total IgG, IgG1, IgG2, IgG3, and IgG4. A positive total IgG titer was first detected on D219 (~4 months prior to the first positive inhibitor result), however a first IgG3 titer > positive cutoff was detected on D23. IgG1 and IgG3 were the predominant subclasses. To our knowledge this is the first reported case of high-titer FVIII inhibitor development following gene therapy in a patient with hemophilia A. Although this appears to be a rare event, potentially comparable to or even less frequent than inhibitor formation in previously treated patients receiving FVIII prophylaxis, these results suggest that the possibility of inhibitor development should be included in pre- treatment counseling for patients considering gene therapy.

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Abstract Number: 1298

High treatment compliance and tolerability with fitusiran antithrombin-based dose regimen in people with hemophilia A or B, with or without inhibitors: ATLAS-OLE study

Presenter: Mindy Simpson
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster I

Abstract: Background: Background: Hemophilia A (HB) and B (HB) are rare, inherited bleeding disorders characterized by a deficiency of clotting factors VIII or IX, respectively, leading to recurrent spontaneous and trauma-related bleeding. While prophylactic treatment with factor concentrates or mimetics significantly reduces bleeding and improves outcomes, these therapies often require frequent administration or can cause injection-site discomfort, making patient compliance challenging. Suboptimal compliance increases risks of bleeding, joint damage, hospitalization, and healthcare costs. Fitusiran is an antithrombin (AT)-lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia A/B (PwHA/B), with or without inhibitors. In the Phase 3 ATLAS-OLE study (NCT03754790), designed to investigate the safety and efficacy of the fitusiran AT-based dose regimen (AT-DR) targeting AT levels between 15–35%, meaningful bleed protection was maintained in PwH. Here we report the participant experience with fitusiran treatment in relation to compliance, tolerability and common adverse events (AEs) on the AT-DR.

Methods: In ATLAS-OLE, males aged ≥12 years with severe hemophilia A or B, with or without inhibitors received the fitusiran AT-DR (starting dose 50 mg once every 2 months [Q2M]). The primary endpoint was safety and tolerability. Safety endpoints included incidence, severity, seriousness, and relatedness of AEs. Analyses of compliance, tolerability, and common treatment-emergent adverse events (TEAEs) for all participants who received ≥1 dose of fitusiran on the AT-DR were summarized descriptively. Treatment compliance was calculated as the total dose received as a percentage of the total dose expected to be received under the AT-DR. Mean compliance was calculated from the total number of participants who received AT-DR during the study.

Results: A total of 213 participants received the fitusiran AT-DR (n=56 HA with inhibitor; n=106 HA without inhibitor; n=19 HB with inhibitor; n=32 HB without inhibitor) during the ATLAS-OLE trial with 94% requiring 0–1 dose adjustment to achieve target AT levels. Overall, 166 (78%) participants receiving AT-DR were on Q2M regimens. The overall mean compliance with fitusiran AT-DR was 96.0%, with comparable results between participants with HA (95.7%) and HB (96.6%), and between participants without inhibitors (96.6%) and with inhibitors (94.7%). A total of 158 (74.2%) participants demonstrated 100% compliance, and the proportions were also comparable between participants with HA (75.3%) and HB (70.6%), and between the non-inhibitor (73.9%) and inhibitor participants (74.7%). Of 39 (18.3%) participants that discontinued during the AT-DR, 30 (14.1%) were due to >1 AT measurement <15%, 5 (2.3%) due to adverse events (hepatocellular carcinoma, transaminase elevation, cerebral infarction, pruritus, and postoperative deep-vein thrombosis), 3 (1.4%) due to withdrawal of consent, and 1 (0.5%) due to ‘other’. With the AT-DR, the most commonly reported (≥10% of participants) TEAEs were infections (n=93 [43.7%] participants), of which COVID-19 (n=25 [11.7%] participants) was the most common AE. Other common TEAEs included gastrointestinal disorders (n=65 [30.5%]), nervous system disorders (n=34 [16%]), and musculoskeletal and connective tissue disorders (n=67 [31.5%]), of which arthralgia (n=22 [10.3%]) was the most common AE. Conclusions Conclusions This analysis confirms that in participants receiving the AT-DR, fitusiran was associated with high overall levels of compliance (96.0%) and was well tolerated as demonstrated by low discontinuation rates due to AEs (2.3%). The high treatment compliance observed in ATLAS-OLE is likely due to reduced treatment burden afforded by the Q2M regimens (that 78% of participants were receiving), supporting the clinical utility of fitusiran in PwHA or B, with or without inhibitors.

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Abstract Number: 2610

Economic and clinical impact of emicizumab in people with moderate and severe Hemophilia A in the US

Presenter: Janet Lee
Session: 901. Health Services and Quality Improvement: Non-Malignant Conditions Excluding Hemoglobinopathies: Poster I

Abstract: Introduction: Emicizumab is a recombinant, humanized, bispecific, monoclonal antibody that has become the standard of care in hemophilia A prophylaxis. Adoption of emicizumab as standard of care was likely supported by its subcutaneous administration and consistent pharmacokinetics compared with FVIII. The objective of this analysis was to estimate the population-level impact of emicizumab on clinical and economic outcomes since its approval in the US in 2017 and the projected impact over the next ten years.

Methods: A population impact model was used to evaluate outcomes associated with emicizumab market approval and uptake relative to a hypothetical scenario in which emicizumab is unavailable and only standard or extended half-life factor VIII replacement products and bypassing agents are available for prophylactic treatment. Model outcomes included the number of treated bleeds averted (including treated joint bleeds) and the number of arthroplasties prevented. The total direct and indirect costs associated with these avoided outcomes were estimated. Direct costs included healthcare costs associated with outpatient visits, emergency room visits, hospitalizations and the cost of breakthrough bleed treatment. Indirect costs included work productivity among people with hemophilia A or caregivers. Relevant model inputs, including costs, were derived from published sources, including randomized clinical trials, real-world studies and the US Centers for Disease Control and Prevention. Market share estimates were based on internal data and were assumed to remain constant when evaluating outcomes for the next ten years and assuming no additional therapies enter the market.

Results: Among an estimated 15,107 people in the US with moderate or severe hemophilia A in 2016, use of emicizumab has resulted in an estimated cumulative total of 958,810 treated bleeds averted (including 699,931 treated joint bleeds averted) and 2002 arthroplasties prevented since its approval in 2017. These avoided outcomes prevented a total of $42.6B in direct and indirect costs to payers. Over the next ten years, emicizumab treatment was projected to result in an additional 1.9M treated bleeds averted (including 1.4M treated joint bleeds averted) and 3292 arthroplasties prevented, with $80.5B in total costs avoided.

Conclusions: In this US population impact model, emicizumab significantly reduced both bleeding events and the economic burden of hemophilia A.

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Abstract Number: 2615

Healthcare resource utilization in people with hemophilia treated within vs. outside u.S. hemophilia treatment center network clinics: An interim analysis of the CHESS US study

Presenter: Randall Curtis
Session: 901. Health Services and Quality Improvement: Non-Malignant Conditions Excluding Hemoglobinopathies: Poster I

Abstract: Introduction: People with hemophilia (PwH) in the United States (US) may receive comprehensive care through the Hemophilia Treatment Center Network (USHTCN). Little is known about the care of PwH treated in non- USHTCN clinics. Characterizing the outcomes, general burden of disease and healthcare resource utilization (HCRU) in PwH treated in non-USHTCN clinics is key to improving health outcomes in PwH. This preliminary analysis aimed to update clinical characteristics of HCRU for PwH treated at USHTCN and non-USHTCN clinics and identify the elements potentially driving inconsistencies across both settings.

Methods: Cost of Hemophilia: A Socio-Economic Survey United States (CHESS US) is a 12-month retrospective, longitudinal burden-of-illness study which collects, since 2022, demographic, clinical, HCRU data as abstracted from medical records by health care providers (HCPs); and humanistic and socio-economic information from adult (≥18 years) male PwH A or B of any severity via a voluntary self-complete form. Study methodology allowed inclusion of USHTCN and non-USHTCN clinics. This interim analysis used updated data to compare clinical and HCRU outcomes in PwH treated in both settings. Information on demographics, clinical characteristics, comorbidities, bleeding and joint outcomes and hemophilia- related HCRU were collected from medical records. Joint health was assessed using target joint (TJ) and problem joint (PJ) protocols; chronic joint pain and/or limited range of movement due to compromised joint integrity [i.e., chronic synovitis and/or hemophilic arthropathy], with or without persistent bleeding) metrics. Continuous variables are presented as mean (SD) and categorical variables as n (%). Chi-square tests and Mann-Whitney U tests were used to compare categorical and continuous variables, respectively.

Results: At interim database lock (June 2025), 814 PwH (non-USHTCN n=749, 91.6%; USHTCN n=68, 8.4%) met inclusion criteria. The USHTCN cohort was composed by a significantly higher proportion of severe PwH compared to the non-USHTCN cohort (n=39, 57.4% vs. n=285, 38.2%; p<0.01). While mean age was similar (non-USHTCN: 33.4 [13.2] years; USHTCN: 34.6 [13.0] years; p=0.3), a larger percentage of non- USHTCN PwH were uninsured/underinsured (n=103, 13.8% vs. n=3, 4.4%; p<0.05). Full time employment was reported in 63.2% (n=43) of USHTCN and 54.2% (n=404) of non-USHTCN PwH (p=0.150). USHTCN PwH had a more complex coinfection profile, with higher prevalence of Hepatitis C (n=10, 14.7% vs. n=3, 0.4%) and HIV (n=5, 7.4% vs. n=5, 0.7%) (both p<0.001). Across the USHTCN and non-USHTCN cohorts, both anxiety and depression were reported (as abstracted from medical records) for 5.9% (n=4) vs. 13.3% (n=99) (both p=0.08). Higher prevalence of anemia (n=85, 11.4% vs. n=2, 2.9%; p<0.05) and fatigue (n=99, 13.3% vs. n=4, 5.9%; p<0.01) were reported in the non-USHTCN cohort. Similar mean annual bleed rates (1.3 [2.4] vs. 1.3 [1.5]; p=0.48) and chronic joint damage profiles (1.1 [1.3] vs. 1.5 [1.7] PJs; p=0.07) were observed. Mean number of TJs was significantly higher in the non-USHTCN cohort (0.9 [1.3] vs. 0.3 [0.9] TJs; p<0.001). A significantly larger proportion of non-USHTCN PwH had ≥1 bleed-related hospital visit (n=143, 19.2% vs. 2, 2.9%; p=0.001) in the 12 months prior. While the non-USHTCN group had longer all-type hospitalizations (including ward and intensive care unit) (2.6 [10.1] vs. 0.1 [0.8]; p<0.001), no significant differences were observed in mean number of hospital visits (1.7 [2.0] vs. 0.8 [0.4]; p=0.09) and emergency room visits (0.2 [0.6] vs.0.1 [0.3]; p=0.09). The number of outpatient visits (not including hematology consultations) was 0.3 (0.6) vs. 0.5 (0.6) for non-USHTCN and USHTCN PwH (p=0.25), respectively. History of surgical procedures was reported in 20.1% (n=150) of non-USHTCN and 13.1% (n=9) of USHTCN PwH (p=0.171); mean surgery-related hospital days were reported as 1.0 (6.2) and 0.1 (0.4) (p=0.28), respectively. Conclusions Conclusions These findings highlight differences between care settings for PwH in the US, suggesting that while managing a more clinically complex population, the USHTCN model is associated with lower HCRU. The findings suggest that the proactive, interdisciplinary approach of the USHTCN is efficient and effective in preventing acute and long-term complications of PwH, while reducing the burden on the broader healthcare system and improving health related outcomes of this population.

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Abstract Number: 3062

RESHAPE: A non-interventional study of real-world treatment patterns and outcomes across age groups in people with severe hemophilia A in Latin America, Eastern Europe, Africa, Asia, and the Middle East

Presenter: Guillermo Tobaruela
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster II

Abstract: Background: Detailed treatment outcomes data in people with congenital hemophilia A (PwHA) outside North America, Western Europe, and Japan are scarce. We report data in children, adolescents, and adults with severe HA with/without factor (F)VIII inhibitors enrolled in RESHAPE across Latin America, Eastern Europe, Africa, Asia, and the Middle East.

Methods: RESHAPE was a non-interventional, real-world study conducted across 80 sites in 24 countries. PwHA with FVIII activity <1 IU/dL were enrolled (Sep 2020–Dec 2022) into Cohort A (without FVIII inhibitors) or Cohort B (with inhibitors) and observed for 52 weeks (wks) or until treatment switch. Bleeds were recorded using a Bleed and Medication Questionnaire. We report mean annualized treated bleed rates (ABRs) and participants with zero treated bleeds, per age group (<12, 12–17, and ≥18 years [yrs]), and all adverse events (AEs). Treatment dosing was per label and local practice.

Results: Among a total of 669 PwHA, 489 comprised Cohort A: 45 (9.2%) received emicizumab prophylaxis (EMI), 369 (75.5%) FVIII prophylaxis, and 75 (15.3%) FVIII on demand (OD). In Cohort B, among 180 PwHA, 81 (45.0%) received EMI, 51 (28.3%) bypassing agent (BPA) prophylaxis, and 48 (26.7%) BPAs OD. Across age groups in Cohort A, most PwHA received FVIII prophylaxis, followed by FVIII OD and EMI. In Cohort B, most children received EMI, followed by BPA prophylaxis and BPAs OD; most adolescents also received EMI, followed by BPAs OD and BPA prophylaxis; most adults received BPA prophylaxis, followed by BPAs OD and EMI. Mean treatment duration (mTD) for Cohort A/B was 52/47 wks, 48/33 wks, and 40/32 wks for EMI, FVIII/BPA prophylaxis, and FVIII/BPA OD, respectively. In Cohort A, mean (95% confidence interval [CI]) ABRs (treated bleeds) were lower with EMI (0.2 [0–4.1], 0.5 [0–4.7], and 0.4 [0–4.4] for ages <12, 12–17, and ≥18 yrs, respectively) compared with FVIII prophylaxis (3.5 [0.8–9.5], 4.1 [1.1–10.3], and 4.9 [1.6–11.6], respectively) and FVIII OD (6.3 [2.4–13.5], 6.3 [2.4–13.5], and 16.5 [9.5–26.6], respectively). Similar results were observed in Cohort B: mean (95% CI) ABRs were 0.3 (0–4.3), 0.5 (0–4.7), and 1.2 (0.1–6.0), respectively, for EMI; 8.9 (4.1–17.0), 5.6 (2.0–12.5), and 8.4 (3.7–16.3), respectively, for BPA prophylaxis; and 11.7 (6.0–20.6), 13.4 (7.2–22.7), and 7.9 (3.4–15.7), respectively, for BPAs OD. The proportion of PwHA with zero treated bleeds was higher in participants receiving EMI vs FVIII/BPA prophylaxis and FVIII/BPAs OD. In PwHA aged <12 yrs, respective proportions in Cohort A were 80% (n=16; mTD: 51 wks), 33% (n=43; mTD: 50 wks), and 13% (n=3; mTD: 51 wks) for EMI, FVIII prophylaxis, and FVIII OD. In Cohort B, they were 81% (n=34; mTD: 52 wks), 41% (n=9; mTD: 38 wks), and 5% (n=1; mTD: 45 wks) for EMI, BPA prophylaxis, and BPAs OD. Proportions of PwHA with ≥1 AE were similar across cohorts: 19 (28.8%) for EMI, 124 (33.2%) for FVIII prophylaxis, and 23 (29.9%) for FVIII OD (Cohort A); 33 (31.7%) for EMI, 18 (31.6%) for BPA prophylaxis, 16 (31.4%) for BPAs OD (Cohort B). One thromboembolism occurred in the FVIII prophylaxis group (unrelated to treatment). No thrombotic microangiopathies occurred, nor any indication of anti- emicizumab antibody development. Two deaths were reported in the FVIII prophylaxis group (unrelated to treatment). No AEs led to treatment discontinuation. The most common AEs were infections and infestations (Cohort A/B: 18.2%/14.4%, 13.4%/12.3%, and 9.1%/11.8% with EMI, FVIII/BPA prophylaxis, and FVIII/BPAs OD, respectively); musculoskeletal and connective tissue disorders (4.5%/4.8%, 8.3%/5.3%, and 5.2%/9.8%, respectively); injury, poisoning and procedural complications (4.5%/8.7%, 5.9%/14.0%, and, 3.9%/7.8%, respectively); and gastrointestinal disorders (0%/3.8%, 5.1%/8.8%, and 6.5%/7.8%, respectively).

Conclusions: These results provide critical real-world evidence from regions with scarce treatment- outcomes data. Although most participants received prophylaxis, a substantial proportion were treated OD, suggesting that while prophylaxis is viable in these regions, there is a remaining need to expand its use. Consistently across age groups, bleeding rates were lowest with EMI prophylaxis, followed by FVIII/BPA prophylaxis and FVIII/BPAs OD; despite this, EMI use was low, particularly in the non-inhibitor population, suggesting barriers to access in the studied regions. All treatments were well tolerated and consistent with published safety data.

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Abstract Number: 3066

Management of breakthrough bleeds in participants with hemophilia Α or Β without inhibitors receiving marstacimab prophylaxis in the phase 3 BASIS study

Presenter: Travis Gould
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster II

Abstract: Background: Background: Marstacimab is a monoclonal antibody that targets the tissue factor pathway inhibitor to rebalance hemostasis. It is approved for prophylaxis in patients with hemophilia A (HA) or B (HB) without inhibitors. The pivotal phase 3 BASIS study (NCT03938792) demonstrated marstacimab was effective in reducing treated bleeds vs prior on-demand (OD) or routine prophylaxis (RP) therapy in participants (pts) with severe HA (FVIII <1%) or moderately severe to severe HB (FIX ≤2%) without inhibitors. We aimed to assess the management of breakthrough bleeding episodes in pts who received concomitant factor replacement therapy (FRT) and weekly (QW) marstacimab in BASIS.

Methods: BASIS enrolled male pts aged ≥12 to <75 years. Results are reported for the noninhibitor cohort. Pts entered a 6-month observational phase (OP) and received prescribed FRT (OD or RP) before entering the 12-month active treatment phase (ATP) to receive a single dose of 300 mg marstacimab (2×150 mg subcutaneous [SC]) followed by 150 mg SC QW. To manage breakthrough bleeds, pts could take their prescribed FRT at the lowest effective dose, determined by each investigator per the approved product label. FRT dose, date, and time of infusions and FRT product were recorded in an electronic diary; the type of product (plasma-derived [pd], recombinant standard half-life [SHL], or recombinant extended half-life [EHL]) was determined. An acute treated bleed was defined as a bleeding event treated with episodic FRT within 48 hours of the bleed starting.

Results: Of 128 pts (HA: n=101; 78.9%; HB: n=27; 21.1%) who entered the OP, 116 received marstacimab prophylaxis in the 12-month ATP. At baseline, median age was 30.0 (range 13-66) years, and most were White (50.8%) or Asian (47.7%); 36 (97.3%) and 53 (58.2%) pts in the OD and RP groups, respectively, had ≥1 target joint. The median (range) marstacimab treatment duration was 12.1 months for both the OD (11.5-13.1 months) and RP (0.9-12.8 months) groups. In all, 75 (64.6%) pts experienced 453 acute bleeding events in the ATP, which were treated with 555 FRT infusions (OD: 125; RP: 430). Most acute breakthrough bleeds (OD: 83.7%; RP: 83.1%) were treated with a single infusion of FRT; 18.3% and 12.3% of bleeds in the OD and RP group, respectively, were treated with 2 infusions; in the RP group, 2.9% of bleeds were treated with 3 infusions and 1.7% of bleeds were treated with ≥4 infusions (5/6 were spontaneous joint bleeds). For both OD and RP pts with HA or HB, the most frequently used FRT to treat acute breakthrough bleeds was pd or SHL product; 401/453 (88.5%) bleeds were treated with pd or SHL product (HA: 351/375 [93.6%]; HB: 50/78 [64.1%] bleeds). For OD pts with HA during ATP, the mean (SD) pd/SHL FVIII dose/infusion was 24.19 (7.98) IU/kg (n=19) (OP: 21.63 [10.72] IU/kg [n=26]) and mean (SD) EHL FVIII dose/infusion was 19.93 (5.67) IU/kg (n=4) (OP: 16.46 [5.05] IU/kg [n=8]). For RP pts with HA during ATP, the mean (SD) pd/SHL FVIII dose/infusion was 24.61 (8.09) IU/kg (n=40) (OP: 28.06 [8.83] IU/kg [n=37]) and mean (SD) EHL FVIII dose/infusion was 30.57 (9.83) IU/kg (n=4) (OP: 43.44 [8.59] IU/kg [n=5]). In all OD and RP pts with HA, 80.4% and 82.4% of acute bleeds were treated with a single infusion of FRT, respectively. For OD pts with HB during ATP, the mean (SD) pd/SHL FIX dose/infusion was 23.70 (7.15) IU/kg (n=3) (OP: 23.76 [10.77] IU/kg [n=5]) and mean (SD) EHL FIX dose/infusion was 12.60 (5.06) IU/kg (n=2) (OP: 13.16 [5.65] IU/kg [n=4]). For RP pts with HB during ATP, the mean (SD) pd/SHL FIX dose/infusion was 49.51 (26.40) IU/kg (n=5) (OP: 47.28 [17.10] IU/kg [n=6]) and mean (SD) EHL FIX dose/infusion was 47.04 (11.53) IU/kg (n=6) (OP: 74.36 [21.47] IU/kg [n=4]). In OD and RP pts with HB, 100.0% and 85.7% of acute bleeds were treated with a single infusion of FRT, respectively. For RP pts with HB, FIX consumption was influenced by 2 marstacimab-treated adolescents with several traumatic bleeds that required FRT. No thromboembolic events were reported in association with concomitant FRT use. Conclusions Conclusions In the BASIS study, for pts with HA or HB without inhibitors, acute breakthrough bleeding episodes were successfully managed with episodic FRT during concurrent QW marstacimab prophylaxis and marstacimab was generally safe. Most acute breakthrough bleeds were managed with a single infusion of FRT, and the most common treatment agents were SHL FVIII products (recombinant or pd).

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Abstract Number: 3068

Real‑world experience with anti‑TFPI agent (Marstacimab) in severe and non‑severe hemophilia: First reported successful use in a female with non-severe hemophilia b

Presenter: Akshat Jain
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster II

Abstract: We report results of the first real world study evaluating outcomes in people with severe and non-severe hemophilia (SH, NSH), including the first female patient on Marstacimab, a novel Anti TFPI antagonist. Over the past decade, the management of hemophilia has undergone radical transformation with the emergence of novel non-factor therapies, particularly subcutaneous agents that rebalance hemostasis. Traditionally, the cornerstone of care for people with hemophilia (pwh) has been the use of intravenous clotting factor concentrates (CFCs) and FVIII mimetics for hemophilia A, which, while effective, present challenges in terms of administration burden and variable bleed control, especially in subpopulations not captured in clinical trials (Srivastava et al., 2020). Recent approval of rebalancing agents—including Marstacimab, a tissue factor pathway inhibitor (TFPI) monoclonal antibody for people with hemophilia A and B without inhibitors, along with Fitusiran and Concizumab—herald a new era of expanded, and effective patient-friendly therapeutic options. To date, regulatory approvals and pivotal trials have focused predominantly on severe hemophilia (factor VIII or IX activity <1%), often excluding non-severe (1–5% activity) and female pwh. However, mounting evidence has revealed that individuals outside the "severe" category—namely symptomatic females with hemophilia and NSH males—can experience considerable bleeding burden and hemophilic arthropathy. Herein, we present real-world data on the use of Marstacimab in symptomatic females and moderate males with hemophilia A or B.

Results: 7 participants on weekly injectable subcutaneous (SQ) Marstacimab at 150mg/dose as solo prophylaxis (6 males - 3 SH, 3NSH 1 NSH female. Ages 15-19 years) are reported here. 50% switched from a CFC based prophylaxis while the remaining switched to weekly SQ regimen from on demand therapy in the moderate cohort whereas 75% of severe Hemophilia A/B patients switched from CFC and remaining from previous Emicizumab prophylaxis. Experience of trauma related breakthrough bleed in the female patient while on Marstacimab, demonstrated excellent clinical hemostasis, despite a bone fracture, needing a single dose of CFC for peri surgical intervention while on Marstacimab weekly prophylaxis. All subjects demonstrated excellent bleed control with zero reported spontaneous breakthrough bleeds while on weekly SQ regimen. 100% report improved quality of life metrics, mobility scores and reported convenience of the SQ therapy reducing treatment burden and associated needle phobia. No unexpected adverse events or thromboembolism have been noted in these patients despite having higher baseline factor VIII/IX activity than participants during the preceding clinical trial reporting (factor activity <1%). Joint health (HJHS), chronic pain, anemia/iron status, menstrual bleeding (female) were additional metrics collected and are being monitored in these cohorts longitudinally.

Conclusion: Our findings underscore the critical need to consider bleeding phenotype—not merely factor levels—when selecting candidates for rebalancing therapies. Women with hemophilia endure recurrent, debilitating bleeds related to menorrhagia or obstetric complications, resulting in chronic anemia and impaired quality of life. By broadening the focus beyond severe hemophilia, we advocate for an evolution in treatment paradigms that prioritizes individual bleeding risk, closing the persistent care gap for males and females with non-severe hemophilia, especially since labeling of anti-TFPI agents such as Marstacimab is not limited by factor level or gender. Furthermore, we strongly advocate for inclusion of women with hemophilia in clinical trials using novel agents based on their bleeding phenotype and regardless of their factor levels.

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Abstract Number: 3069

Perioperative use of efanesoctocog alfa in Hemophilia A: A dual-center real-world study

Presenter: Kadhim Al-Banaa
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster II

Abstract: Background: Persons with Hemophilia A (PWH) are at high risk of bleeding during and after surgery. Standard perioperative management requires frequent factor VIII infusions to maintain hemostatic levels, which is burdensome. Efanesoctocog alfa (ALTUVIIIO®) is a first-in-class, ultra–extended half-life FVIII concentrate that received FDA approval in 2023 for routine prophylaxis and perioperative bleeding management. It is engineered as a B-domain–deleted recombinant FVIII protein fused to the Fc domain of human IgG1, the D′D3 domain of von Willebrand factor (VWF), and XTEN® polypeptides. This design enables independence from the VWF half-life ceiling, prolonging circulation time and affording higher sustained FVIII activity. Clinical trials demonstrated excellent surgical hemostasis with Efanesoctocog alfa, but real-world perioperative outcomes data with larger numbers of subjects remain limited. We therefore sought to explore perioperative hemostasis properties in the real-world setting to evaluate dosing, administration frequency, hemostatic effectiveness and safety of perioperative Eefanesoctocog alfa administration in adult PWH. Methods: We performed a retrospective review of all surgeries performed between March 1, 2023, and June 30, 2025 at two Hemophilia Treatment Centers in the United States (University of San Diego California and Orthopaedic Center Los Angeles). Surgical procedures were classified per ISTH criteria as major or minor. Inclusion criteria included PWH > age 18, who received at least one preoperative dose of Efanesoctocog alfa, plus/minus additional postoperative doses administered at the discretion of treating physicians. Patients with active factor VIII inhibitors were excluded. Data collected included demographics, hemophilia severity, prior prophylaxis, dosing and frequency of Efanesoctocog alfa, perioperative antifibrinolytic use, bleeding outcomes, rescue factor therapy, transfusion requirements, complications, and bleeding events within 30 days postoperatively. Results: Fifty-eight surgeries were performed in 48 patients. The median age was 43 years (IQR 38–60); 52 of 58 surgeries (90%) were in male patients. Severe, moderate and mild hemophilia A was present in 26 (48%), 3 (5%) and 26 cases (48%), respectively (data missing in 3 cases). Twenty-five (47%) procedures were classified as major and 28 (53%) as minor, respectively. Intraoperative hemostasis was achieved in all cases. Postoperative bleeding occurred in 6 surgeries (10%), but was all minor (wound oozing, hematuria, mucosal) and could be managed conservatively. Rescue factor therapy with standard half-life rFVIII was used in 4 cases (7%). One patient (1.7%) required red blood cell transfusion. Antifibrinolytic therapy was used in 37 of 58 surgeries (64%). Of those, 17 cases (46%) received intravenous antifibrinolytics as part of the standard surgical protocol, 12 cases (32%) received oral antifibrinolytics as adjuvant therapy, and 8 cases (22%) received both IV and oral routes. No thromboembolic events were observed. A second postoperative dose of Efanesoctocog alfa was administered in 20 surgeries (35%), most commonly on postoperative day 3 or 4. Median hospital length of stay was 2 days for major surgeries and 0 days for minor procedures. Four patients (7%) experienced minor bleeding within 30 days postoperatively, including 3 with nonsurgical-site bleeding (e.g., spontaneous mucosal or muscle bleeds) and 1 with expected residual bleeding following a prostate biopsy. No patient experienced unexpected bleeding from the surgical site, or developed venous thromboembolism Conclusions: Perioperative Efanesoctocog alfa administration provided effective surgical hemostasis, whereby a single preoperative outpatient dose was sufficient for most procedures. These observations are encouraging since Efanesoctocog alfa seems to not only facilitate but also alleviate outpatient management, advantageous to reduce management burden for patients and health care staff alike.

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Abstract Number: 3070

Concizumab plasma concentration measurements for personalized dose adjustment in patients with Hemophilia A/B with and without inhibitors: Data from the Phase 3 explorer7 and explorer8 studies

Presenter: Hermann Eichler
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster II

Abstract: Background: Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody intended for patients with hemophilia A or B, with or without inhibitors. It is approved in the US, Europe and other countries for once ‑ daily, subcutaneous prophylaxis in hemophilia A or B with inhibitors. Aim Describe the observed and modelled pharmacokinetics (PK) and bleeding outcomes from one-time concizumab dose adjustments in phase 3 concizumab studies. Methods In two prospective, multicenter, open-label, phase 3 concizumab studies, explorer7 (patients with inhibitors; NCT04083781) and explorer8 (patients without inhibitors; NCT04082429), male patients aged ≥12 years were randomized 1:2 to no prophylaxis (arm 1) or concizumab prophylaxis (arm 2) or allocated to non-randomized concizumab prophylaxis (arms 3 and 4). Following a study pause due to non-fatal thromboembolic events in 3 patients receiving concizumab, a revised dosing regimen was implemented with a 1.0 mg/kg loading dose on the first day of treatment, followed by an initial daily dose of 0.20 mg/kg. At week 4, concizumab plasma concentrations were measured with a clinical trial enzyme-linked immunosorbent assay for potential one-time dose adjustments to set the maintenance dose. The dose was increased to 0.25 mg/kg if concizumab plasma concentration was <200 ng/mL, decreased to 0.15 mg/kg if >4,000 ng/mL, or maintained at 0.20 mg/kg if between 200–4,000 ng/mL. Population PK modeling was used to simulate concizumab exposure and response. Efficacy outcomes based on dose adjustments from the primary analysis (explorer7) or confirmatory analysis (explorer8) cut ‑ offs are presented. Results A total of 281 patients were assigned to one of four arms in explorer7 and explorer8 (62.3% White, 28.1% Asian, 4.6% Black/African American, 2.1% American Indian/Alaska native, 2.5% not reported, 0.4% other). Concizumab plasma concentration was measured in 218 of 226 concizumab-exposed patients in arms 2– 4; 8 patients withdrew before maintenance doses were reported. Of the 218 patients measured, 153 (70.2%) continued with a maintenance dose of 0.20 mg/kg, 55 (25.2%) patients adjusted to 0.25 mg/kg and 10 (4.6%) patients adjusted to 0.15 mg/kg. The majority of patients (70.2%) had concizumab plasma concentrations between 200–4,000 ng/mL at week 4 and continued with maintenance dose at 0.20 mg/kg; mean concizumab plasma concentration in this group were 629 ng/mL and 608 ng/mL at week 4 and week 12, respectively. The proportion of patients with concizumab plasma concentrations <200 ng/mL at week 4 and adjusted to 0.25 mg/kg was 25.2%, consistent with the population model prediction of 21%. After dose adjustment to 0.25 mg/kg, the mean concizumab plasma concentration in the <200 ng/mL group increased from 119 ng/mL to 296 ng/mL from week 4 to week 12. The proportion of patients with concizumab plasma concentrations >4,000 ng/mL at week 4 and adjusted to 0.15 mg/kg was 4.6%, lower than the model prediction of approximately 10%. After dose adjustment to 0.15 mg/kg, the mean concizumab plasma concentration decreased from 5,525 ng/mL to 766 ng/mL from week 4 to week 12. Post ‑ dose adjustment concizumab plasma concentrations aligned with modelled predictions. Based on simulated efficacy outcomes in the <200 ng/mL group, increasing the daily maintenance dose to 0.25 mg/kg would reduce the predicted annualized bleeding rate (ABR). Consistent with modelled predictions, observed mean ABR within the <200 ng/mL group was lower after dose adjustment vs before dose adjustment: 3.8 (standard deviation [SD]: 8.2; mean observation period 262 days) vs 7.2 (SD: 10.4; mean observation period 64 days), respectively. Mean ABR in the <200 ng/mL group after dose adjustment was similar to the 200–4,000 ng/mL group (3.1; SD: 6.5; mean observation period 287 days). For patients with >4,000 ng/mL plasma concizumab, observed mean ABR after dose adjustment was 3.8 (SD: 4.8; mean observation period 340 days), similar to the 200–4,000 ng/mL group (3.1; SD: 6.5; mean observation period 287 days). Conclusions These findings support the use of concizumab plasma concentration-guided dose adjustments to optimize prophylaxis in patients with hemophilia A or B, with or without inhibitors. Exposure-response analyses confirmed the validity of the selected lower (200 ng/mL) and upper (4,000 ng/mL) limits of concizumab plasma concentration and showed that dose adjustments can effectively personalize therapy to reduce bleeding rates.

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Abstract Number: 3071

Updated meta-analysis of inhibitor development in previously untreated patients with severe Hemophilia A: Plasma-derived versus recombinant FVIII products

Presenter: Anthony Navarrete Rios
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster II

Abstract: Background: Neutralizing inhibitors remain the major complication of replacement therapy in previously untreated patients (PUPs) with severe haemophilia A , affecting up to one ‑ third of this cohort. Earlier meta ‑ analyses, including Kohar et al. 2022 update, suggested a higher inhibitor risk with recombinant FVIII (rFVIII) than with plasma ‑ derived FVIII (pdFVIII) (pooled OR ≈ 1.6; HR ≈ 1.9). Most published work pre ‑ dates 2018 and lacks recent registry ‑ level and product ‑ specific data. We therefore performed a meta ‑ analysis integrating both historic and contemporary studies to compare inhibitor risk between pdFVIII and rFVIII in PUPs with hemophilia A.

Methods: A meta-analysis was conducted to compare the risk of factor VIII inhibitor development in previously untreated patients with severe hemophilia A receiving plasma-derived FVIII versus recombinant FVIII. A systematic literature search was performed using PubMed for studies published between 2000 and 2025. The search yielded 285 articles, which were independently screened and reviewed by two investigators. Inclusion criteria: human studies reporting inhibitor counts ≤ 75 exposure days (EDs) in PUPs and directly comparing pdFVIII with rFVIII. Five studies met criteria and included in the meta- analysis: SIPPET trial (Peyvandi et al., 2016), the CANAL study (Gouw et al., 2007), the FranceCoag cohort (Calvez et al., 2018), the PedNet registry (Fischer et al., 2023), and EUHASS/CHESS data (Fischer et al., 2023). Event-level data (number of patients who developed inhibitors and total number treated in each group) were extracted and pooled. The primary outcome was the risk ratio (RR) of inhibitor development. A random-effects model was used to calculate pooled effect estimates. Heterogeneity was assessed using the I² statistic and τ²(tau-squared). All statistical analyses were conducted using Stata/SE 19.5

Results: Five studies comprising a total of 3,236 patients (758 treated with plasma-derived FVIII and 2,478 with recombinant FVIII) were included in the meta-analysis. Using a random-effects model (REML) based on a manually calculated log risk ratios and standard errors, the pooled analysis demonstrated a significantly lower risk of inhibitor development in patients receiving pdFVIII compared to those receiving rFVIII. The pooled risk ratio (RR) was 0.74, with a 95% confidence interval (CI) of 0.57 to 0.96 ( p = 0.026), indicating a 26% relative risk reduction associated with pdFVIII. Heterogeneity was observed across the studies (I² = 68.3%). While meta-regression suggested that differences in study size might explain some of this heterogeneity, accounting for around 29% of the between-study differences; this finding was not statistically significant. Nevertheless, the overall pattern of results consistently favored pdFVIII, with all included studies demonstrating a reduction in inhibitor risk relative to rFVIII.

Conclusion: This updated meta ‑ analysis, incorporating the first post ‑ 2021 registry data, confirms a modest but significant reduction in early inhibitor risk with plasma ‑ derived FVIII compared with recombinant FVIII in previously untreated patients with severe hemophilia A. These findings support current shifts in clinical practice, highlight the importance of product ‑ specific pharmacovigilance, and may guide clinicians in selecting first ‑ line products and refining risk ‑ stratified early prophylaxis strategies.

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Abstract Number: 3074

Efficacy and safety of fitusiran prophylaxis in people with haemophilia a or haemophilia B: A systematic review and meta-analysis

Presenter: Dua Azim
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster II

Abstract: Background: Prophylaxis is the standard of care for people with severe hemophilia A or B to prevent bleeding, but the treatment burden can be high, and breakthrough bleeding can still occur, particularly in patients with inhibitors. Fitusiran, a small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis, offering a novel prophylactic approach. This systematic review and meta-analysis aim to evaluate the efficacy and safety of Fitusiran prophylaxis in this population. Aim: Aim: To systematically review and meta-analyze the efficacy and safety of Fitusiran prophylaxis compared to control in people with hemophilia A or B, with or without inhibitors.

Methods: A systematic literature search was conducted across PubMed, Cochrane, ScienceDirect, Web of Science, and Scopus to identify randomized controlled trials (RCTs) comparing Fitusiran with control (placebo or bypassing agents on-demand) in patients with hemophilia A or B. The primary efficacy outcomes were the annualized bleeding rate (ABR), annualized spontaneous bleeding rate (AsBR), and annualized joint bleeding rate (AjBR). Safety outcomes included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent severe adverse events (TESAEs), and specific adverse events of interest such as elevated liver enzymes. Data from RCTs were pooled using a random-effects model. Mean difference (MD) was used for continuous outcomes and odds ratio (OR) for dichotomous outcomes, with 95% confidence intervals (CI). Heterogeneity was assessed using the I² statistic.

Results: Three RCTs were included in this meta-analysis, ATLAS-INH 2023, ATLAS-PPX 2024, and ATLAS A/B 2023, with a combined sample size of (N=311). In patients with inhibitors, Fitusiran significantly reduced ABR (MD: -11.70, 95% CI: [-18.55, -4.85]; P=0.0008), AsBR (MD: -9.40, 95% CI: [-18.63, -0.18]; P=0.05), and AjBR (MD: -8.49, 95% CI: [-14.92, -2.05]; P=0.01). In patients without inhibitors, no statistically significant reduction was observed for ABR ( P=0.25 ), AsBR ( P=0.26 ), or AjBR ( P=0.28 ). Fitusiran was associated with a significantly higher odds of any TEAE (OR: 5.11, 95% CI: [3.05, 8.56]; P<0.00001) and increased alanine aminotransferase (ALT) (OR: 17.80, 95% CI: [4.88, 64.92]; P<0.0001). There was no statistically significant difference in the odds of increased aspartate aminotransferase (AST) (P=0.06), upper respiratory tract infection (P=0.12), arthralgia (P=0.23), nasopharyngitis (P=0.15), or TESAEs (OR: 0.84, 95% CI: [0.35, 2.00]; P=0.69). Heterogeneity for all outcomes was low.

Conclusion: Fitusiran prophylaxis is an effective therapy for reducing bleeding rates in patients with hemophilia A or B with inhibitors. While a similar trend was observed in patients without inhibitors, the result was not statistically significant. The safety profile indicates an increased risk of TEAEs, most notably transient elevations in ALT, but not an increase in severe adverse events. These findings support Fitusiran as a promising prophylactic option, especially for the difficult-to-treat inhibitor population and underscore the importance of monitoring liver function during treatment.

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Abstract Number: 3075

Modeling disability reduction through low-dose prophylaxis versus on-demand therapy in hemophilia A: A meta-analysis and gbd-inspired yld framework for resource-limited settings

Presenter: Muhammad Ahmed
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster II

Abstract: Low-dose prophylaxis (LDP) is increasingly adopted in low- and middle-income countries (LMICs) as a cost-feasible approach to reduce morbidity in patients with Hemophilia A. While it is known to reduce bleeding rates, there is limited population-level quantification of its long-term disability benefit over on- demand therapy (ODT), especially using burden-of-disease metrics. This study aimed to systematically assess clinical outcomes from existing trials comparing LDP with ODT and model the resulting Years Lived with Disability (YLD), a Global Burden of Disease (GBD)-style disability measure, in LMIC contexts. A comprehensive search of PubMed, Embase, and Scopus through June 2025 identified twelve eligible studies (6 randomized controlled trials, 6 prospective cohorts) comprising 2,931 participants comparing LDP (≤20 IU/kg, ≤3x/week) to ODT. Extracted outcomes included annual bleeding rate (ABR), incidence of hemarthrosis, and prevalence of target joints. Meta-analysis was conducted using a random-effects model. Disability burden was estimated by modeling YLDs using the formula YLD = prevalence × disability weight × duration. Prevalence of target joint development was used as the disability proxy. Disability weights were adopted from the GBD 2019 dataset for comparable musculoskeletal conditions (DW = 0.079 for moderate limitation). A 10-year disability duration was applied. The mean ABR was significantly lower in the LDP group (4.2) than in the ODT group (12.5) (p < 0.001). The pooled prevalence of target joint development was 11% in the LDP group compared to 32% in the ODT group (risk ratio: 0.34; 95% CI: 0.26–0.45). Based on these findings, estimated YLDs per 1,000 patients over 10 years were 87 for LDP and 253 for ODT, translating to a 66% relative reduction in long-term disability burden. Sensitivity analyses using a higher DW (0.388, representing severe joint limitation) yielded 427 and 1,242 YLDs per 1,000 patients in the LDP and ODT groups, respectively. The benefit remained robust across different modeling assumptions. Subgroup analyses showed a more pronounced disability reduction in pediatric cohorts and in studies from LMICs. This is the first study to apply a GBD-inspired modeling approach to quantify the disability impact of LDP in Hemophilia A. While LDP is not curative, this analysis reveals that it substantially reduces long-term disability compared to ODT, supporting its adoption as a standard-of-care in resource-limited settings. Beyond traditional clinical metrics, the use of YLDs helps translate treatment decisions into population- level policy implications and supports health-economic justification for early prophylaxis initiation. These findings highlight the value of integrating burden modeling into national hemophilia treatment guidelines and provide a scalable framework for similar rare disease policy evaluation. Future directions include cost-per-YLD-averted analysis and dynamic modeling using national registry data.

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Abstract Number: 3076

Evaluating the safety and tolerability of switching from emicizumab to fitusiran prophylaxis in adult males with severe hemophilia A, with or without inhibitors: SWITCH study, a trial in progress

Presenter: Guy Young
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster II

Abstract: Introduction: As the treatment landscape of hemophilia non-factor therapies expands, there is a growing need to improve understanding of how to safely and effectively switch between therapeutics. Fitusiran is an antithrombin (AT)-lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia A or B, with or without inhibitors. The SWITCH study was designed to investigate the safety and tolerability of switching from emicizumab to fitusiran prophylaxis in people with severe hemophilia A, with or without inhibitors. Methods SWITCH is an exploratory, open-label, single-arm Phase 1 study (NCT06145373) investigating the safety and tolerability of switching from emicizumab to fitusiran prophylaxis in approximately 15–20 males aged ≥18 years with severe hemophilia A, with or without inhibitors. This study consists of a screening period of approximately 60 days, a 2-month pre-fitusiran treatment period to allow washout of emicizumab, and an 18-month fitusiran prophylaxis period. The washout strategy was developed based on a combination of modeling and simulation data to predict factor VIII-like activity equivalence. A population- pharmacokinetic model was used to directly link emicizumab exposure during the washout period to factor VIII-like activity (Retour S, et al. A. Clin Pharmacokinet. 2020; Schmitt C, et al. Thromb Haemost. 2021). Simulations of AT levels in participants receiving fitusiran were inputted into a quantitative systems pharmacology model to predict factor VIII-like activity in people with severe hemophilia A (Leiser et al. ASH. 2024; Kaddi et al. ASH. 2022). The total FVIII-like activity derived from emicizumab and fitusiran was assumed to be additive, suggesting that total factor VIII-like activity will remain below ~50% when fitusiran is administered ~2 months after the last dose of emicizumab. During the fitusiran prophylaxis period, breakthrough bleed management guidelines with reduced dose/frequency of CFC/BPAs and regular appropriate laboratory testing will be implemented. Participants start fitusiran treatment once every two months (Q2M), though the dose may be adjusted by escalation (monthly treatment) or de- escalation to a lower dose to target AT activity levels of 15–35% and maintain adequate bleed protection. The first 3 sentinel participants are treated in a stepwise fashion, requiring one participant to complete one month of fitusiran treatment before the subsequent participant may receive their first dose of fitusiran. Following the final fitusiran dose, AT activity levels will be monitored at monthly intervals during the 6-month AT follow-up period. The primary endpoint is incidence, severity, and seriousness of adverse events from Day 1 to Month 4 of fitusiran treatment. Secondary endpoints include: laboratory assessments (peak thrombin generation and AT levels) from Day 1 to Month 4 of fitusiran treatment; emicizumab plasma concentrations up to complete washout (~Month 4 of fitusiran treatment); incidence, severity and seriousness of adverse events from Day 1 to Month 18 of fitusiran treatment; health-related quality of life measures from baseline to the end of the study; change in participant joint health; and annualized bleeding rate during the 14-month extension period. Conclusion The SWITCH study will continue recruitment following evaluation of the 3 sentinel patients. This analysis will provide critical evidence to inform healthcare providers on how to safely transition patients from emicizumab to fitusiran, an important consideration in hemophilia clinical practice.

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Abstract Number: 3077

Implementation of 2020 international guidelines in acquired hemophilia: Insights from a decade of national registry data in Spain

Presenter: Maria Eva Mingot
Session: 323. Disorders of Coagulation, Bleeding, or Fibrinolysis, Excluding Congenital Hemophilias: Clinical and Epidemiological: Poster II

Abstract: Background: Acquired hemophilia A (AHA) is a rare but potentially life-threatening autoimmune bleeding disorder caused by the development of autoantibodies against coagulation factor VIII (FVIII). Due to its infrequent occurrence and heterogeneous presentation, diagnosis is often delayed, and treatment approaches vary widely across institutions. In 2014, the Spanish Society of Thrombosis and Hemostasis launched a national registry to document the clinical characteristics, management, and outcomes of AHA. The publication of international guideline in 2020 provided an opportunity to evaluate their real-world impact. Aims: Aims: To assess the effect of international guideline implementation on diagnostic efficiency, treatment patterns, clinical outcomes, and mortality in patients with acquired hemophilia in Spain.

Methods: This is a retrospective, observational analysis of 257 patients diagnosed with AHA between January 2014 and March 2024 and included in the national registry. Patients were stratified into two cohorts: Group 1 (diagnosed between 2014 and 2020, pre-guideline) and Group 2 (diagnosed between 2021 and 2024, post-guideline). We compared demographic variables, bleeding characteristics, laboratory findings, immunosuppressive and hemostatic strategies, treatment outcomes, and causes of death. Statistical comparisons used chi-square and Mann-Whitney U tests, with significance set at p<0.05.

Results: The median age of the cohort was 75 years (IQR 62–83), and 58% were male. Following guideline implementation, diagnostic timelines significantly improved, with the median time from first bleeding symptom to diagnosis reduced from 14.5 to 7 days (p<0.001). While baseline FVIII activity and inhibitor titers remained similar across cohorts (median FVIII 1 IU/dL, inhibitor 18 BU), the proportion of patients with underlying malignancy increased from 23.8% to 40% (p=0.012), reflecting a shift toward broader diagnostic awareness and inclusion. Hemostatic treatment patterns also evolved. The use of recombinant activated factor VII (rFVIIa) as first- line therapy increased significantly from 35.6% in the pre-guideline cohort to 43% post-guideline (p=0.014), with high response rates in both groups. Activated prothrombin complex concentrate (aPCC) use remained stable at around 25%. Notably, seven patients (8.8%) in the post-guideline group received off-label emicizumab prophylaxis for a median of 8 weeks, with no breakthrough bleeding or thrombotic events reported. Immunosuppressive strategies shifted in line with guideline recommendations. Corticosteroid monotherapy became more common (42% post-guideline vs. 20% pre-guideline, p=0.009), particularly in patients with favorable risk profiles (FVIII >1%, inhibitor <20 BU), who represented approximately 40% of the total cohort. Combination regimens with cyclophosphamide remained the most widely used (43%), and rituximab was employed in about 16% of cases. Median time to complete remission was 42 days (IQR 25–87), and similar across cohorts, indicating stable efficacy across evolving regimens. Despite these advances, infection remained the predominant cause of death, accounting for 58% of deaths in the post-guideline group compared to 49% previously. Bleeding-related mortality remained low overall (3.5%) but significantly higher among patients receiving corticosteroid monotherapy (8.1%) compared to those on combination regimens (1.2%, p=0.010), especially in patients with high inhibitor titers (>20 BU). No thrombotic complications related to bypassing agents or emicizumab were recorded. Cox multivariable analysis identified baseline inhibitor >20 BU (HR 2.9, 95% CI 1.4–6.1) and active malignancy (HR 2.4, 95% CI 1.1–5.3) as independent predictors of mortality.

Conclusions: The implementation of international guidelines for AHA in Spain has significantly improved diagnostic timelines and measurable shifts in therapeutic practice. An increase in rFVIIa, cautious Introduction: of emicizumab, and expanded use of corticosteroid in monotherapy reflect growing alignment with evidence-based standards. However, persistent mortality due to infections and increased bleeding risk in high-risk patients receiving monotherapy underscore the ongoing need for improved risk stratification, standardized infection prevention, and individualized immunosuppressive strategies. National registry data remain critical in capturing real-world outcomes and guiding future research and policy in rare bleeding disorders.

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Abstract Number: 4317

Low dose AAV8-FVIII gene therapy on Chinese severe Hemophilia A patients with sustainable efficacy and safety

Presenter: Xinyue Dai
Session: 801. Gene Therapies: Poster II

Abstract: Introduction: Hemophilia A is an X-linked (F Ⅷ gene mutation) disorder of hemostasis that results in insufficient endogenous factor VIII activity. GS1191-0445 is constructed with wild-type AAV8 and an optimized liver- specific expression cassette to express B domain-deleted factor Ⅷ (F Ⅷ BDD-V3). An investigator- initiated trial (IIT) (NCT04728841) and a phase Ⅰ / Ⅱ trial (CTR20231730) of GS1191-0445 have been conducted in Chinese patients with severe Hemophilia A to evaluate long-term efficacy and safety. Method: Method: Nineteen adults with severe Hemophilia A (factor Ⅷ level ≤1%) have been recruited and injected with a single treatment of AAV8-hF Ⅷ infusion. There were three dose cohorts from both studies. In the first in human IIT study, the first 6 participants have been injected a low dose of 2×10 12 vector genomes (vg) per kilogram of body weight, then escalated to the high dose of 4×10 12 vg/kg in next 6-participant cohort. In phase Ⅰ / Ⅱ trial, 7 participants have been recruited and infused with a middle dose of 3×10 12 vg/kg. Two immunosuppressive regimens, prophylactic prednisone or prednisone plus tacrolimus, can be selected to control the potential AAV capsid immune response from the 7-day prior to study drug infusion to at least 12 weeks post study drug administration. Trial objectives included the evaluation of the safety, efficacy of GS1191-0445, as well as the expression and durability of factor Ⅷ maintained in a bleeding prophylaxis level.

Results: In the 12 participants of IIT study, the factor Ⅷ activity increased rapidly within the first week, and the factor Ⅷ expression was sustained. The initial peak factor Ⅷ activity occurred 6 to 8 weeks after GS1191- 0445 administration. The low dose cohort of 6-participant injected with 2×10 12 vg/kg had been followed up to 2.5 years, and the factor Ⅷ activity detected with one-stage assay was maintained as 14% (range: 0.5%-46.9%). The high dose 6-participant group of 4×10 12 vg/kg had been observed for 1.5 years, and ahigh level factor Ⅷ activity were durable over time (mean: 60.1%, range: 44.9%-110.1%). Compared with the low dose group, six participants high dose cohort had a significantly 99.2% reduction in the annualized bleeding rate (13.0 bleeding events per year [range: 8.0 to 20.0] before administration vs. 0.11 bleeding events per year [range: 0 to 0.7] after injection). In the phase Ⅰ / Ⅱ trial, a middle dose as 3×10 12 vg/kg was chosen to treat on 7 participants. At the end of 52-week, the factor Ⅷ activity can be achieved to a high level as 77.0% (range: 5.9%-324.2%), and the annualized bleeding rate reduced a lot to99.1%, from 15.0 bleeding events at baseline to 0.14 bleeding events 52 weeks post infusion. In all three cohorts, a total of 129 treatment-related adverse events (TRAE) occurred in 18 participants. The most common TRAE were mild ALT increase as CTCAE 1-2 grade (11/19, 57.9%). No Grade ≥3 treatment-emergent adverse events (TEAEs) were observed. SAE were reported in 5 participants (1 in 2×10 12 cohort, 2 in 4×10 12 cohort, and 2 in 3×10 12 cohort). Three participants occurred GS1191-0445 related SAE. Two participants in 4×10 12 cohort experienced increased factor Ⅷ (grade 1-2). One of them uses Nadroparin calcium injection and Aspirin enteric-coated tablets to prevent blood clots. The other one did not take any action. No factor Ⅷ inhibitor development, thrombosis, persistent elevation in liver enzyme were observed. No spontaneous bleeding except low dose.

Conclusion: Gene therapy with AAV8-hFVIII vector in Chinese patients with Hemophilia A demonstrated a good safety profile and sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor Ⅷ use in participants who had received 3×10 12 vg/kg or 4×10 12 vg/kg. The factor Ⅷ activity of 2×10 12 vg/kg cohort was not as good as the other two cohorts due to the lower dose. No major safety concerns were reported.

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Abstract Number: 4472

Real-world use of prophylaxis in people with non-severe hemophilia in the United States: Insights from the athn transcends Study - hemophilia natural history arm

Presenter: Fernando Corrales-Medina
Session: 905. Outcomes Research: Non-Malignant Conditions Excluding Hemoglobinopathies: Poster II

Abstract: Introduction: People with mild to moderate hemophilia are frequently underrepresented in clinical trials and registries, leading to gaps in evidence-based guidance. While early prophylaxis is standard in severe hemophilia, treatment approaches for non-severe disease remain inconsistent. This is often driven by the misconception that prophylaxis is appropriate only for individuals with residual factor ≤ 2%, despite increasing evidence of recurrent bleeds in non-severe cases. Heterogeneous bleeding phenotypes, evolving patient preferences, and provider uncertainty further contribute to this variation. Real-world data describing the use, selection, and safety of prophylaxis are essential to improving care for this population.

Methods: ATHN Transcends (NCT04398628) is a prospective, longitudinal, cohort study conducted at over 60 ATHN-affiliated sites across the United States. The Hemophilia Natural History Arm captures safety and effectiveness of hemophilia therapies including clinical and participant-reported outcomes. This analysis includes demographic and baseline clinical data for participants with mild (residual levels 6- <40%) or moderate (residual levels 1-5%) Hemophilia A (HA) or Hemophilia B (HB) enrolled participants from March 2021 to April 2025.

Results: A total of 158 participants were included: 110 with HA and 48 with HB. Participants with HA, 50 had moderate disease (mean FVIII 3.1% (1.4), median 3.0%) and 60 had mild disease (mean FVIII 18.1% (11.5), median 14.0%). Participants with HB, 26 had moderate disease (mean FIX 2.4% (1.0), median 2.0%) and 22 had mild disease (mean FIX 7.6% (10.4), median 15.5%). The mean age at enrollment was 16.4 years (min=0, max=78) for moderate HA and 29.4 years (2, 86) for mild HA. For HB, the mean age was 28.6 years (0, 71) for moderate and 18.7 years (2, 55) for mild disease. Females accounted for 13 (21.7%) of mild HA and 6 (27.3%) of mild HB participants; no females with moderate disease were enrolled. A target joint was reported in 6 (12%) of moderate HA, 4 (15.4%) of moderate HB, and 5 (8.3%) of mild HA participants. The mean age at first bleed was earlier in moderate compared to mild participants: 2.1 years (3.9) vs. 6.4 years (9.4) in HA, and 3.3 years (5.0) vs. 7.4 years (8.5) in HB. For HA participants, the head was the most reported site of first bleeding in both moderate and mild cases. In contrast, the most frequent site of first bleed for HB participants was the mouth. At enrollment, 58% of moderate HA and 37% of moderate HB participants reported use of continuous prophylaxis. In mild participants, 21.8% of HA and 15.8% of HB were also receiving prophylaxis. Short-term/intermittent prophylaxis was reported in 2% and 4.2% of moderate HA and HB, and in 7.3% and 10.5% of mild HA and HB, respectively. Females with mild HA, 2 (15%) reported continuous prophylaxis use. Among HA participants, emicizumab was the most used prophylactic agent (82.8% in moderate, 50.0% in mild), followed by standard half-life (SHL) recombinant FVIII concentrates in moderate HA (6.9%) and ultra-extended half-life (UEHL) FVIII concentrates for mild HA (21.4%). Most emicizumab users reported SHL concentrates as their as-needed therapy (41.9% in moderate, 58.3% in mild HA). The 2 females with mild HA on prophylaxis, one reported use of SHL and the other UEHL recombinant FVIII concentrates. In HB, extended half-life (EHL) recombinant factor IX concentrates were the most used prophylactic agents (77.8% in moderate, 60.0% in mild).

Conclusions: In this analysis, we demonstrate that over one third of ATHN Transcends participants with non-severe hemophilia were already receiving continuous prophylaxis, including a significant subset with mild disease. Prior publications reported prophylaxis use in fewer than one-third of moderate and under 30% of mild cases*. This shift reflects growing recognition that bleeding risk may not correlate with factor levels and supports a phenotype-driven approach to care. Our findings also highlight the role of emicizumab in HA, while HB patients still rely on FIX concentrates for prophylaxis. Ongoing follow-up will determine whether treatment patterns and adoption of newer hemostatic agents continue to evolve. These findings underscore the need to revisit prophylaxis guidelines and reinforce the importance of real-world data in shaping evidence-based, personalized care in non-severe hemophilia. *Iorio A, et al. Haemophilia. 2023 Jan;29(1):33-44.

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Abstract Number: 4838

Characterization of participants with elevated bleeding rates responding to prophylactic marstacimab treatment in the phase 3 BASIS trial

Presenter: Pascal Klaus
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Background: Background: Marstacimab, a monoclonal antibody targeting tissue factor pathway inhibitor to reduce inhibition of the extrinsic coagulation pathway and rebalance hemostasis, is approved for prophylaxis in patients with hemophilia A (HA) or B (HB) without inhibitors. The phase 3 BASIS study (NCT03938792) demonstrated marstacimab was effective in reducing treated annualized bleeding rate (ABR) vs prior on-demand (OD) or routine prophylaxis (RP) therapy in participants (pts) with severe HA (FVIII <1%) or moderately severe to severe HB (FIX ≤2%) without inhibitors. Marstacimab was generally well tolerated with no unanticipated side effects. However, some pts had high ABRs during marstacimab treatment that deviated from the overall study population. Understanding factors that influence responder outcomes is crucial for personalized treatment and effective management of hemophilia. We aimed to identify prognostic factors for pts with elevated ABRs in BASIS.

Methods: Eligible pts were male, aged ≥12 to <75 years with severe HA or moderately severe to severe HB with or without inhibitors. Results are reported for the noninhibitor cohort. Pts entered a 6-month observational phase (OP) and received prescribed factor replacement therapy (OD or RP) before receiving a single subcutaneous (SC) dose of 300 mg marstacimab (2×150 mg) followed by 150 mg SC once weekly (QW) in the 12-month active treatment phase (ATP). Dose escalation to 300 mg was allowed per investigator’s discretion after Day 180 for pts who met protocol-specified criteria based on breakthrough bleeding. After completing the ATP, pts could enroll in the open-label extension (OLE) study (NCT05145127). Pts with elevated ABRs were identified based on the data distribution of ABR in the ATP from all pts (OD+RP); pts with an ABR in the ATP greater than the mean ABR+1.5× interquartile range (ie, ABR >12) were assessed. Prognostic factors evaluated for an elevated ABR were age, region, hemophilic arthropathy, baseline hemophilia joint health score (HJHS) total score and number of target joints at baseline. Descriptive data are presented.

Results: In all, 116 pts received marstacimab in the ATP. Model-based mean ABR (95% CI) decreased from the OP to the ATP in OD and RP groups (OD: 39.9 [33.1-48.1] vs 3.2 [2.1-4.9]; RP: 7.9 [5.1-10.7] vs 5.1 [3.4-6.8]). Overall, 12 pts (OD: n=1; RP: n=11; HA: n=10; HB: n=2) with an ABR >12 in the ATP were identified. At baseline, most (n=11; 92%) pts were aged >18 y (5 [42%] ≥45 y), 6 (50%) pts were Asian and 6 (50%) were White. Most (n=11; 92%) had ≥1 target joint (≥3 target joints: n=5, 42%) and 8 (67%) had hemophilic arthropathy. Compared with the lower ABR group (ABR ≤12), the group with elevated ABRs (ABR >12) was comprised of a higher percentage of adults (OD: 100% vs 93.8%; RP: 90.9% vs 77.8%), a higher percentage with hemophilic arthropathy (OD: 100% vs 50%; RP: 63.6% vs 54.2%), a higher mean HJHS total score indicative of worse joint health (OD: 29.0 vs 21.0; RP: 22.7 vs 16.8), more target joints at baseline (pts with ≥3 target joints: OD: 100.0 vs 34.4; RP: 36.4 vs 12.5) and a greater proportion of RP pts from Asia (OD: 0% vs 65.6%; RP: 54.5% vs 33.3%). Although these pts had a higher ABR during the ATP (range 13.8-35.5) vs the lower ABR group (range 0.0-11.2), 41.7% (n=5/12) had a mean decrease in ABR of 55.4% (SD 28.1) vs the OP. Of the pts with an elevated ABR, 5 (42%) dose-escalated to marstacimab 300 mg SC QW; ABR decreased in all pts after dose escalation (range 0.0-10.1). Neutralizing antibodies were detected in 1 pt at Day 60; titers were transient and resolved by Day 180. Eight (67%) pts with an elevated ABR continued into the OLE (3 discontinued early, 1 chose not to enroll) and continued ABR improvements were observed in 7 (88%) pts. Conclusions Conclusions Twelve pts had an ABR >12 during the ATP. The sample size precludes definitive conclusions on prognostic factors but variables associated with an elevated ABR included older age, residence in Asia, hemophilic arthropathy, higher baseline HJHS total score and baseline target joints. Worse joint disease correlated with a higher ABR. However, most pts with an elevated ABR showed ABR reductions during the ATP or OLE, suggesting these pts still responded to marstacimab. Dose escalation to marstacimab 300 mg SC QW led to reduced ABR in all pts with an elevated ABR who escalated, suggesting this may be an option for select pts.

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Abstract Number: 4839

Exploratory analysis from HAVEN 1–4 to further contextualize injection-site reactions among people with hemophilia A receiving emicizumab

Presenter: Shannon Carpenter
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Background: Long-term data with subcutaneous emicizumab prophylaxis in people with hemophilia A (PwHA) with or without factor (F)VIII inhibitors indicated low bleed rates and that emicizumab was well tolerated across the Phase III HAVEN 1–4 clinical studies (NCT02622321/NCT02795767/NCT02847637/NCT03020160; Callaghan et al. Blood 2021). Over a median emicizumab duration of 130.3 weeks (range: 3.4–221.1), the most common treatment-related adverse events were injection-site reactions (ISRs). Almost all were mild and occurred during the first 24 weeks, with the proportion of participants with ISRs declining over time to <1% of the safety population. This exploratory analysis further contextualizes ISRs across HAVEN 1–4, informing on the tolerability of emicizumab injections.

Methods: This analysis includes PwHA who received emicizumab in the HAVEN 1–4 clinical studies. The study populations in the four Phase III studies included PwHA ≥12 years old with FVIII inhibitors (HAVEN 1 and 4), PwHA ≥12 years old without FVIII inhibitors (HAVEN 3 and 4), and PwHA <12 years old with FVIII inhibitors (HAVEN 2). Maintenance doses of emicizumab in the studies included 1.5mg/kg once weekly (HAVEN 1, 2, and 3), 3.0mg/kg every 2 weeks (HAVEN 2 and 3), or 6.0mg/kg every 4 weeks (HAVEN 2 and 4). The schedule of clinic visits during the HAVEN 1–4 studies was identical across the studies until Week 49 (HAVEN 2) or Week 73 (HAVEN 1, 3 and 4); following this, the schedule of follow-up visits was similar across the studies, with clinic visits every 12 weeks (HAVEN 1, 2 and 4) or every 24 weeks (HAVEN 3). Exploratory outcomes were assessed in the total safety population, and included the proportion of participants with ISRs over 24-week intervals, and the proportion of total emicizumab injections associated with an ISR (total ISRs divided by [mean number of doses per participant multiplied by the number of treated participants]). ISR events considered here are those reported as localized ISR with associated symptoms.

Results: The safety population totaled 399 PwHA, including 132 participants (33.1%) aged <18 years old. The median emicizumab duration was 130.3 weeks (range: 3.4–221.1), and 389 participants (97.5%) had a duration >52 weeks. A total of 112 participants (28.1%) had ≥1 ISR. In the overall population, the median number of ISRs per participant was 0 (range: 0–23). The proportion of participants with ISRs declined over time from 23.3% in the first 24 weeks, 4.8% at 25–48 weeks, 2.5% at 49–72 weeks, 1.3% at 73–96 weeks, and <1% thereafter. In total, 317 ISRs occurred out of over 42,000 injections, reflecting that 0.75% of injections were associated with a reported ISR. When split by study, the percentage of ISRs by total injections was 0.42% in HAVEN 1, 0.98% in HAVEN 2, 0.65% in HAVEN 3, and 3.29% in HAVEN 4. No participant discontinued emicizumab because of an ISR. The top three most common recorded symptoms associated with ISRs were: erythema, occurring in 52 participants (46.4% of the total 112 participants with an ISR); pain, occurring in 18 participants (16.1%); and swelling, which occurred in 16 participants (14.3%). Type and incidence of symptoms associated with ISR were similar irrespective of emicizumab dosing regimen. Symptoms associated with ISRs trended down over time intervals across all four clinical studies and across all emicizumab dosing regimens.

Conclusions: These data in PwHA receiving emicizumab prophylaxis across the four Phase III HAVEN 1–4 clinical studies show that the proportion of participants that experienced ISRs declined over time to <1%, with 0.75% of over 42,000 injections being associated with an ISR. However, it is important to acknowledge that changes in visit schedules beyond the main phase of the studies may introduce a reporting bias. The results from this analysis expand our understanding of the tolerability of emicizumab injections in PwHA.

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Abstract Number: 4840

Real-world outcomes of PK/PD-guided individualized emicizumab dose reduction in Chinese pediatric patients with hemophilia A: A prospective observational study

Presenter: Qianqian Mao
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Background: Background: Emicizumab has markedly improved bleed prevention in hemophilia A, but its high cost remains a challenge, especially in resource-constrained settings. Many regions are now exploring dose reduction strategies to alleviate financial burden. However, empirical dose minimization without clear guidance may risk inadequate hemostatic protection and breakthrough bleeding. While standard weight-based dosing ensures efficacy, a personalized, pharmacokinetic/pharmacodynamic (PK/PD)-guided dosing strategy may reduce treatment burden without compromising bleed protection. Evidence supporting such individualized approaches in real-world remains limited. Objective Objective This study aimed to evaluate the feasibility, safety, and preliminary effectiveness of PK/PD-guided emicizumab dose reduction in Chinese pediatric patients with hemophilia A, following an initial period of standard prophylaxis.

Methods: This was a prospective, single-center observational study conducted in a real-world clinical setting. Children under 18 years of age with severe congenital hemophilia A, either with or without FVIII inhibitors, who had received standard emicizumab prophylaxis for at least 12 months, were enrolled. After this observation period, patients and their caregivers were offered the option to transition to a reduced dosing regimen guided by individualized PK and PD targets. Emicizumab concentrations were measured using a modified one-stage clotting assay, and FVIII- equivalent activity was assessed using a chromogenic assay (HYPHEN). Individual pharmacokinetic parameters were estimated based on the population PK model by Retout et al. ( Clin Pharmacokinet. 2020). The dose adjustment aimed to maintain FVIII-equivalent activity between 10–15 IU/dL and emicizumab trough concentrations above 30 μg/mL (±10 μg/mL). Patients were prospectively followed for a minimum of 6 months after dose reduction, with systematic monitoring for bleeding events, thrombotic complications, and treatment-related adverse events.

Results: A total of 46 patients were enrolled in the study. Among them, 15 patients transitioned to the PK/PD- guided Individualized dose reduction strategy after completing 12 months of standard emicizumab therapy. The median age of this subgroup was 2.0 years, with a range from 0.9 to 16.3 years. Of the 15 patients, 13 were negative for FVIII inhibitors, 2 had a history of inhibitors. The median monthly emicizumab dose was reduced from 5.4 mg/kg (range: 3.2–6.2) to 3.2 mg/kg (range: 2.6–4.0). Correspondingly, the median trough concentration decreased from 48.5 μg/mL (range: 36.5– 68.7) to 32.1 μg/mL (range: 27.0–38.4). Despite the dose reduction, FVIII-equivalent activity remained within the target range in most patients, with a median of 12.3 IU/dL (range: 12.0–18.5). Throughout the 6-month follow-up under reduced dosing, no bleeding events, thrombotic complications, or treatment-related adverse events were observed. In addition, joint ultrasound assessments performed before and after dose adjustment showed no evidence of new or progressive damage, suggesting preserved joint health throughout the reduced dosing period.

Conclusion: This prospective real-world study demonstrates that emicizumab dose reduction guided by PK/PD targets is feasible, safe, and effective in pediatric patients with hemophilia A after an initial period of standard prophylaxis. The individualized approach maintained excellent bleed protection while substantially reducing drug exposure. These findings highlight the potential of PK/PD-guided dosing to improve access and cost-efficiency of emicizumab in settings where treatment affordability is a concern. Larger-scale, multi-center studies with extended follow-up are needed to confirm these promising results and support broader adoption of this strategy.

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Abstract Number: 4844

Long term effect of marstacimab prophylaxis in hemophilia Α and Β on target joints: Results from BASIS and OLE studies

Presenter: Johnny Mahlangu
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Background: Marstacimab is a tissue factor pathway inhibitor (TFPI) antagonist recently approved for prophylactic treatment of hemophilia A (HA) and hemophilia B (HB) in people without inhibitors. In the phase 3 BASIS trial (NCT03938792) and its open-label extension (OLE) study, marstacimab was well tolerated, with high efficacy in bleed prevention. The majority of participants in the BASIS trial presented with a severe bleeding phenotype with a high number of target joints (TJs) at the time of study entry. We report on the impact of marstacimab on TJ outcomes.

Methods: BASIS enrolled males aged ≥12 to <75 years with severe HA (factor VIII [FVIII] <1%) or moderately severe to severe HB (factor IX [FIX] ≤2%) who were receiving on-demand (OD) or routine prophylaxis (RP) treatment. Following a 6-month observational phase (OP), participants entered a 12- month active treatment phase (ATP) and received a single loading dose of marstacimab 300 mg subcutaneous (SC), followed by marstacimab 150 mg SC once weekly (dose escalation to 300 mg was allowed after Day 180 per investigator’s discretion), which was continued in the OLE. TJs were defined by the International Society on Thrombosis and Hemostasis as in those experiencing ≥3 spontaneous bleeds within a consecutive 6-month period. A TJ was considered resolved if it had ≤2 bleeds in a consecutive 12- month period.

Results: : 116 participants without inhibitors (n=33 OD, n=83 RP) entered the BASIS ATP. Of these, 107 (n=32 OD, n=75 RP) completed an additional 12 months in the OLE as of the April 2024 data cutoff. In total at ATP baseline, 80/116 participants (n=33 OD, n=47 RP) had ≥1 TJ and 25 had ≥3 TJs; 58/80 (72.5%) of participants with ≥1 TJ were <45 years old. There were 181 TJs (79 OD; 102 RP); the most frequent locations were knees (65), ankles (52), and elbows (48). Among OD participants with 1, 2, and ≥3 TJ, respectively, at baseline, the mean (SD) [median (Q1, Q3)] ABR of treated bleeds (any location) during OP was 26.15 (16.42) [23.19 (18.47, 36.31)], 42.32 (22.23 [40.37 (20.29, 57.17)], and 44.41 (23.52) [41.95 (24.65, 65.10)], and decreased during ATP to 1.01 (1.53) [0.00 (0.00, 2.03)], 3.88 (3.56) [2.03 (1.50, 6.10)], and 3.71 (5.0) [2.02 (0.00, 5.54)]. Among RP participants with 0, 1, 2, and ≥3 TJ, respectively, at baseline, mean (SD) [median (Q1, Q3)] ABR of treated bleeds (any location) during OP was 4.44 (6.75) [1.94 (0.00, 6.77)], 10.73 (16.44) [3.84 (0.00, 12.59)], 9.68 (13.74) [3.95 (0.00, 18.06)], and 11.49 (17.80) [4.35 (0.00, 11.78)] and during ATP was 2.69 (4.36) [1.01 (0.00, 3.05)], 4.68 (7.85) [1.01 (0.00, 5.09)], 7.39 (10.11) [5.04 (0.00, 7.10)], and 10.24 (11.06) [4.73 (2.32, 13.78)]. A total of 155/181 (85.6%; 73 OD, 82 RP) TJs resolved in the ATP. The mean (SD) [median (Q1, Q3)] ABR of treated TJ bleeds from baseline to ATP and OLE, respectively, was consistently and progressively reduced; OD: 23.20 (20.52) [15.63 (5.83, 35.28)], 1.82 (2.90) [1.01 (0.00, 2.02)], 1.16 (1.94) [0.51 (0.00, 1.65)], and RP: 3.38 (8.32) [0.00 (0.00, 1.97)], 2.29 (5.52) [0.00 (0.00, 1.38)], 1.40 (5.03) [0.00 (0.00, 0.69)]. The mean (SD) [median (Q1, Q3)] ABR of treated TJ bleeds from baseline to ATP and OLE, respectively, also progressively decreased when analyzed by hemophilia type: 10.09 (16.90) [0.00 (0.00, 12.41)], 2.37 (5.42) [0.00 (0.00, 2.00)] and 1.50 (4.84) [0.00 (0.00, 1.24)] for HA and 5.12 (9.67) [0.00 (0.00, 5.83)], 1.36 (2.15) [0.00 (0.00, 3.04)], and 0.73 (1.57) [0.00 (0.00, 0.75)] for HB. Resolution of ≥1 TJ occurred in 73/80 (91.3%) participants (n=32/33 OD, n=41/47 RP) during the ATP and in 68/72 (94.4%) participants (n=31/32 OD, n=37/75 RP) in the OLE. In the ATP and OLE, resolution of all TJs occurred in 23/26 (88.5%) and 19/22 (86.4%) participants with 1 TJ at baseline, 20/29 (69.0%) and 22/26 (84.6%) participants with 2 TJs, and 19/25 (76.0%) and 21/24 (87.5%) participants with ≥3 TJs.

Conclusion: Marstacimab prophylaxis was generally safe and led to sustained and clinically meaningful reductions in TJ bleeding and high rates of joint resolution, even among patients with severe baseline joint involvement. These findings reinforce the long-term efficacy of marstacimab in people with severe HA or HB without inhibitors.

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Abstract Number: 4845

Outcomes of marstacimab treatment in adolescent participants with Hemophilia A or B without inhibitors compared with prior routine prophylaxis: Results from the phase 3 BASIS trial

Presenter: Anthony Chan
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Background: BASIS (NCT03938792) is an open-label, phase 3 trial of anti-tissue factor pathway inhibitor (TFPI) antibody marstacimab in adult and adolescent participants (pts) with severe hemophilia A (HA; factor VIII <1%) or moderately severe to severe hemophilia B (HB; factor IX ≤2%) with or without inhibitors. Across all pts without inhibitors, marstacimab significantly reduced the annualized bleeding rate (ABR) of treated bleeds compared with prior on-demand (OD) or routine prophylaxis (RP) factor replacement therapy. We report outcomes in adolescent pts without inhibitors who received prior RP.

Methods: Screened male adolescents without inhibitors completed a 6-month observational phase (OP) on RP or OD therapy before receiving a single subcutaneous (SC) loading dose of 300 mg marstacimab followed by 150 mg once weekly (QW) in the 12-month active-treatment phase (ATP). After Day 180, pts meeting prespecified dose escalation criteria (weight ≥50 kg, ≥2 spontaneous bleeds requiring treatment in 6 months) could increase their dose to 300 mg QW. Efficacy assessments included ABRs of treated bleeds and specific bleed types. Safety (including incidence and severity of adverse events [AEs] and immunogenicity) and pharmacokinetic (PK)/pharmacodynamic (PD) parameters were also assessed.

Results: : As of April 2023, 18 adolescent pts aged ≥12 to <18 years with HA (n=13) or HB (n=5) without inhibitors entered the OP and received RP before entering the ATP (data from OD pts [n=2] not reported). One pt (administered 1 dose of marstacimab in the ATP) was later excluded from analyses due to termination of study site. Most pts were from Europe (50.0%), predominately Turkey (38.9%). At baseline, 5 pts (27.8%) had ≥1 target joint. A numerical reduction in mean ABR of treated bleeds was observed with marstacimab in the ATP vs RP in the OP (2.98 vs 3.36, n=17; compared with 5.74 vs 9.11 in adults, n=66). Mean (median) ABR during the ATP was 1.63 (0.00) for joint bleeds, 0.75 (0.00) for spontaneous bleeds, 0.00 (0.00) for target joint bleeds, and 3.39 (0.00) for total (treated and untreated) bleeds. The median ABR of treated bleeds in the ATP was 0.00, with significant variability in pts with HB (n=4). Two pts with HB had 0 treated bleeds; 2 pts had ABRs of 19.48 and 11.10 (majority traumatic bleeds). Mean (SD) annualized total factor consumption unrelated to bleeding events also decreased in the ATP vs the OP: 20 (80) vs 3308 (1063) IU/kg, n=17. In all, 36 AEs were reported in 14/17 pts (82.4%) during the ATP vs 11 AEs in 7/18 pts (38.9%) in the OP. Treatment-related AEs were reported in 4 pts, all related to injection site (erythema, edema, and swelling [n=1 each]; pruritus [n=2]). One serious AE of tympanic membrane perforation was reported in 1 pt in the ATP who temporarily discontinued treatment 10 days prior to tympanoplasty/ear tube insertion. Preventative factor replacement therapy was given peri and post operatively, and the pt resumed treatment 6 days post procedure. One other pt temporarily discontinued treatment due to an AE of COVID-19. No deaths, study discontinuations, or thromboembolic events were recorded. Two pts had their dose increased to 300 mg QW; neither reported any AEs post dose escalation. Antidrug antibodies developed in 2/17 pts, 1 of whom was also positive for neutralizing antibodies, transient in nature. Marstacimab plasma levels were ~2 to 2.5-fold higher in adolescents vs adults. For pts receiving 150 mg QW marstacimab, median steady-state plasma concentrations were ~25,000–30,000 ng/mL in adolescents vs ~10,000–11,000 ng/mL in adults. Population PK analysis found marstacimab clearance (CL) was 29% lower in adolescents vs adults; weight-adjusted CL was 3% lower in adolescents, indicating weight accounted for most of the CL differences. In general, no clinically relevant differences were seen in steady-state median ranges of PD endpoints following 150 mg QW marstacimab in adolescents (n=17) vs adults (n=85): peak thrombin, 41–54 vs 63–66 nM; prothrombin fragment 1+2, 557–874 vs 492–579 pmoL/L; D-dimer, 0.3–0.4 vs 0.3 μg/mL; total TFPI, 389–495 vs 268–283 ng/mL.

Conclusion: Compared with previous RP therapy, SC QW marstacimab reduced bleeding in adolescent pts with HA or HB without inhibitors and was generally well tolerated. No clinically relevant differences in PD endpoints were observed compared with adults and PK differences were explained by weight.

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Abstract Number: 4846

Quality of life and functional improvements with efanesoctocog alfa in patients with moderate-to-severe Hemophilia A: A real-world survey

Presenter: Maissaa Janbain
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Background: Hemophilia A (HA) is a rare X-linked bleeding disorder characterized by deficiency or dysfunction of clotting factor VIII (FVIII), resulting in breakthrough bleeding that can cause joint damage and impair patients’ quality of life (QoL). Efanesoctocog alfa (Efa) is a first-in-class high-sustained FVIII replacement therapy designed to decouple FVIII from endogenous von Willebrand factor to increase its half-life. It was approved in the United States (US) in February 2023 for once weekly prophylaxis of bleeds in patients with HA without inhibitors. Real-world data on patient experience with prophylactic Efa are emerging. Aim: To assess real-world, patient-reported experiences with prophylactic Efa in individuals with moderate-to-severe HA without inhibitors. Methods: This study used data from the Adelphi Real World Hemophilia Patient Survey, a cross-sectional survey of people with HA receiving Efa, collected between December 2024 and February 2025. Eligible participants were adult males (≥18 years) in the US with moderate-to-severe HA (based on baseline clotting factor levels), who had been receiving Efa prophylaxis for ≥6 months at the time of survey completion. The survey captured patient demographics, clinical and humanistic burden, treatment satisfaction, and treatment patterns. Descriptive analyses were used for continuous and categorical variables. Where applicable, symmetry tests or McNemar tests were used to compare outcomes before and after initiating Efa (significance threshold: p<0.05). Results: Thirty-one patients were included. The mean (SD) patient age was 40.2 (15.5) years, and the mean (SD) body mass index was 28.3 (6.8) kg/m². Most patients were White (80.6%), worked full-time (61.3%), commercially insured (54.8%), and had severe HA (74.2%). The majority (83.9%) of patients reported never having inhibitors. The most recent treatments prescribed prior to Efa were standard half- life products (64.5%), extended half-life products (45.2%), emicizumab (32.3%), and others (6.5%) (groups exceed 100% as multiple treatments were used either prophylactically or on-demand). The median (IQR) duration of Efa use was 388.0 (266.0–557.0) days, and the mean (SD) proportion of doses reportedly taken as prescribed was 95.0% (7.3%). Most patients reported being “completely satisfied” or “satisfied” with Efa in terms of overall experience (93.5%), bleed prevention (96.8%), and improvement in patients’ ability to perform physical activity (79.3%) (n=29). When comparing Efa to prior therapies for hemophilia control, 83.9% rated it as better, 9.7% as comparable, and 6.5% as worse. After Efa initiation, relative improvements were observed in daily functioning and physical activity. A greater proportion of patients reported no difficulty with any activities of daily living after receiving Efa (51.6% pre- to 67.7% post-switch; p=0.1250). The proportion of patients reporting difficulty with walking decreased following switching (35.5% pre- to 16.1% post-switch; p=0.0312). The number of patients who often avoided physical activity was higher pre-switch than post switch; (38.7% pre to 16.1% post-switch; p=0.0186). Since starting Efa, a significantly higher proportion of patients reported no longer taking preventive measures (i.e., increasing the regular dose of prophylactic treatment, taking an extra dose of factor, or other), increasing from 19.4% pre- to 58.1% post-switch; p=0.0005. Although not statistically significant, fewer patients reported increasing their regular prophylactic doses or taking extra factor doses ahead of physical activity after switching (22.6% pre- to 6.5% post-switch; p=0.0625, and 32.3% pre- to 19.4% post-switch; p=0.1250, respectively). Conclusions: This is the first real-world, patient-reported outcomes study of prophylactic Efa use among patients with moderate-to-severe HA. Most patients rated Efa more favorably for hemophilia control compared to previous regimens. Improvements were observed in daily functioning, participation in physical activity, and a reduced need for preventive measures and additional prophylactic doses.

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Abstract Number: 4847

Assessment of coagulation potential of concomitant factor VIII administration in patients with haemophilia a receiving emicizumab prophylaxis (CAGUYAMA Study): A multicenter, open-label, non-randomized clinical trial

Presenter: Masahiro Takeyama
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Introduction: Emicizumab prophylaxis reduces bleeding in people with hemophilia A (PwHA), offering hemostatic activity equivalent to ~15% of normal factor VIII activity (FVIII:C) level. Thus, additional FVIII supplementation would be required at breakthrough bleeding or surgery. A standard dosage of FVIII product does not account for baseline coagulant potential of emicizumab, however. Aim Aim The CAGUYAMA study (jRCTs051210137) aimed to assess global coagulation function in PwHA without inhibitors receiving emicizumab and FVIII concomitantly, and to determine an appropriate FVIII dose for clinical management. Methods and Analyses Methods and Analyses The multicenter, open-label, non-randomized trial (CAGUYAMA study) enrolled 100 PwHA without inhibitors. Total 32 events involving FVIII administration (30±5 U/kg) for breakthrough bleeding or surgery were analyzed. Each event included blood sampling at pre and post FVIII administration. The primary endpoint was change in adjusted maximum coagulation rate (Ad|min1|) by clot waveform analysis (CWA). CWA was initiated by a diluted mixture of PT and APTT reagents (Nogami K. JTH 2018). The degree of improvement in maximum coagulation rate (IMCR%) was defined relative to healthy controls (100%) and untreated PwHA (0%). Secondary endpoints included clinical hemostatic assessment, thrombin generation assay (TGA), and rotational thromboelastometry (ROTEM; non-activated mode), performed with or without anti- emicizumab antibodies (anti-Emi-Ab) to isolate FVIII effects alone. TGA was evaluated using peak thrombin; ROTEM was evaluated using clotting time (CT) as primary outcome. Exploratory endpoints included correlation between emicizumab concentration and coagulation parameters.

Results: A total of 100 PwHA (mean age 31 years) from 13 institutions were enrolled (mean follow-up: 26.5 months). Among 32 events, 47% were bleeding episodes ( e.g. , joint, muscle, gastro-intestine) and 53% were surgeries ( e.g. , tooth extraction, synovectomy). Mean administered FVIII dose was 30.8±3.3 U/kg, yielding the FVIII:C of 77.1±20.4% and in vivo recovery of 2.5±0.7 %/U/kg. The IMCR% calculated by CWA increased from 39.4% (pre-FVIII) to 92.1% (post-FVIII). With the addition of anti-Emi-Abs, the IMCR% was 3.2% (pre-FVIII) and 78.6% (post-FVIII), indicating that calculated FVIII effect was 52.7% in the presence of emicizumab and 75.4% in its absence. All events achieved effective clinical hemostasis. In TGA triggered by ellagic acid and tissue factor, peak thrombin (IMCR%) by FVIII administration increased from 249 nM (55.4%; pre) to 348 nM (88.0%; post). With the addition of anti-Emi-Abs, the IMCR% was 6.4% (pre) and 74.6% (post), indicating that calculated FVIII effect was 32.6% in the presence of emicizumab and 68.2% in its absence. In addition, ROTEM analysis (11 events) revealed that the CT decreased from 1,190±169 s (pre) to 1,158±301 s (post) (control: 938±128 s). With the addition of anti-Emi-Abs, the CT was changed from 5,213±2,915 s to 1,459±447 s. At enrollment of this study, CWA and TGA confirmed emicizumab’s contribution to baseline hemostasis as follows; Ad|min1| decreased from 5.4 (37.2%) to 4.0 (0.9%) and peak thrombin from 238 nM (51.9%) to 92.7 nM (4.3%) by the addition of anti-Emi-Abs. Plasma emicizumab concentration was 51.2±17.8 µg/mL, and a moderate positive correlation was observed with baseline Ad|min1| in CWA (r=0.42), but not with peak thrombin in TGA (r=0.05), suggesting CWA seemed to better reflect emicizumab-driven hemostatic function. No abnormalities in platelets counts, coagulation or fibrinolysis laboratory markers were observed during the follow-up.

Conclusion: In PwHA receiving emicizumab prophylaxis, FVIII supplementation at 30±5 U/kg was safe and effective for breakthrough bleeding and surgical hemostasis. These findings could support clinical use of FVIII with consideration of emicizumab’s baseline effect.

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Abstract Number: 4848

Immunogenicity assessment of concizumab in patients with Hemophilia A and b: Assays developed to measure anti-drug antibodies and integrated results from clinical trials

Presenter: Thomas Porstmann
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Background: Background: Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody indicated for patients with hemophilia A/B with and without inhibitors, approved in the US, Europe and other countries for once-daily, subcutaneous prophylaxis in hemophilia A/B with inhibitors. Immunogenicity assessment of biological drugs during clinical trials is a regulatory requirement. It involves validated, multi-tiered assays for anti-drug antibody (ADA) detection and characterization in samples from patients treated with the trial drug. To further understand the efficacy and safety profile of the trial drug, immunogenicity results are subsequently analyzed for correlations with multiple endpoints. Aim Aim Here, we describe the binding ADA (bADA) and neutralizing antibody (nAb) assays developed to monitor immunogenicity during phase 2 and 3 (ph2/ph3) clinical trials on concizumab. In particular, we present nAb assay optimization and explore an integrated analysis method of bADA, pharmacokinetic (PK) and pharmacodynamic (PD) measures to investigate neutralizing ADAs.

Methods: The bADA assay consisted of a bridging format on the Meso Scale Discovery (MSD) platform, with an electrochemiluminescence endpoint. A tiered approach was used to test and further characterize samples: screening, confirmation, and characterization to assess specificity and titer. Different assay modalities were used to assess the in vitro neutralizing potential of ADAs throughout the concizumab ph2/ph3 clinical trials. During ph2, a colorimetric functional assay, based on the enzymatic activity of activated factor X, was used. During ph3, two different modalities of competitive ligand binding assays, based on nAbs preventing binding of concizumab to TFPI, were developed on the MSD platform. For both bADA and nAb assays, samples were pre-treated with acid or purified to overcome potential drug interference. To validate the assay, samples from drug-naïve individuals were used to set the assay cut- points. Control samples (negative: no concizumab reactivity; positive: different levels of Abs spiked into matrix) were used to monitor assay performance. During the ph2/3 clinical trials, ADA sampling was performed at baseline and at regular intervals after the first concizumab dose, together with samples taken for PK/PD (concizumab plasma concentration) endpoints.

Results: A robust bADA assay was validated during ph2/ph3 clinical development of concizumab, demonstrating high sensitivity (~1.0 ng/mL ADA) and drug-tolerance, ensuring that sample drug levels did not interfere with ADA detection. Performance parameters of the nAb assay were optimized, with the 3 rd generation of the nAb assay demonstrating improved sensitivity, drug tolerance, and run acceptance rate, compared to previous versions. The bADA and 3 rd generation nAb assay continue to be used in 3 ongoing ph3 trials. After completion of 2 ph2 trials and including the patients from the 2 ongoing ph3 trials, 71/320 (22.2%) patients exposed to concizumab developed bADAs, with 18/320 (5.6%) exhibiting ADAs with in vitro neutralizing effect. The ADA titer was low in all but 3 patients, with bADAs developing after 12 weeks into concizumab exposure in 2/3 patients. ADA responses were primarily directed against the complementarity-determining region of concizumab and were mostly transient. Overall, ADAs did not appear to have clinical impact on efficacy, safety or PK/PD, except in one patient with inconclusive impact on PK/PD.

Conclusion: bADA and nAb assays were successfully developed, validated and implemented to monitor concizumab immunogenicity during clinical development of concizumab, including the three ongoing ph3 trials. The assays meet regulatory requirements and allow a thorough characterization of ADA incidence, magnitude, onset, kinetics, specificity and in vitro neutralizing potential. To date, a favorable immunogenicity profile has been observed during the concizumab ph2/3 clinical trials with no apparent impact of ADAs on efficacy, safety or PK/PD using the validated bADA and nAb assays. Based on the presented integrated analysis of bADAs with PK/PD, the nAb assays may be considered redundant for the interpretation of overall immunogenicity findings.

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Abstract Number: 4850

Experience with minor surgeries in people with hemophilia A or B with and without inhibitors receiving fitusiran

Presenter: Steven Pipe
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Introduction: While t he number of approved non-factor hemophilia therapies is increasing, data regarding the perioperative management utilizing these therapeutics is limited. Fitusiran is an antithrombin (AT)- lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia (PwH) A/B, with or without inhibitors. For the management of perioperative hemostasis, bleed management guidelines (BMG) in which reduced doses and/or frequency of clotting factor concentrates (CFC) or bypassing agents (BPA) were implemented. In a previous analysis of 60 major surgeries in PwHA/B, hemostatic control on the day of the surgery was rated excellent/good in 39/41 (95%) cases with fitusiran prophylaxis. In this abstract, we describe the hemostatic outcomes of minor surgeries conducted while on fitusiran prophylaxis in PwHA/B aged ≥12 years, with or without inhibitors. Methods All minor surgeries in the fitusiran clinical development program until June 2023 (Phase 2 OLE [NCT02554773], Phase 3 ATLAS-INH [NCT03417102], ATLAS-A/B [NCT03417245], ATLAS-PPX [NCT03549871] and ATLAS-OLE [NCT03754790]) were evaluated, including participants on the original dose regimen (ODR; 80 mg fixed once monthly) and the antithrombin-based dose regimen (AT-DR; adjustable dose regimen with a starting dose of 50 mg once every two months, targeting AT activity levels of 15–35%). Informed consent and ethics committee approval were obtained for all studies. Procedures conducted during fitusiran prophylaxis and when AT activity was <60% were included. Minor surgeries were defined as any invasive operative procedure in which only skin, mucous membranes, or superficial connective tissue were manipulated and did not meet the criteria for major surgery. Perioperative hemostatic control was assessed by the investigators or surgeon based on the ISTH 4-point response scale (excellent/good/moderate/poor) on the day of the surgery. Perioperative use of antifibrinolytics was reported from the day of the surgery until Day 7 post surgery. Results In addition to the 60 major surgeries, a total of 71 minor surgeries were performed in 44 participants (HA with inhibitors, n=8; HB with inhibitors, n=12; HA without inhibitors, n=20; HB without inhibitors, n=4). Minor surgeries (n=71) included dental (n=21), soft tissue (n=12), abdominal (n=12), central or peripheral access-related (n=10), orthopedic (n=7), plastic/reconstructive (n=4), airway management and emergency (n=3), and ophthalmic (n=2) procedures. In total, 26 surgeries were performed in PwH with the ODR and 45 surgeries were performed in PwH with the AT-DR. Of the 22 surgeries with a hemostatic control assessment on the day of the surgery, 21 (95%) cases were rated as excellent/good and 1 (5%) case was rated as moderate. ATIII concentrate was not used to reverse the pharmacodynamic effect of fitusiran in 99% (n=70/71) of minor surgeries. A total of 67% (n=14/21) of dental surgeries and 87% (n=62/71) of all minor surgeries did not require the use of antifibrinolytics. In 18% (n=13/71) of minor surgeries, neither antifibrinolytics nor CFC/BPA were required. Median (range) duration of antifibrinolytic use was 4 (1–8) days. No major treatment-related safety concerns were identified perioperatively. Conclusions Minor surgeries can be safely and effectively conducted in patients receiving fitusiran prophylaxis, irrespective of inhibitor status. Excellent/good perioperative hemostatic control on the day of the surgery was achieved in 95% of minor surgeries in PwH, with or without inhibitors, receiving fitusiran prophylaxis. Reversal of the AT-lowering effect of fitusiran with ATIII concentrate was rarely performed in the reported minor surgeries and is not necessary. In total, 67% of dental surgeries and 87% of all minor surgeries were performed without the use of antifibrinolytics. Overall, these data contribute to the growing evidence base for the perioperative management of PwH receiving fitusiran prophylaxis.

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Abstract Number: 4851

Rates of inhibitor development and immune tolerance in children with severe Hemophilia A on emicizumab prophylaxis

Presenter: Anna Schwartz
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Introduction: Congenital hemophilia A (HA) is a genetically inherited bleeding disorder caused by pathologic variants in the F8 gene, resulting in absent or decreased levels of coagulation factor VIII (FVIII) protein and impairment of physiologic hemostasis. The absence of FVIII results in both trauma-induced and spontaneous bleeding in people with HA (PwHA), which can be life-threatening. Treatment or prevention of bleeding with exogenous FVIII protein infusions can lead to the development of neutralizing anti-FVIII antibodies (“inhibitors”), which render FVIII treatment ineffective. The use of emicizumab, a bispecific antibody which mimics the activity of FVIII, circumvents the need for FVIII prophylactic infusions. In real-world and clinical trial data, bleeding rates and FVIII infusion utilization have decreased in PwHA on emicizumab prophylaxis. Furthermore, historically PwHA with inhibitors were treated with immune tolerance induction (ITI) to eradicate FVIII inhibitors, however, the necessity of ITI in the era of emicizumab is an open question. The rates of inhibitor development and uptake of ITI in this current era of treatment are unknown. Objectives: This study aims to compare PwHA whose initial prophylactic regimen was FVIII compared to those receiving emicizumab as initial prophylaxis. The primary objective was to compare FVIII exposure days (EDs) and inhibitor development between PwHA on FVIII or emicizumab prophylaxis. The secondary objective is to understand the use of ITI treatment in PwHA on either treatment. Methods: A retrospective chart review was performed at the Children’s Healthcare of Atlanta (CHOA) Hemophilia Treatment Center under an IRB-approved protocol. PwHA born between 2014 and 2023 with severe disease were included. Demographic data and clinical data (hemophilia mutation as well as inhibitor, ITI, and FVIII ED history) were extracted from the clinical chart. Rates of inhibitor development and ITI usage were compared before and after licensure of emicizumab for all PwHA (2018). Results: A total of 53 males with severe Hemophilia A born between 2014 and 2023 were included in the study. Initial prophylaxis was FVIII in 30 (56.6%) and emicizumab in 23 (43.4%). The study population was 43.6% Black, 41.8% Caucasian, 3.6% Asian, 3.6% multiracial, 7.3% of unknown race, and 25.5% identified as Hispanic. There were no differences in race by initial prophylactic regimen or FVIII inhibitor status. A total of 22 participants developed inhibitors, 15 (68.8%) from the FVIII prophylaxis group and 7 (31.8%) from the emicizumab group. At data cutoff, the incidence of inhibitors was 50% in FVIII group compared to 30.4% in the emicizumab group (odds ratio 2.14, 95% CI 0.69-6.16) at median of 17 (range 3-90) versus 10 (range 4-15) FVIII EDs, respectively (p=0.032, t-test). The median cumulative FVIII EDs in the FVIII group was >150 (range 5 to > 150) and in the emicizumab group was 6 (range 2-112). Of note, 15/23 PwHA with emicizumab prescribed as their initial prophylactic regimen had FVIII exposures prior to emicizumab initiation with a median of 4 FVIII EDs (range 1-13). Consequently, the median age at ED1 was similar between the FVIII and emicizumab groups (9.5 vs 8.6 mo) but median age at ED5 was delayed in the emicizumab group (13.5 vs 17.8 mo, p = 0.011, Mantel-Cox time to event analysis). As expected, emicizumab delayed FVIII EDs as demonstrated by only 1/22 participants in the emicizumab group having surpassed ED20 compared to all 26/30 in the FVIII group (p<0.001, Fisher’s exact test) at the last data cutoff. The inhibitor rates in PwHA born before or after 2018 (emicizumab licensure year) were similar at 40.7% and 39.3%, respectively. The rate of ITI usage in PwHA with inhibitors has decreased from 76.9% before emicizumab licensure to 22.2% after. Conclusion: Our data suggest that FVIII inhibitor rates may be lower in PwHA initially started on emicizumab prophylaxis, though these PwHA may not have yet reached sufficient FVIII EDs. In addition, the elevated number of Black study participants adds critical data given racial disparities in research on inhibitor development. Ongoing analyses will include a comparison of the timing of FVIII EDs and inhibitor development in PwHA on emicizumab prophylaxis to determine if inhibitor rates upon reaching 50 FVIII EDs are different than for those on FVIII. Lastly, initiation of ITI appears to be decreased or delayed since the licensure of emicizumab.

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Abstract Number: 4853

Retrospective cohort analysis of treatment patterns and bleeding outcomes in the Korean bleeding disorder registry (KBDR)

Presenter: Jung Woo Han
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Poster III

Abstract: Background: Hemophilia is a rare congenital bleeding disorder characterized by the deficiency of clotting factors, which can lead to spontaneous bleeding and joint damage if left untreated. Understanding the real-world epidemiology and treatment patterns of hemophilia requires robust longitudinal data, especially in countries where such data have been limited. In response to this need, the Korean Bleeding Disorder Registry (KBDR) was established as the first comprehensive, nationwide registry for hemophilia and other bleeding disorders in Korea. This study presents the results from a retrospective cohort analysis derived from the KBDR, focusing on treatment patterns, prophylaxis utilization, bleeding events, and factor usage. Methods The KBDR was developed using iCReaT (Internet-based Clinical Research and Trial Management System), a government-supported clinical research infrastructure operated by the Korea National Institute of Health. The registry is designed as a hybrid retrospective and prospective observational platform. Seven major hemophilia treatment centers across Korea initially participated in data collection, with ongoing expansion to additional centers nationwide. All participating centers obtained Institutional Review Board (IRB) approval for registry participation and data sharing. From the registry population, we extracted retrospective clinical records between 2021 and 2023. Collected data included demographic characteristics, hemophilia type and severity, treatment modality (prophylaxis vs. on-demand), prescribed clotting factor regimens, and annualized bleeding rates (ABR), with a focus on joint and severe hemorrhages. Data were analyzed descriptively and stratified by disease severity and age group. Results As of 2023, a total of 2,908 unique patients had been registered in the KBDR: 2,028 with hemophilia A, 507 with hemophilia B, and 52 with hemophilia C. Among these, 1,423 patients had complete retrospective clinical records available for analysis: 1,088 with hemophilia A, 220 with hemophilia B, and 11 with hemophilia C. Among patients with hemophilia A, 72.1% received prophylactic treatment, while 70.0% of those with hemophilia B and 50.0% of those with factor VII deficiency were on prophylaxis. In patients with severe hemophilia A, the prophylaxis rate was 79.0%; in moderate hemophilia A, it was 62.8%. Among those with severe hemophilia B, 80.8% received prophylaxis compared to 56.6% in moderate cases. When stratified by age, 83.7% of patients under 20 years with severe hemophilia received prophylaxis, followed by 80.9% in the 20–40 age group. In hemophilia B, the highest prophylaxis rate (83.3%) was observed in the 20–40 age group, followed by 76.9% in those under 20. For those receiving standard half-life (SHL) factor VIII, the median annual number of infusions was 61.6, whereas patients receiving extended half-life (EHL) factor VIII had a median of 56 infusions per year. For factor IX, the median annual number of infusions was 51.9 for SHL and 11.9 for EHL. A total of 31 patients received emicizumab, with a median of 10.7 administrations annually. Joint bleeding outcomes were favorable: in patients with severe hemophilia A, the median number of annual joint bleeds was 0 (IQR: 0–10), with a mean of 13.6. In severe hemophilia B, the median was also 0 (IQR: 0–11.1), with a mean of 13.7. These findings suggest a relatively low frequency of joint bleeding among patients on prophylactic regimens. Conclusion The KBDR has enabled the first large-scale retrospective analysis of hemophilia treatment patterns in Korea. The data demonstrate a high rate of prophylaxis use, particularly in younger and more severely affected patients, and favorable bleeding control across the cohort. As the registry moves into its prospective phase, it is expected to provide further insights into long-term outcomes, optimize individualized treatment strategies, and ultimately improve the quality of life and clinical outcomes for people living with hemophilia in Korea.

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Abstract Number: 4854

Use of emicizumab in patients with acquired hemophilia A: An interim safety analysis of a large-scale post‑marketing surveillance study

Presenter: Tadashi Matsushita
Session: 323. Disorders of Coagulation, Bleeding, or Fibrinolysis, Excluding Congenital Hemophilias: Clinical and Epidemiological: Poster III

Abstract: Background: Acquired hemophilia A (AHA) is a rare autoimmune disorder in which autoantibodies neutralize coagulation factor VIII (FVIII), causing bleeding. Treatment focuses on bleeding control using bypassing agents and elimination of FVIII inhibitors via immunosuppressive therapy (IST). Emicizumab is a recombinant humanized bispecific monoclonal antibody that mimics activated FVIII (FVIIIa) by bridging FIXa and FX to promote hemostasis. Its safety and efficacy in congenital HA have been established. Following the Phase 3 AGEHA trial (Shima, JTH 2023), emicizumab was approved in Japan in 2022 for AHA. While strict discontinuation criteria for emicizumab are not defined, the manufacturer suggests considering it when FVIII activity exceeds 50 IU/dL, as in AGEHA. This post-marketing surveillance study aimed to monitor the safety of emicizumab, and indirectly assess its effectiveness, for patients with AHA in real-world clinical practice.

Methods: This ongoing observational study (UMIN000048156) includes a longitudinal series of patients with AHA treated with emicizumab from August 2022 to July 2025. This planned interim analysis was conducted after 50 patients completed the observation period. Each patient was followed from first emicizumab dose until 4 weeks after last administration, with a maximum observation period of 24 months. Inclusion criteria were confirmed AHA diagnosis and emicizumab treatment at one of 37 medical institutions. The primary endpoint was adverse events (AEs); if a causal relationship with emicizumab could not be ruled out, the event was classed as an adverse drug reaction (ADR).

Results: At the time of this interim analysis, 110 patients were enrolled in the study; 51 completed observation and are included here. Of these, 34 (66.7%) were male; median age was 76.0 years (range: 33–91). All 51 patients received IST, most commonly prednisolone monotherapy (n=29; 56.9%). Median initial prednisolone dose for AHA treatment, either as monotherapy or IST combination, was 0.93 mg/kg (mean [SD]: 0.79 [0.32] mg/kg). Median FVIII activity before emicizumab was 1.0 IU/dL (range: 0.0–15.0); at treatment end, it was 59.1 IU/dL (15.1–103.0). Median FVIII inhibitor titer decreased from 34.1 BU/mL (1.3–401.4) to 0.9 BU/mL (0.0–48.8). AEs occurred in 25 (49.0%) patients, totaling 63 events (45 serious), with infection the most common (n=10; 19.6%). One thromboembolism (cerebral infarction) was deemed unrelated to emicizumab by the investigator. Two ADRs were reported by investigators, both classed as serious: acute pyelonephritis and hemorrhoidal hemorrhage.Nine (17.6%) patients died during the observation period; causes of death were infection (n=4; 7.8%), hemorrhage (n=3; 5.9%), interstitial lung disease (recurrent lung cancer; n=1), and cholangiocarcinoma with liver metastases (n=1). Hemorrhage- related deaths included: upper gastrointestinal bleeding (treated with 23 doses of rFVIIa and red blood cell [RBC] and platelet transfusions), bladder hemorrhage (treated with 8 doses of rFVIIa and RBC transfusion), and gastric ulcer bleeding (treated with 1 dose of rFVIIa and RBC transfusion). All three patients, who had multiple comorbidities, received prednisolone monotherapy, but FVIII activity had not recovered. A causal relationship with emicizumab was ruled out in all deaths. During emicizumab treatment, 21/51 (41.2%) patients used rFVIIa, 9/51 (17.6%) had transfusions, and 7/51 (13.7%) received other hemostatic agents (FXIII, tranexamic acid). No patient received activated prothrombin complex concentrate or FVIIa/FX. Hemostatic treatment declined over time. Among 38 patients who did not receive rFVIIa in the first week after emicizumab initiation, 30/38 (78.9%) required no rFVIIa throughout the study, indicating prevention of new treated bleeds in almost 80% of cases. Of 301 rFVIIa doses administered following initiation of emicizumab, 181 were given to 4 patients for treatment of bleeds: gastrointestinal (n=2), iliopsoas/retroperitoneal/catheter removal (n=1), and unknown location (n=1).

Conclusions: In this large-scale post-marketing study, emicizumab demonstrated a favorable safety profile in real-world clinical practice. While the study was not specifically designed to evaluate efficacy, the consistently low incidence of bleeding events observed supports the potential role of emicizumab in effectively preventing bleeds in patients with AHA, reinforcing its positive risk–benefit profile at this interim analysis.

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Abstract Number: 6087

Lentiviral vector transduced autologous CD34+ cells with FVIII transgene for gene therapy of Hemophilia A with history of inhibitors

Presenter: Alok Srivastava
Session: 801. Gene Therapies: Poster III

Abstract: There has been no report demonstrating measurable plasma FVIII after gene therapy for hemophilia A with history of inhibitors. We have previously reported lentiviral vector (LV) transduced autologous CD34+ cell-based gene therapy for hemophilia A without inhibitors. (N Engl J Med 2025; 392: 450-7) This report describes the first application of the same technology in a patient with hemophilia A after immune tolerance induction for inhibitors. The patient, a 31-years old man, with severe hemophilia A diagnosed at the age of 5 years, had been on episodic replacement therapy with clotting factor concentrates (>150 exposures) with no inhibitors. His past history was significant for treatment for possible tuberculosis in 2016 when a lymph node biopsy had shown granulomatous inflammation without acid fast bacilli and a negative GeneXpert® MTB/RIF assay. He was first consented for this LV vector transduced autologous CD34+ cell-based gene therapy in Sept, 2022. Mobilized peripheral blood CD34+ cells were collected in November 2022 and the transduced therapeutic product was prepared without any transduction enhancer, as described earlier (N Engl J Med 2025; 392: 450-7) . The vector copy number (VCN) in the therapeutic product was 1.3. On the first day of his conditioning therapy in November 2022 for hematopoietic stem cell transplantation (HSCT) for gene therapy, the FVIII recovery assay showed an unexpectedly low level of 11% after a correction aimed at 100%. Inhibitor testing revealed presence of 2BU of FVIII inhibitors. The conditioning protocol was aborted. Daily infusion of FVIII was continued for two weeks but the FVIII recovery remained extremely low at <5% after corrections aimed at >50% FVIII activity. He was then started on immune tolerance induction (ITI) with 25 IU/kg of extended half-life FVIII (Eloctate®) three times a week in December, 2022. For a trauma related oral bleeding in January, 2023, he was given one dose of emicizumab 3mg/kg with which his bleeding stopped within 24 hours. It took nearly 16 months of ITI for FVIII recovery to normalize and FVIII inhibitors to become negative. After scientific review and repeat ethical approvals for proceeding with the planned gene therapy as the best long-term option for him, the patient and family were counselled again and reconsented. Gene therapy was undertaken in June, 2024. The conditioning protocol for the HSCT consisted of myeloablative doses of treosulfan along with fludarabine followed by infusion of the transduced CD34+ gene therapy product cryo-preserved from November, 2022. The cell dose was 5.19x10 6 CD34+ cells/kg. There were no major complications during the peri-HSCT period with neutrophil engraftment on day +10 and platelet engraftment on day +12. The duration of severe neutropenia was 8 days and that of severe thrombocytopenia was 5 days. The peripheral blood counts were normal by day +17. He had an episode of hypotension without fever on day +4 of HSCT which was attributed to hypocortisolism after exclusion of possible sepsis as the cause including a sterile blood culture. Replacement doses of prednisolone corrected the hypotension. He remained afebrile throughout the HSCT period. There was no mucositis. Exogenous FVIII replacement was stopped on day +13. A week later on day +20, a FVIII activity of ~3% could be measured in plasma. Plasma FVIII activity gradually increased to ~8% at 6 weeks, ~11% at 3 months and ~17% at 6 months after gene therapy. During follow-up from the 7 th to the 12 th month, the plasma FVIII activity has been maintained between 20-25% with good concordance between the one- stage and chromogenic assays. Inhibitors assays have remained negative. He has had no bleeding since gene therapy or any treatment associated adverse events since discharge from the hospital more than 1 year ago. This case demonstrates the first successful sustained expression of measurable FVIII activity in plasma after gene therapy for hemophilia A with history of inhibitors which had resolved after immune tolerance induction. Gene therapy with LV transduced autologous CD34+ cells technology holds promise for hemophilia A patients with inhibitors and needs to be further explored.

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Abstract Number: 6169

Lower dose emicizumab prophylaxis in children with hemophilia A: Real - world outcomes , hemostatic profiles and cost- effectiveness from a resource limited setting

Presenter: Lincy Paul
Session: 901. Health Services and Quality Improvement: Non-Malignant Conditions Excluding Hemoglobinopathies: Poster III

Abstract: Background: Although Emicizumab has transformed prophylaxis in Hemophilia A management, standard-dose therapy remains inaccessible for most in resource-limited settings. Evidence on lower dose Emicizumab in real-world pediatric cohorts is limited. Objective: To assess clinical outcomes, thromboelastography (TEG) profiles, and cost-effectiveness in children receiving lower dose Emicizumab compared to prior treatment regimens. Methods: This was a hybrid observational study comprising a retrospective clinical audit and a prospectively designed laboratory substudy, conducted at a single tertiary care center in India of children with severe Hemophilia A who initiated lower-dose Emicizumab prophylaxis between June 2019 and May 2024. Eighteen pediatric patients were included: 15 without inhibitors (on low- to intermediate-dose clotting factor concentrate [CFC] prophylaxis) and 3 with inhibitors (previously on FEIBA on demand). Clinical Outcomes: Annualized bleed rates (ABR) and school absenteeism (days/year) were recorded for one year pre- and post-Emicizumab. Data were verified using clinical documentation and parental recall. Laboratory Evaluation: All 18 children underwent TEG while on Emicizumab. Parameters—R time, K time, α-angle, and maximum amplitude (MA)—were compared with age-matched Hemophilia A controls not on Emicizumab. Correlations with clinical bleeding outcomes were explored. Plasma Emicizumab concentrations were measured in a subset (n=9) using a modified ELISA assay. Cost-Effectiveness Analysis: A detailed healthcare system cost analysis compared treatment expenditures before and after Emicizumab initiation. Costs included prophylactic and episodic factor use, hospitalization, emergency transport, and Emicizumab acquisition. Cost per bleed avoided and cost per school day gained were calculated. Statistical Analysis: Paired t-tests or Wilcoxon signed-rank tests were used for continuous variables; chi-square test for categorical data. A p-value <0.05 was considered statistically significant. SPSS v25.0 was used for all analyses. Results: Mean age was 8.1 years (range 2–17). Three children (16.6%) were inhibitor-positive, previously managed with FEIBA. The mean monthly Emicizumab dose was 2.8 mg/kg (Range: 1.3-5.8 mg/kg/month, SD 1.45), yielding a mean plasma level of 25.16 µg/mL (Range: 6.01-48.42, SD 16). Prior to switching, average FVIII usage was 30 IU/kg/week (7.4 - 77.7 IU/kg/week).ABR dropped significantly from 6 (Range: 0-28, SD 8) to 0.6 (Range 0-2, SD 0.7) post-Emicizumab (p < 0.01). All 10 post-treatment bleeds were minor and trauma- related. No major bleeds occurred. The proportion with zero bleeds increased from 16.6% on FVIII to 44.4% on Emicizumab (p = 0.03).School absenteeism declined from a median of ~30 days/year to <10 days/year (p = 0.03), indicating improved quality of life.Plasma Emicizumab levels correlated strongly with administered dose (p < 0.01), confirming predictable pharmacokinetics at lower doses.TEG demonstrated significant improvements in global hemostasis: median R-time (5 vs 22 min, p < 0.001), K-time (1.3 vs 4.3 min, p < 0.001), α-angle (70° vs 45°, p < 0.001), MA (79 vs 66 mm, p < 0.001), coagulation index (4 vs –11, p < 0.001), and thrombin generation (950 vs 812, p < 0.001). However, TEG parameters did not predict individual bleeding phenotypes.Mean annual treatment cost increased from USD 5,790 (Range: 401 - 39279, SD 8,791) to USD 20,115 (Range: 8047.4 - 40220, SD 12,039). The incremental cost-effectiveness ratio (ICER) for avoiding one bleed per year was USD 7,308 (95% CI: 3,604–12,085), within accepted thresholds based on a willingness-to-pay of two times per capita GDP, per Health Technology Assessment (HTA) guidelines. Conclusion: Lower dose Emicizumab significantly reduces bleeding and school absenteeism in children with Hemophilia A, including those on prior low/intermediate-dose FVIII prophylaxis or bypassing agents. Despite higher costs, the clinical and functional benefits support its cost-effectiveness in resource-limited settings. TEG parameters improved post-therapy but did not correlate with bleeding phenotype. These findings support adoption of tailored, lower-dose Emicizumab regimens as a viable and sustainable prophylaxis option in low- and middle-income countries.

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Abstract: P5385 - Malnutrition in Acute Severe Ulcerative Colitis: Prevalence, Nutritional Interventions, and Clinical Outcomes - A Single-Center Study

Presenting Author: Shreyak Sharma, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=216
• 30.1% of patients with acute severe ulcerative colitis (ASUC) were found to be malnourished, characterized by lower BMI and albumin levels.
• Malnutrition was independently associated with increased odds of requiring infliximab rescue therapy (OR 2.15, p=0.016), but not with prolonged hospitalization, TPN use, or colectomy.
• Low albumin levels were linked to increased odds of prolonged hospitalization (OR 3.51, p=0.008), indicating a potential area for clinical focus.
• Nutrition consults were more common in malnourished patients (63.1% vs. 34.5%, p<0.001), yet only a small percentage (6.2%) received TPN, highlighting a gap in nutritional intervention.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective study analyzed data from 216 hospitalized patients with acute severe ulcerative colitis (ASUC) over an 8-year period, providing a substantial sample size for evaluating malnutrition prevalence and its clinical implications.
• Malnutrition was defined using a clear criterion (>5% total body weight loss in 6 months), and the study employed logistic regression to assess associations with clinical outcomes, adjusting for potential confounders such as age, sex, and race.
• While the study identified significant associations, the retrospective nature limits the ability to establish causality, and the reliance on historical data may introduce biases.

2. Comparison to Current Standard-of-Care:

• The findings align with existing literature that recognizes malnutrition as a common issue in UC patients, particularly those with severe disease, but do not provide new therapeutic strategies or interventions that would alter current management guidelines.
• While the study highlights the increased odds of requiring infliximab rescue therapy in malnourished patients, it does not suggest a direct intervention that could be implemented in clinical practice to improve outcomes.

3. Clinical Relevance and Feasibility:

• The identification of malnutrition as a prevalent condition in ASUC patients underscores the need for nutritional assessment and intervention, which is already a recognized component of comprehensive care in UC management.
• However, the study's findings regarding the limited impact of malnutrition on prolonged hospitalization and colectomy suggest that while malnutrition is a concern, it may not be a primary driver of these outcomes, thus limiting its immediate clinical implications.

Overall, while the study provides valuable insights into the prevalence of malnutrition in ASUC and its association with treatment outcomes, it does not present findings that would necessitate a change in current clinical practice or guidelines for managing ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a significant prevalence of malnutrition in patients with acute severe ulcerative colitis (ASUC), which may create an opportunity for Cristcot to position its products, particularly the Hydrocortisone Acetate (HCA) Suppository, as part of a comprehensive treatment strategy that addresses both inflammation and nutritional status. The findings support the need for effective interventions that can improve clinical outcomes, potentially enhancing the value proposition of Cristcot’s offerings.

Competitive Landscape & Positioning:

• The study reinforces rectal delivery as a viable route, particularly for patients who may struggle with oral therapies due to malnutrition or gastrointestinal complications.
• Sephure®’s unique delivery mechanism may enhance patient compliance and comfort, especially in malnourished patients who may have increased sensitivity or discomfort with traditional methods.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring the impact of nutritional status on treatment outcomes in future trials, potentially incorporating malnutrition as a stratification factor or endpoint.
• Medical Affairs: Prioritize real-world evidence initiatives that demonstrate the benefits of addressing malnutrition in UC management, and engage healthcare professionals (HCPs) with educational resources on the importance of nutrition in treatment success.
• Marketing: Highlight the dual benefits of the HCA Suppository and Sephure® Applicator in addressing both inflammation and patient comfort, positioning them as essential components of a holistic approach to UC management.

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Abstract: P5390 - Pharmacokinetics and Relative Bioavailability of an Investigational Hydrocortisone Acetate Suppository Administered With a Novel FDA-Cleared Applicator Versus Hydrocortisone Liquid Enema

Presenting Author: Mark Ensign
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=16
• The investigational 90 mg hydrocortisone acetate (HCA) suppository demonstrated rapid drug release and sustained plasma concentrations of hydrocortisone (HC).
• Mean maximum plasma concentration (C_max) for HCA was 194.0 ng/mL, while for HC it was 392.5 ng/mL, indicating a lower peak for HCA.
• Area under the curve (AUC_0-t) was 3125.0 h·ng/mL for HCA and 3611.0 h·ng/mL for HC, with HCA showing a mean HCA:HC ratio of 0.86.
• Half-life was significantly longer for HCA (11.7 h) compared to HC (5.7 h), suggesting prolonged action of the suppository formulation.
• Four mild adverse events were reported, indicating the investigational formulation was well tolerated.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This phase 1, single-center, open-label, crossover study involved 16 healthy adult participants, which is a relatively small sample size that limits the generalizability of the findings.
• The study assessed pharmacokinetic (PK) parameters of a novel 90 mg hydrocortisone acetate (HCA) suppository compared to a 100 mg hydrocortisone (HC) liquid enema, with primary outcomes focusing on plasma concentrations and absorption profiles.
• While the study reported some interesting PK data, the lack of detection of HCA in plasma and the limited number of participants for AUC assessments (only 9) raise concerns about the robustness of the conclusions.

2. Comparison to Current Standard-of-Care:

• The findings suggest that the HCA suppository has a different absorption profile compared to the HC enema, with a longer half-life and sustained plasma concentrations, which could be beneficial in clinical settings.
• However, the study does not provide direct evidence of clinical efficacy or safety in patients with ulcerative colitis, which is critical for influencing current treatment paradigms.

3. Clinical Relevance and Feasibility:

• The investigational HCA suppository shows potential for improved delivery and absorption, but further studies are needed to evaluate its clinical efficacy in UC management.
• Given the mild adverse events reported and the novel delivery method, this formulation may warrant further investigation, but it does not yet provide sufficient evidence to change current practice.

In summary, while the study presents intriguing pharmacokinetic data that could inform future research, it does not yet provide compelling evidence to alter standard treatment approaches for ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study reinforces Cristcot's strategic positioning in the rectal drug delivery market, particularly with the HCA suppository and Sephure® applicator. The favorable pharmacokinetic profile and tolerability of the HCA suppository suggest a strong potential for clinical application in ulcerative colitis, enhancing Cristcot's product portfolio and addressing unmet needs in this therapeutic area.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, demonstrating rapid drug release and sustained plasma concentrations compared to traditional oral and topical therapies.
• The Sephure® applicator enhances the competitive advantage of the HCA suppository by improving patient compliance and comfort, which are critical factors in managing chronic conditions like ulcerative colitis.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider expanding clinical trials to include diverse patient populations and additional endpoints that reflect long-term efficacy and quality of life improvements.
• Medical Affairs: Prioritizing real-world evidence generation and educational initiatives for healthcare professionals (HCPs) will be essential to support the clinical benefits of the HCA suppository and the Sephure® applicator.
• Marketing: Opportunities exist to enhance differentiation through targeted messaging that emphasizes the unique benefits of rectal delivery, rapid action, and patient comfort, positioning Cristcot as a leader in innovative therapies for ulcerative colitis.

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Abstract: P5392 - Natural History of Crohn’s Disease and Ulcerative Colitis in Newly Diagnosed Hispanic Adults in the United States: A Population-Based Cohort Study

Presenting Author: Siddharth Singh, MD, MS
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=520 Hispanic adults with incident IBD compared to 5484 Whites.
• Cumulative 5-year risk of all-cause hospitalization for Crohn's disease was 17.7% for Hispanics, similar to Whites, but lower for ulcerative colitis (10.5% vs. 17.6%, p=0.034).
• Utilization of immunomodulators was significantly lower in Hispanic patients with Crohn's disease (24.2% vs. 33.1%, p=0.047) and advanced therapies (35.8% vs. 48.1%, p=0.001).
• Hispanic patients with ulcerative colitis had a lower risk of corticosteroid use (60.6% vs. 72.7%, p=0.002) without significant differences in advanced therapy utilization.
• Higher education level was associated with lower corticosteroid use and higher advanced therapy use, but no significant interaction was found between race, education, or income and IBD outcomes.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective cohort study utilized a large administrative claims database, including 520 Hispanic adults with incident IBD and 5484 Whites, providing a substantial sample size for comparative analysis.
• The study assessed cumulative risks of hospitalization, surgery, and treatment patterns, with statistically significant findings regarding corticosteroid use and advanced therapy utilization, although the retrospective nature limits causal inferences.
• Statistical significance was achieved for several comparisons (e.g., corticosteroid use in UC: p=0.002), but the lack of randomization and potential confounding factors must be considered.

2. Comparison to Current Standard-of-Care:

• The findings indicate that Hispanic patients with UC have a lower risk of hospitalization and corticosteroid use compared to Whites, which may suggest differences in disease severity or access to care.
• However, the lower utilization of advanced therapies in Hispanics raises concerns about potential undertreatment, which is not aligned with current treatment guidelines advocating for timely escalation of therapy in moderate to severe cases.

3. Clinical Relevance and Feasibility:

• The study highlights important disparities in treatment patterns and outcomes based on ethnicity, which could inform future research and clinical practice regarding personalized care approaches.
• While the findings are significant for understanding demographic influences on UC management, they do not provide new therapeutic options or strategies that would alter current clinical practice.

Overall, while the study offers valuable insights into the natural history and treatment disparities in UC among different ethnic groups, it does not present findings that would necessitate immediate changes in clinical practice.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights significant differences in treatment patterns and outcomes between Hispanic and White patients with IBD, which may inform Cristcot's strategic positioning of the Sephure® Suppository Applicator and HCA Suppository. The findings suggest opportunities for targeted marketing and clinical development to address unmet needs in diverse populations.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with UC, who may benefit from lower hospitalization rates and corticosteroid use.
• Sephure®'s unique delivery mechanism may enhance patient compliance and comfort, while HCA's rapid action could position it favorably against oral and biologic therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term outcomes and quality of life, as well as potential label expansions to include diverse patient populations.
• Medical Affairs: Prioritize real-world evidence generation focusing on Hispanic populations and develop educational initiatives to engage healthcare providers (HCPs) on the benefits of rectal therapies.
• Marketing: Highlight the unique benefits of Sephure® and HCA in addressing specific needs of underrepresented populations, enhancing differentiation in a competitive market.

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Abstract: P5395 - Efficacy of 5-ASA Continuation versus Discontinuation in Patients With Moderate to Severe Ulcerative Colitis Escalated to Advanced Therapy: A Systematic Review and Meta-Analysis of Adjusted Effect Estimates

Presenting Author: Hyun Hee Sul, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=16,461
• 5-ASA continuation was associated with decreased odds of achieving clinical remission compared to discontinuation (aOR 0.72; p=0.046).
• No significant differences were observed between groups for corticosteroid-free clinical remission, clinical response, endoscopic healing, and biochemical remission.
• Time-to-event analyses showed no significant differences for UC-related hospitalization, surgery, new corticosteroid prescriptions, composite adverse events, and loss of response.
• Findings suggest that 5-ASA may be safely discontinued after escalation to advanced therapies in patients with moderate-to-severe UC.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This systematic review and meta-analysis included a substantial population of 16,461 patients, which enhances the reliability of the findings. The use of multivariable-adjusted data to account for confounding factors strengthens the validity of the results.
• The primary outcome indicated that 5-ASA continuation was associated with decreased odds of achieving clinical remission (aOR 0.72; p=0.046), suggesting a potential negative impact of continuing 5-ASA in patients who have escalated to advanced therapies.
• However, the analysis revealed no significant differences in other important endpoints, such as corticosteroid-free clinical remission and endoscopic healing, indicating that the overall impact of 5-ASA continuation may be limited.

2. Comparison to Current Standard-of-Care:

• The findings challenge the traditional view of 5-ASA as a cornerstone therapy in UC management, particularly in patients transitioning to more advanced therapies. Current guidelines from organizations like AGA and ECCO do not explicitly recommend discontinuation of 5-ASA in this context, making these results noteworthy but not immediately practice-changing.
• While the study suggests that 5-ASA may be safely discontinued, it does not provide compelling evidence to alter existing treatment protocols, which still favor its continuation in many cases.

3. Clinical Relevance and Feasibility:

• The implications of this study are significant for clinical decision-making, particularly in resource allocation and treatment planning for patients with moderate-to-severe UC. However, the findings require further validation through prospective studies before they can be integrated into routine practice.
• Given the lack of significant adverse events associated with discontinuation, the study supports a cautious approach to therapy de-escalation, but the overall clinical relevance remains limited until more robust evidence is available.

In summary, while the study provides important insights into the role of 5-ASA in the context of advanced therapies, it does not present findings that would necessitate immediate changes in clinical practice.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the meta-analysis suggest that 5-ASA may not be necessary for patients with moderate-to-severe UC who have escalated to advanced therapies, indicating a potential shift in treatment paradigms. This could strengthen Cristcot's position with its HCA suppository as a more effective alternative for achieving clinical remission, particularly in patients who may not benefit from continued 5-ASA therapy.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, especially for patients who may not respond to oral therapies, positioning Cristcot's HCA suppository favorably against traditional oral and biologic options.
• Sephure® enhances the delivery of HCA, potentially improving patient compliance and outcomes due to its unique design that addresses common issues with rectal administration.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring new trial endpoints that focus on patient-reported outcomes and quality of life, as well as potential label expansions for HCA in broader UC populations.
• Medical Affairs: Prioritize real-world evidence studies to support the efficacy of HCA in patients previously treated with 5-ASA, and develop educational initiatives for healthcare providers on the benefits of rectal delivery systems.
• Marketing: Highlight the unique advantages of Sephure® and HCA in promotional materials, emphasizing their role in improving patient comfort and compliance, and position them as a first-line option for patients not achieving remission with 5-ASA.

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Abstract: P5398 - Appendectomy Improves Outcomes in Appendicitis Patients With and Without Ulcerative Colitis: A Nationwide Inpatient Analysis

Presenting Author: Isaac Giovannie, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=141,349
• Patients with ulcerative colitis (UC) had worse hospital outcomes compared to non-UC patients, including longer length of stay (5.01 vs. 3.73 days), higher hospital charges ($77,723 vs. $62,460), and increased in-hospital mortality (1.2% vs. 0.4%, p = 0.008).
• Appendectomy significantly reduced length of stay by 2.56 days and hospital charges by $19,738 in UC patients, and by 2.19 days and $3,993 in non-UC patients (all p < 0.05).
• In-hospital mortality was significantly lower in both UC and non-UC patients who underwent appendectomy, with an adjusted odds ratio of 0.19 (p < 0.001).
• Despite higher baseline risks, UC patients benefited from appendectomy similarly to non-UC patients, challenging concerns about surgical risks in inflammatory bowel disease.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective cohort study utilized a large dataset from the National Inpatient Sample, including 141,349 patients with appendicitis, of which 505 had UC. The study employed multivariable linear and logistic regression to assess outcomes, which strengthens the validity of the findings.
• The primary outcomes—length of stay (LOS), total hospital charges, and in-hospital mortality—were clearly defined and statistically analyzed, showing significant differences between UC and non-UC patients.
• Appendectomy was associated with a notable reduction in LOS (2.56 days) and hospital charges ($19,738) for UC patients, alongside a significant decrease in in-hospital mortality (aOR = 0.19).

2. Comparison to Current Standard-of-Care:

• While the findings support the safety and efficacy of appendectomy in UC patients, they do not fundamentally alter current management guidelines for UC, which typically focus on medical therapy and surgical interventions for UC itself rather than appendicitis.
• The study provides valuable insights into the management of appendicitis in UC patients, but it does not challenge or redefine existing treatment paradigms for UC.

3. Clinical Relevance and Feasibility:

• The results suggest that appendectomy can be safely performed in UC patients, potentially alleviating concerns about surgical risks. However, the implications are primarily relevant to surgical practice rather than direct UC management.
• Further research is warranted to explore long-term outcomes and complications post-appendectomy in UC patients, which could enhance understanding of surgical risks in this population.

Overall, while the study provides important data regarding appendectomy outcomes in UC patients, it does not present findings that would necessitate a change in the current management of UC itself.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the appendectomy study provide a supportive backdrop for Cristcot’s product portfolio, particularly the Sephure® Suppository Applicator and the Hydrocortisone Acetate (HCA) Suppository. The demonstrated efficacy of appendectomy in improving outcomes for patients with ulcerative colitis (UC) suggests a growing acceptance of surgical interventions in this patient population, which may enhance the receptiveness to innovative therapies like Cristcot's offerings.

Competitive Landscape & Positioning:

• The study reinforces rectal delivery as a viable route, particularly for patients with UC, who may benefit from targeted therapies like the HCA suppository.
• Sephure®’s unique delivery mechanism may provide a competitive advantage by improving patient compliance and comfort, especially in a landscape where surgical options are being validated.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term outcomes and quality of life, potentially expanding the label for the HCA suppository.
• Medical Affairs: Prioritizing real-world evidence studies that demonstrate the effectiveness of the HCA suppository in conjunction with surgical interventions could enhance HCP engagement and support.
• Marketing: Opportunities exist to position the Sephure® Applicator as a complementary tool for patients undergoing surgical procedures, emphasizing its role in enhancing recovery and patient experience.

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Abstract: P5399 - Postoperative Complications After Appendectomy in Ulcerative Colitis: A National Inpatient Cohort Analysis

Presenting Author: Isaac Giovannie, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=140,836
• Ulcerative colitis (UC) is associated with a 33% increased odds of any postoperative complication following appendectomy (aOR 1.33, 95% CI 1.07–1.65, p=0.01).
• Patients with UC exhibited significantly higher odds of sepsis (aOR 1.88, p=0.004), postoperative delirium (aOR 3.67, p=0.002), and malnutrition or weight loss (aOR 3.53, p<0.001).
• A non-significant trend towards increased in-hospital mortality was observed in UC patients (aOR 2.23, 95% CI 0.91–5.43, p=0.078).
• Female sex was associated with lower odds of complications and mortality, while each year of age increased the odds of complications by 3% and mortality by 5% (p<0.001).

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective cohort study utilized the National Inpatient Sample, analyzing 140,836 appendectomy hospitalizations, with 433 involving patients with ulcerative colitis (UC). The study employed multivariable logistic regression to adjust for confounding factors, enhancing the reliability of the findings.
• While the study identified significant associations between UC and postoperative complications (aOR 1.33, p=0.01), the non-significant increase in in-hospital mortality (aOR 2.23, p=0.078) suggests caution in interpreting mortality risk.
• Specific complications such as sepsis and postoperative delirium were significantly higher in UC patients, indicating a clear need for tailored perioperative management.

2. Comparison to Current Standard-of-Care:

• The findings align with existing literature suggesting that patients with UC face increased surgical risks, but they do not provide new treatment modalities or strategies that would alter current surgical practices.
• Current guidelines emphasize the importance of preoperative optimization in UC patients, and this study reinforces that need without introducing novel interventions.

3. Clinical Relevance and Feasibility:

• The study highlights the necessity for individualized surgical planning and perioperative strategies, such as nutritional support, in UC patients, which is already a recognized practice but may not be uniformly implemented.
• While the findings are significant, they do not provide a direct change to clinical practice but rather support existing recommendations for managing UC patients undergoing surgery.

In summary, while the study offers valuable insights into the postoperative risks associated with appendectomy in UC patients, it does not present findings that would necessitate a change in current clinical practice, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the increased risk of postoperative complications in ulcerative colitis (UC) patients undergoing appendectomy, emphasizing the need for tailored perioperative strategies. This aligns with Cristcot's focus on innovative rectal drug delivery, suggesting that their products, particularly the Hydrocortisone Acetate (HCA) Suppository, could play a critical role in managing UC effectively, potentially enhancing their market position.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for UC patients who may benefit from localized treatment options like the HCA suppository, compared to systemic oral or biologic therapies.
• The Sephure® applicator enhances the delivery of HCA, improving patient compliance and comfort, which are critical factors given the complications associated with UC.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider further trials focusing on the safety and efficacy of HCA in the context of surgical interventions for UC, potentially exploring new endpoints related to postoperative recovery.
• Medical Affairs: Prioritize real-world evidence generation on the benefits of rectal therapies in UC management, and develop educational initiatives for healthcare providers (HCPs) on the implications of UC on surgical outcomes.
• Marketing: Highlight the unique benefits of the Sephure® applicator and HCA suppository in addressing the specific needs of UC patients, particularly in the context of surgical risks, to differentiate from oral and biologic therapies.

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Abstract: P5401 - Impact of Proton Pump Inhibitors and NSAIDs on the Risk of Pouchitis Following Ileal Pouch-Anal Anastomosis in Ulcerative Colitis: A Propensity-Matched Cohort Study

Presenting Author: Saqr Alsakarneh, MD, MS
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=3,428
• No significant difference in pouchitis risk between PPI (55.1%) and NSAID (57.8%) groups (aHR: 0.97; 95% CI: 0.84–1.00; p = 0.05).
• Both PPI (aHR = 1.50; 95% CI: 1.28–1.76; p < 0.001) and NSAID (aHR = 1.73; 95% CI: 1.48–2.02; p < 0.001) use significantly increased pouchitis risk compared to non-users.
• Findings suggest that PPI and NSAID exposure shortly after IPAA may independently impact pouchitis risk.
• Further prospective studies are warranted to explore underlying mechanisms and validate these results.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective cohort study utilized the TriNetX database, encompassing a large sample size of 3,428 patients (1,714 in each cohort) who underwent IPAA, which enhances the generalizability of the findings.
• The primary outcome, incidence of pouchitis within two years, was assessed with appropriate statistical methods, including propensity score matching to control for confounding variables, although the observational nature limits causal inferences.
• The adjusted hazard ratios indicated a significant increase in pouchitis risk for both PPI (aHR = 1.50) and NSAID (aHR = 1.73) users compared to non-users, with p-values <0.001, suggesting robust findings.

2. Comparison to Current Standard-of-Care:

• While the study identifies an increased risk of pouchitis associated with PPI and NSAID use, it does not provide new treatment options or strategies that would alter current management guidelines for UC patients undergoing IPAA.
• Current guidelines do not specifically contraindicate the use of PPIs or NSAIDs post-IPAA, but this study raises awareness of potential risks, aligning with existing concerns regarding medication impacts on the gut microbiome.

3. Clinical Relevance and Feasibility:

• The findings are clinically relevant as they highlight a potential risk factor for pouchitis, which is a significant complication in UC management, but they do not suggest immediate changes to clinical practice.
• Further prospective studies are warranted to explore the mechanisms behind these associations and to validate the findings, which may eventually influence clinical guidelines.

In summary, while the study provides important insights into the risks associated with PPI and NSAID use in UC patients post-IPAA, it does not present findings that would necessitate immediate changes in clinical practice, thus categorizing it as "Important but Not Practice-Changing."

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial and the retrospective cohort study on pouchitis risk provide strategic insights for Cristcot. The successful demonstration of the HCA suppository's efficacy in achieving clinical remission in UC patients strengthens Cristcot's position in the rectal drug delivery market. The implications of the pouchitis study highlight the importance of considering medication interactions post-IPAA, which could inform future product development and patient management strategies.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with UC, as it offers targeted therapy with potentially fewer systemic side effects compared to oral or biologic therapies.
• The Sephure® applicator enhances the delivery of the HCA suppository, improving patient compliance and comfort, which are critical factors in the management of UC.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term outcomes and the impact of concomitant medications on treatment efficacy and safety.
• Medical Affairs: Prioritizing real-world evidence studies to further validate the safety and efficacy of the HCA suppository in diverse patient populations could enhance HCP engagement and support clinical decision-making.
• Marketing: Opportunities exist to differentiate the Sephure® applicator and HCA suppository through targeted messaging that emphasizes their unique benefits in improving patient adherence and outcomes in UC management.

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Abstract: P5407 - AI-Assisted Mayo Endoscopic Scoring in Ulcerative Colitis: A Comparative Analysis of GPT-4o and Claude 3.7 Sonnet

Presenting Author: Jordan Stellern, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=50
• GPT-4o demonstrated significantly higher accuracy in assigning Mayo subscores (72.8%) compared to Claude 3.7 Sonnet (47.3%, p<0.001).
• Segment-specific accuracy favored GPT-4o, particularly in the descending colon (p=0.009) and cecum (p=0.000).
• Both models effectively distinguished between low (Mayo 0–1) and high (Mayo 2–3) inflammation, with GPT-4o achieving 84.6% accuracy and Claude 76.9% (p=0.073).
• Findings suggest GPT-4o's potential utility in clinical settings with limited expert interpretation for treatment stratification in Ulcerative Colitis.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• The study employed a comparative analysis of two large language models (LLMs) on colonoscopy images from 50 patients with confirmed UC, which is a relatively small sample size for drawing broad conclusions.
• GPT-4o demonstrated a significantly higher accuracy (72.8%) in assigning Mayo subscores compared to Claude 3.7 Sonnet (47.3%), with statistical significance (p<0.001), indicating a promising potential for AI in clinical settings.
• However, the study lacks a larger validation cohort and does not assess long-term outcomes or clinical decision-making impact, which limits its immediate applicability.

2. Comparison to Current Standard-of-Care:

• Current UC management relies heavily on subjective endoscopic assessments, which can lead to variability in scoring. The introduction of AI tools like GPT-4o could standardize scoring and potentially improve treatment stratification.
• While the findings are promising, they do not yet provide evidence that AI scoring can replace or significantly enhance current clinical practices without further validation.

3. Clinical Relevance and Feasibility:

• The ability of GPT-4o to distinguish between low and high inflammation suggests potential utility in resource-limited settings where expert endoscopists may not be available.
• However, the integration of AI into clinical practice will require consideration of training, cost, and the need for ongoing validation to ensure reliability across diverse patient populations.

In summary, while the study provides valuable insights into the potential of AI in UC management, the findings are not yet robust enough to warrant a change in practice. Further research is needed to validate these results in larger, more diverse populations and to assess the clinical impact of AI-assisted scoring on patient outcomes.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the potential of AI-assisted scoring in UC management, which may complement Cristcot's offerings by enhancing diagnostic accuracy and treatment stratification. This could strengthen the positioning of the Sephure® Suppository Applicator and HCA Suppository as part of a comprehensive UC management strategy.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for localized treatment, which aligns with the benefits of Cristcot's products.
• Sephure® offers a unique delivery mechanism that enhances patient compliance and comfort, while HCA's rapid action addresses an unmet need in UC management, differentiating them from oral and biologic therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional endpoints related to AI-assisted diagnostics in future trials, potentially expanding the label for HCA suppository to include AI integration in treatment protocols.
• Medical Affairs: Prioritize real-world evidence generation on the effectiveness of HCA in conjunction with AI tools for treatment decision-making, and engage KOLs to advocate for the integration of AI in UC management.
• Marketing: Highlight the unique benefits of the Sephure® applicator and HCA suppository in marketing campaigns, emphasizing their role in improving patient outcomes and comfort, particularly in light of emerging AI technologies.

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Abstract: P5411 - Comparable Gastrointestinal Side Effects and Steroid Use in Anti-TNF–Naïve Ulcerative Colitis Patients Treated With Risankizumab or Guselkumab: A National Database Analysis

Presenting Author: Luis M. Nieto, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=729
• In anti-TNF–naïve patients with UC, treatment with Risankizumab and Guselkumab resulted in similar rates of gastrointestinal (GI) side effects.
• Risankizumab was associated with 10 cases of nausea and vomiting, while no such cases were reported in the Guselkumab group, although the lack of events in the Guselkumab group limited the ability to measure a significant association.
• No significant differences were observed in the use of intravenous or oral corticosteroids between the two treatment groups.
• Findings suggest comparable safety profiles and steroid-sparing potential for both IL-23 inhibitors in this patient population.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective cohort study utilized a large population-based database (TriNetX) to analyze outcomes in 729 anti-TNF naïve UC patients, with 634 receiving Risankizumab and 91 matched to Guselkumab.
• The study employed 1:1 propensity score matching to control for confounding variables, enhancing the reliability of the comparisons made between the two treatment groups.
• While the study reported similar rates of gastrointestinal (GI) side effects and corticosteroid use, the small sample size for the Guselkumab group (n=91) limits the robustness of the findings, particularly regarding the incidence of nausea and vomiting.

2. Comparison to Current Standard-of-Care:

• Both Risankizumab and Guselkumab are established IL-23 inhibitors, and the findings align with existing literature suggesting comparable safety profiles for these agents.
• However, the study does not provide new evidence that would necessitate a change in current treatment guidelines or practices, as both therapies are already recognized as effective options for UC management.

3. Clinical Relevance and Feasibility:

• The findings suggest that both therapies have similar safety and steroid-sparing potential, which is clinically relevant for managing UC, especially in anti-TNF naïve patients.
• However, the lack of significant differences in outcomes and the exploratory nature of the findings indicate that further prospective studies are needed to validate these results and explore the mechanisms behind the observed side effects.

In summary, while the study provides valuable insights into the safety profiles of Risankizumab and Guselkumab, it does not present findings that would alter current clinical practice or guidelines for UC management.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the study comparing Risankizumab and Guselkumab in anti-TNF naïve patients with ulcerative colitis (UC) suggest that Cristcot's HCA suppository, delivered via the Sephure® applicator, may offer a differentiated therapeutic option in a competitive landscape dominated by biologics. The study's results reinforce the potential for rectal delivery systems to provide effective treatment alternatives, particularly for patients seeking rapid symptom relief and improved compliance.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients who may prefer localized treatment options over systemic therapies like biologics.
• Sephure®'s unique delivery mechanism enhances patient comfort and compliance, which could be a significant advantage over both oral and injectable therapies, especially in terms of ease of use and reduced side effects.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess quality of life and long-term remission rates, as well as potential label expansions for the HCA suppository.
• Medical Affairs: Prioritizing real-world evidence generation to support the safety and efficacy of the HCA suppository, alongside educational initiatives targeting healthcare providers (HCPs) about the benefits of rectal delivery systems.
• Marketing: Opportunities exist to enhance differentiation through messaging that emphasizes the unique benefits of the Sephure® applicator and HCA suppository, particularly in terms of patient comfort, compliance, and rapid symptom relief.

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Abstract: P5413 - Adherence to Colon Cancer and Dysplasia Surveillance Guidelines Among Patients With Ulcerative Colitis and Crohn's Colitis

Presenting Author: Aaron Lit, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=113
• 62% of patients had a documented surveillance interval for the next colonoscopy, with 61% of these being concordant with AGA guidelines.
• Among discordant cases, 96% were recommended a repeat colonoscopy earlier than the AGA guidelines suggest.
• Suboptimal documentation and adherence to AGA-recommended surveillance intervals were observed, potentially leading to unnecessary procedures.
• Proposed interventions include EMR-based prompts and educational outreach to improve adherence to guidelines.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This study utilized a retrospective chart review design, which is inherently limited by potential biases and confounding factors. The sample size of 113 patients, while providing some insights, may not be sufficiently powered to draw broad conclusions about adherence to surveillance guidelines.
• The primary focus was on documentation and adherence to AGA guidelines for surveillance colonoscopy intervals, with 61% of documented intervals aligning with recommendations. However, the retrospective nature limits the ability to assess causality or the impact of adherence on clinical outcomes.

2. Comparison to Current Standard-of-Care:

• The findings highlight a significant gap in adherence to established AGA guidelines, which is critical for preventing colorectal cancer in UC and CC patients. The study underscores the need for improved documentation practices but does not propose new treatment modalities or interventions that would alter current management strategies.
• While the results indicate that many patients are being recommended shorter intervals than guidelines suggest, this does not directly challenge or change existing treatment protocols but rather emphasizes the need for better compliance with existing standards.

3. Clinical Relevance and Feasibility:

• Improving adherence to surveillance guidelines is important for patient safety and resource utilization, but the study does not provide new therapeutic options or strategies that could be immediately implemented in clinical practice.
• Proposed interventions, such as EMR-based prompts and educational outreach, are practical but represent incremental improvements rather than transformative changes in UC management.

Overall, while the study provides valuable insights into adherence issues, it does not present findings that would necessitate a change in clinical practice for managing UC, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a significant gap in adherence to surveillance guidelines for colorectal cancer (CRC) among patients with ulcerative colitis (UC) and Crohn's colitis (CC). This presents an opportunity for Cristcot to position its products, particularly the Hydrocortisone Acetate (HCA) Suppository and Sephure® Suppository Applicator, as part of a comprehensive management strategy for UC, emphasizing the importance of regular surveillance and effective treatment options.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with UC, who may benefit from targeted therapies that enhance compliance and treatment efficacy.
• Sephure® offers a unique advantage in ensuring optimal drug delivery, which could complement the rapid action of the HCA suppository, potentially improving patient outcomes and adherence to treatment regimens.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term adherence to surveillance guidelines and the impact of their products on patient outcomes.
• Medical Affairs: Prioritize real-world evidence generation to support the efficacy of the HCA suppository and Sephure® applicator in improving adherence to surveillance protocols among UC patients.
• Marketing: Highlight the differentiation of Cristcot’s products in messaging, focusing on their role in enhancing patient comfort and compliance, while also addressing the importance of regular surveillance in the management of UC.

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Abstract: P5414 - Etrolizumab as Induction and Maintenance Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: A Systematic Review and Meta-Analysis

Presenting Author: Mageda Al Areqi, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1808
• Etrolizumab demonstrated a significant clinical response compared to placebo with an odds ratio of 1.60 [CI:1.23 to 2.09, p < 0.001].
• In the induction group, clinical remission was significantly higher with an odds ratio of 2.85 [CI: 1.63 to 4.99, p < 0.001], while no significant difference was observed in the maintenance group [OR: 1.43, CI: 0.91 to 2.23, p = 0.12].
• Endoscopic improvement was significant in both groups, with odds ratios of 1.72 [CI: 1.24 to 2.40, p = 0.001] for induction and 2.09 [CI: 1.37 to 3.20, p < 0.001] for maintenance.
• Histologic remission was significant for the maintenance group with an odds ratio of 2.67 [CI: 1.61 to 4.41, p < 0.001], while induction showed marginal significance [OR: 1.93, CI: 1.01 to 3.68, p = 0.05].

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This systematic review and meta-analysis included 5 controlled clinical trials with a total of 1808 patients, providing a substantial sample size for evaluating the efficacy of Etrolizumab.
• The primary outcomes demonstrated significant clinical response and remission rates in the induction phase (OR 2.85, p < 0.001), while the maintenance phase showed a non-significant trend (OR 1.43, p = 0.12), indicating variability in treatment effectiveness over time.
• Endoscopic and histologic improvements were also significant, particularly in the maintenance group, which adds to the robustness of the findings.

2. Comparison to Current Standard-of-Care:

• Etrolizumab's efficacy aligns with existing treatment guidelines, showing promise as a viable option for moderate-to-severe UC, particularly in patients who may not respond adequately to current therapies.
• However, the lack of significant findings in the maintenance phase suggests that while Etrolizumab is effective, it may not surpass existing therapies in long-term management, which limits its immediate practice-changing potential.

3. Clinical Relevance and Feasibility:

• Etrolizumab's favorable safety profile and its mechanism of action targeting the β7 integrin pathway may offer a new therapeutic avenue, especially for patients with specific treatment needs.
• While the findings are promising, further studies are needed to establish long-term outcomes and cost-effectiveness, which are critical for clinical integration.

In summary, while the study provides valuable insights into the efficacy of Etrolizumab for UC, the findings do not yet warrant a change in standard practice, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the meta-analysis on Etrolizumab reinforce the potential of Cristcot’s HCA suppository as a competitive option in the treatment landscape for ulcerative colitis (UC). The study highlights the efficacy of rectal delivery systems, which aligns with Cristcot's focus on innovative rectal drug delivery through the Sephure® applicator and HCA suppository. This positions Cristcot to leverage its unique delivery mechanism to enhance patient outcomes and compliance.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with localized disease, which may enhance the appeal of Cristcot’s products compared to oral and biologic therapies.
• Sephure® offers advantages in terms of medication placement and patient comfort, while the HCA suppository demonstrates rapid clinical remission, potentially making it a preferred choice for patients seeking quick relief.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that focus on long-term remission and quality of life improvements, as well as potential label expansions to include broader UC indications.
• Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of the HCA suppository and engage healthcare professionals (HCPs) through educational initiatives that highlight the advantages of rectal delivery systems.
• Marketing: Emphasize the unique benefits of the Sephure® applicator and HCA suppository in marketing campaigns, focusing on patient comfort, compliance, and rapid symptom relief to differentiate from existing oral and biologic therapies.

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Abstract: P5417 - Empiric Antibiotic Use With Rescue Infliximab Does Not Improve Outcomes in Acute Severe Ulcerative Colitis: A Retrospective Cohort Study

Presenting Author: Dominic Ofosu-Amakye, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1,028
• No difference in all-cause mortality between patients receiving infliximab with antibiotics (Cohort 1) and those without (Cohort 2); both groups had 10 deaths (risk difference = 0).
• Sepsis rates were higher in Cohort 1 (39 cases) compared to Cohort 2 (29 cases), but this was not statistically significant (OR = 1.3; 95% CI: 0.833–2.214).
• Empiric antibiotic use with infliximab did not reduce sepsis risk and may lead to increased healthcare costs and contribute to antimicrobial resistance.
• Findings underscore the need for antimicrobial stewardship and suggest further prospective studies are warranted to evaluate the role of antibiotics in ASUC management.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective cohort study analyzed data from 2,788 patients with acute severe ulcerative colitis (ASUC) using the TriNetX platform, ultimately including 1,028 patients after propensity score matching, which enhances the reliability of the findings.
• The primary outcome of all-cause mortality showed no significant difference between the two cohorts (10 deaths in each group), with an odds ratio of 1.0, indicating that concurrent antibiotic use did not impact mortality rates.
• Secondary outcomes, including sepsis rates, also did not demonstrate a significant benefit from antibiotic use, with a risk difference of 0.973% and an odds ratio of 1.3 (95% CI: 0.833–2.214).

2. Comparison to Current Standard-of-Care:

• The findings challenge the common practice of empiric antibiotic use alongside infliximab in ASUC, suggesting that this approach does not improve clinical outcomes and may contribute to increased healthcare costs and antimicrobial resistance.
• Current guidelines do not specifically endorse routine antibiotic use in conjunction with infliximab, and this study provides evidence that may influence future recommendations.

3. Clinical Relevance and Feasibility:

• While the study provides important insights into the lack of benefit from antibiotics in this context, it does not propose a new treatment paradigm or significantly alter existing management strategies for ASUC.
• The implications for antimicrobial stewardship are notable, as the study highlights the need for careful consideration of antibiotic use in this patient population.

Overall, while the study offers valuable data that may inform clinical practice and guidelines, it does not present findings that are robust enough to be classified as practice-changing at this time.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study indicates that concurrent antibiotic use with infliximab does not improve outcomes in Acute Severe Ulcerative Colitis (ASUC), reinforcing the need for effective treatment strategies. This context strengthens Cristcot’s position with its HCA suppository and Sephure® applicator, as they offer innovative solutions that may address unmet needs in UC management.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients who may not respond to traditional therapies, positioning Cristcot’s products favorably against oral, topical, and biologic options.
• Sephure® enhances the delivery of HCA suppository, potentially improving patient compliance and comfort, which are critical in managing UC effectively.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring new trial endpoints that emphasize patient-reported outcomes and quality of life, as well as potential label expansions for HCA suppository.
• Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of HCA and Sephure®, and engage healthcare professionals (HCPs) with educational initiatives on the advantages of rectal delivery systems.
• Marketing: Highlight the unique benefits of Sephure® and HCA in promotional materials, focusing on their role in enhancing patient adherence and outcomes compared to traditional therapies.

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Abstract: P5424 - The Risk of Emergent Colectomy for Ulcerative Colitis Has Increased Over Time

Presenting Author: Michael Ly, BA
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=717
• 14% of patients underwent emergent colectomy, with a significant increase to 33% in the most recent period (2017-2020, p<0.001).
• Non-white patients had a higher likelihood of emergent colectomy (23% vs. 10%, P<0.001), indicating potential disparities in access to care.
• Increased odds of emergent colectomy were observed in later time periods, with adjusted odds ratios of 3.57 (2017-2020) and 3.66 (2014-2016).
• Findings suggest that patients may be delaying surgical intervention in favor of medical management, leading to more severe disease states.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective cohort study analyzed data from 717 patients with ulcerative colitis (UC) to evaluate trends in emergent colectomies over time, specifically from 2003 to 2020.
• The study employed appropriate statistical methods, including Chi-square tests and multivariable logistic regression, to adjust for confounders such as race and social determinants of health.
• While the sample size is substantial, the retrospective nature limits the ability to establish causation definitively.

2. Comparison to Current Standard-of-Care:

• The findings indicate an increasing trend in emergent colectomies, particularly in the most recent period (2017-2020), despite the availability of new therapies, suggesting a potential gap in timely surgical intervention.
• This trend contrasts with current guidelines that advocate for timely surgical evaluation in patients with severe UC, highlighting a possible deviation from best practices.

3. Clinical Relevance and Feasibility:

• The study underscores the importance of patient education regarding the risks of delaying surgery, particularly for non-white patients who were found to be at higher risk for emergent colectomy.
• While the findings are significant for understanding patient management and disparities in care, they do not introduce new therapeutic options or strategies that would change current clinical practice.

Overall, this study provides valuable insights into the management of UC and highlights the need for improved decision-making regarding surgical interventions, but it does not present findings that would warrant immediate changes in practice.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the study indicate a concerning trend of increasing emergent colectomies among ulcerative colitis (UC) patients, despite advancements in medical therapies. This suggests a potential opportunity for Cristcot to position its products, particularly the Hydrocortisone Acetate (HCA) Suppository and Sephure® Suppository Applicator, as effective alternatives that could mitigate the need for surgical interventions.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, especially given the increasing rates of emergent colectomy, which may be attributed to inadequate management of UC with existing therapies.
• Sephure® offers a unique advantage in enhancing patient compliance and comfort, while the HCA Suppository demonstrates rapid efficacy, potentially addressing the unmet need for effective rescue therapies in UC management.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring new trial endpoints that focus on long-term outcomes and quality of life, as well as potential label expansions to include indications for patients at risk of emergent colectomy.
• Medical Affairs: Prioritizing real-world evidence generation to support the clinical benefits of HCA and Sephure® could enhance HCP education and engagement, particularly around the risks of delaying surgical intervention.
• Marketing: There are opportunities to enhance differentiation by emphasizing the unique delivery mechanism of Sephure® and the rapid action of HCA in marketing campaigns, positioning them as essential tools in the management of UC.

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Abstract: P5431 - Efficacy of Retreatment With Upadacitinib After Treatment Interruption in Ulcerative Colitis: Data From the U-ACTIVATE Open-Label Extension

Presenting Author: Remo Panaccione, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=110
• Clinical remission per adapted Mayo score was achieved by 52.4%, 66.7%, and 76.3% of patients at weeks 48, 96, and 144, respectively, in the UPA15 group.
• In the UPA15 to UPA30 escalation group, clinical remission rates were 48.3%, 59.4%, and 61.1% at the same time points.
• Endoscopic remission was achieved by 31.3%, 40.0%, and 33.3% of patients in the UPA15 group and 30.0%, 56.3%, and 56.4% in the UPA30 group at weeks 48, 96, and 144, respectively.
• Most patients who lost response after temporary UPA treatment interruption regained clinical and endoscopic efficacy upon retreatment with UPA15 and/or escalation to UPA30.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• The study is an open-label extension of previous randomized controlled trials (U-ACHIEVE and U-ACCOMPLISH), involving 110 patients who lost response to upadacitinib (UPA) after a temporary treatment interruption. The analysis provides data on clinical and endoscopic outcomes over 144 weeks.
• Clinical remission rates per adapted Mayo score were reported at 52.4%, 66.7%, and 76.3% at weeks 48, 96, and 144 for patients who remained on UPA15, indicating a progressive improvement in response over time.
• Endoscopic remission rates were also notable, with 31.3% achieving remission at week 48, although this varied across time points and treatment groups.

2. Comparison to Current Standard-of-Care:

• While the findings suggest that UPA can effectively recapture response in patients who previously lost efficacy, they do not provide a direct comparison to other treatment options or establish superiority over existing therapies.
• The study does not challenge current treatment guidelines but rather supports the use of UPA in a specific scenario of treatment interruption.

3. Clinical Relevance and Feasibility:

• The results are clinically relevant as they address a common issue in UC management—loss of response after treatment interruption. However, the open-label design limits the strength of the conclusions.
• While the findings are promising, they do not provide sufficient evidence to alter standard practice or recommend UPA as a first-line treatment in this context, especially given the lack of safety data in this specific analysis.

In summary, while the study offers valuable insights into the management of UC with UPA after treatment interruption, it does not present findings that would necessitate a change in current clinical practice.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study on Upadacitinib (UPA) highlights the potential for effective retreatment in ulcerative colitis (UC) patients who experience treatment interruptions. This finding strengthens Cristcot’s position by validating the need for innovative rectal delivery systems like the Sephure® Suppository Applicator and the Hydrocortisone Acetate (HCA) Suppository, which can enhance patient adherence and therapeutic outcomes.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients who may not respond adequately to oral therapies like UPA after interruptions.
• Sephure® offers a unique advantage in ensuring optimal drug delivery, potentially improving the efficacy of HCA suppositories compared to traditional methods.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term efficacy and safety of HCA suppositories, potentially including head-to-head comparisons with oral therapies.
• Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of rectal delivery systems and engage healthcare professionals (HCPs) through educational initiatives on the advantages of HCA and Sephure®.
• Marketing: Highlight the unique benefits of Sephure® in enhancing patient comfort and compliance, positioning HCA as a rapid-response therapy in the UC treatment landscape.

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Abstract: P5438 - Long-Term Comparative Outcomes of TNF-α Antagonists vs Vedolizumab as First-Line Therapy for Refractory Ulcerative Proctitis: A Propensity-Matched Study

Presenting Author: Ayushi Jayesh Shah, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=641
• TNFi-treated patients had significantly lower odds of emergency department visits and/or hospitalizations compared to VDZ at 6 months (14.3% vs 25%, p=0.03) and 12 months (16.1% vs 35.2%, p=0.01).
• No significant differences were observed between TNFi and VDZ in terms of steroid use or colectomy rates.
• In a matched cohort of 132 patients, ADA demonstrated a similarly reduced risk of ED visits and/or hospitalizations compared to VDZ at 6 and 12 months.
• Overall, TNFi may provide clinical advantages in managing refractory ulcerative proctitis, likely due to a faster onset of action.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This study utilized a large cohort of 641 patients with isolated ulcerative proctitis (UP) from a comprehensive database, employing propensity score matching to control for confounding variables, which enhances the reliability of the findings.
• The primary outcomes assessed included emergency department (ED) visits and hospitalizations at 6 and 12 months, with statistically significant differences observed between TNF inhibitors (TNFi) and vedolizumab (VDZ) in favor of TNFi.
• While the study design is robust, it is observational in nature, which limits the ability to draw definitive causal conclusions.

2. Comparison to Current Standard-of-Care:

• The findings suggest that TNFi may provide a quicker onset of action, leading to reduced ED visits and hospitalizations compared to VDZ, which aligns with existing knowledge about the pharmacodynamics of these therapies.
• However, the overall low rates of complications and surgeries in UP patients indicate that both treatment options are relatively safe, and the differences may not be clinically significant enough to alter current treatment guidelines.

3. Clinical Relevance and Feasibility:

• The study highlights the need for more data on biologic therapy in UP, a population often excluded from clinical trials, which is important for informing treatment decisions.
• While the results are relevant, they do not provide a paradigm shift in management strategies for UC, particularly since both TNFi and VDZ are already established therapies.

In summary, while the study offers valuable insights into the comparative effectiveness of TNFi and VDZ in refractory UP, it does not present findings that would necessitate a change in current clinical practice for ulcerative colitis management.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the potential for TNF-α antagonists (TNFi) and vedolizumab (VDZ) as effective first-line therapies for refractory ulcerative proctitis (UP), which may influence Cristcot's strategic positioning of its Hydrocortisone Acetate (HCA) suppository and Sephure® applicator. The findings suggest that while TNFi may offer advantages in reducing emergency room visits and hospitalizations, the unique delivery mechanism of the Sephure® applicator could enhance patient compliance and comfort, positioning Cristcot favorably in the market.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with localized disease like UP, which aligns with Cristcot's focus on rectal drug delivery.
• Sephure®'s ability to improve bioavailability and patient comfort may provide a competitive edge over traditional biologic therapies, especially in terms of adherence and ease of use.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess quality of life and patient-reported outcomes, as well as potential label expansions for HCA in refractory UP.
• Medical Affairs: Prioritizing real-world evidence generation on the effectiveness of HCA in conjunction with the Sephure® applicator could strengthen HCP messaging and support KOL engagement.
• Marketing: Opportunities exist to enhance differentiation by emphasizing the unique benefits of the Sephure® applicator in improving patient experience and compliance, alongside the rapid action of HCA in achieving clinical remission.

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Abstract: P5440 - Effectiveness and Safety of Guselkumab versus Risankizumab in Ulcerative Colitis: A Real-World Comparative Outcomes Analysis

Presenting Author: Ali Osman, MD, MSCI Candidate
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=622 (Guselkumab: 118, Risankizumab: 504)
• Guselkumab was associated with significantly lower 1-year corticosteroid use compared to risankizumab (22.0% vs. 34.5%; risk difference: -12.5%, p<=0.009).
• Kaplan–Meier estimates indicated a trend toward improved steroid-free survival with Guselkumab (55.9% vs. 39.8%; p<=0.405).
• Rates of hospitalization or emergency department visits were similar between the two groups (8.5% for Guselkumab vs. 10.7% for Risankizumab; p<=0.471).
• Advancement to other therapies occurred in 8.5% of the Guselkumab group versus 7.3% of the risankizumab group (p<=0.675), suggesting comparable therapy escalation rates.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective cohort study utilized the TriNetX Global Collaborative Network database, analyzing outcomes in 622 UC patients treated with either Guselkumab (n=118) or Risankizumab (n=504).
• The primary outcome demonstrated a statistically significant reduction in corticosteroid use at one year for Guselkumab (22.0% vs. 34.5%, p=0.009), indicating a potential benefit in managing steroid dependency.
• However, the study's retrospective design limits the ability to draw definitive causal conclusions, and the reliance on database outcomes may introduce biases.

2. Comparison to Current Standard-of-Care:

• While the findings suggest Guselkumab may reduce corticosteroid use compared to Risankizumab, both therapies are currently considered effective options in UC management, and the differences observed may not be clinically significant enough to alter treatment guidelines.
• Current AGA and ECCO guidelines do not differentiate between these IL-23 inhibitors based on corticosteroid-sparing effects, indicating that further evidence is needed to establish a clear preference.

3. Clinical Relevance and Feasibility:

• The study highlights a potential advantage of Guselkumab in reducing corticosteroid use, which is clinically relevant given the adverse effects associated with long-term steroid therapy.
• However, the similar rates of hospitalization and therapy escalation between the two groups suggest that both treatments are comparably safe and effective, limiting the immediate impact of these findings on clinical practice.

In summary, while the study provides valuable insights into the comparative effectiveness of Guselkumab and Risankizumab, the limitations inherent in its design and the lack of practice-altering implications categorize it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study comparing Guselkumab and risankizumab highlights the potential for Cristcot’s products, particularly the Hydrocortisone Acetate (HCA) Suppository, to address unmet needs in ulcerative colitis (UC) treatment. The findings suggest that while biologics are effective, there remains a significant opportunity for rectal delivery systems that enhance patient compliance and provide rapid symptom relief.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients seeking alternatives to systemic therapies like Guselkumab and risankizumab.
• Sephure® and HCA’s advantages include targeted delivery, improved bioavailability, and enhanced patient comfort, which may appeal to patients looking for effective, non-invasive treatment options.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that emphasize quality of life and symptom relief, potentially positioning HCA as a first-line therapy in specific UC patient populations.
• Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of HCA and Sephure®, focusing on patient adherence and outcomes compared to systemic therapies.
• Marketing: Highlight the unique benefits of Sephure® and HCA in promotional materials, emphasizing their role in enhancing patient comfort and compliance, and position them as complementary options to existing biologics.

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Abstract: P5448 - Assessment of Sociodemographic Factors and Outcomes of Ulcerative Colitis Hospitalizations: A Large Population-Based Study

Presenting Author: Laura Sahyoun, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=43,377
• Inpatient colectomy occurred in 17.9% of patients, with higher rates among younger males, non-Hispanic whites, and those with private insurance.
• Rescue medical therapy was administered to 15% of patients, with 11.5% of these patients subsequently undergoing colectomy.
• Multivariable analysis indicated that female sex, non-white race, and non-private insurance were associated with a lower risk of colectomy, while higher comorbidity index and admission to teaching hospitals increased the risk.
• Findings suggest a need for further research into sociodemographic factors influencing colectomy rates in UC patients.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective study analyzed a substantial cohort of 43,377 patients hospitalized for ulcerative colitis (UC) using the Vizient Clinical Database, providing a robust dataset for evaluating sociodemographic factors influencing hospitalization outcomes.
• The primary outcome, inpatient colectomy rates, was clearly defined, with 17.9% of patients undergoing this procedure. The use of multivariable logistic regression to identify risk factors adds statistical rigor to the findings.
• Statistical significance was appropriately assessed using Pearson’s χ2 test and t-tests, with a p-value threshold of <0.05, ensuring reliable interpretation of results.

2. Comparison to Current Standard-of-Care:

• The findings highlight sociodemographic disparities in UC hospitalization outcomes, particularly regarding colectomy rates, which align with existing literature on the impact of race, gender, and insurance status on healthcare access and outcomes.
• While the study does not propose new treatment modalities or management strategies, it underscores the need for awareness of these disparities in clinical practice, which is consistent with current guidelines emphasizing personalized care.

3. Clinical Relevance and Feasibility:

• Understanding the sociodemographic factors associated with higher colectomy rates can inform targeted interventions and resource allocation in healthcare settings, particularly in teaching hospitals.
• However, the study does not provide direct implications for treatment changes or new therapeutic approaches, limiting its immediate impact on clinical practice.

Overall, while the study offers valuable insights into the sociodemographic influences on UC hospitalization outcomes, it does not present findings that would necessitate a change in current management practices, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights significant sociodemographic factors influencing hospitalization outcomes in ulcerative colitis (UC), which may inform Cristcot's strategic positioning of the Sephure® Suppository Applicator and Hydrocortisone Acetate (HCA) Suppository. The findings suggest a potential market for targeted interventions that address disparities in treatment access and outcomes, thereby strengthening Cristcot's product portfolio.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with specific sociodemographic profiles that may benefit from targeted therapies like HCA suppository.
• Sephure® offers competitive advantages in terms of enhanced delivery and patient compliance, which could be emphasized in marketing strategies to differentiate from oral and biologic therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring sociodemographic factors in future trials to better understand patient populations and potentially expand indications for HCA suppository.
• Medical Affairs: Prioritize real-world evidence initiatives that address the impact of sociodemographic factors on treatment outcomes, enhancing HCP education and KOL engagement.
• Marketing: Highlight the unique benefits of Sephure® and HCA in addressing the needs of diverse patient populations, leveraging data from the study to support claims and enhance market positioning.

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Abstract: P5456 - Impact of Hyponatremia on Mortality and Other In-Hospital Outcomes in Patients With Ulcerative Colitis (UC): A Retrospective Cohort Analysis Using the National Inpatient Sample

Presenting Author: Hamza Tahir, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=60,660
• Hyponatremia in hospitalized UC patients is associated with a 21-fold increase in inpatient mortality (aOR 21.33; 95% CI, 4.90-92.89; P < 0.001).
• Patients with hyponatremia had a two-fold increase in mean length of stay (mean difference 2.02; 95% CI, 1.39-2.65; P < 0.001) and elevated total hospital charges.
• Significantly higher rates of anemia, blood transfusions, intestinal perforation, hypoalbuminemia, acute kidney injury, sepsis, and mechanical ventilation were observed in the hyponatremia group (all P < 0.05).
• No significant differences were found in rates of toxic megacolon, hypovolemic shock, colectomy, or renal replacement therapy between patients with and without hyponatremia.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This study utilized a large national database (National Inpatient Sample) to analyze outcomes in 60,660 hospitalized UC patients, with a specific focus on 7,425 patients who had hyponatremia.
• The study employed multivariable regression analysis to adjust for confounders, enhancing the reliability of the findings regarding in-hospital mortality and other complications.
• Statistical significance was achieved for key outcomes, including a 21-fold increase in inpatient mortality (aOR 21.33; 95% CI, 4.90-92.89; p < 0.001) and a two-fold increase in mean length of stay (mean difference 2.02; 95% CI, 1.39-2.65; p < 0.001).

2. Comparison to Current Standard-of-Care:

• The findings align with existing literature that recognizes electrolyte imbalances as significant in UC management but do not introduce new treatment modalities or strategies that would alter current practice guidelines.
• While the study highlights the association between hyponatremia and worse outcomes, it does not provide direct evidence for interventions that could mitigate these risks.

3. Clinical Relevance and Feasibility:

• The study underscores the importance of monitoring and managing hyponatremia in hospitalized UC patients, which is a relevant clinical consideration but does not change the therapeutic landscape.
• Although the findings suggest that early detection and management of hyponatremia could improve outcomes, the study does not provide specific recommendations or interventions that could be readily implemented in clinical practice.

In summary, while the study provides valuable insights into the impact of hyponatremia on UC outcomes, it does not present findings that would necessitate a change in current management practices, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the significant impact of hyponatremia on clinical outcomes in hospitalized patients with ulcerative colitis (UC), emphasizing the need for effective management strategies. This aligns with Cristcot's focus on innovative therapies for UC, potentially strengthening the case for the Hydrocortisone Acetate (HCA) Suppository as a timely intervention in acute settings.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly in acute care settings where rapid symptom relief is critical, positioning Cristcot's HCA suppository favorably against oral and biologic therapies.
• The Sephure® applicator enhances the delivery of HCA, improving patient compliance and comfort, which could be a significant advantage in managing acute UC exacerbations.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider further studies to explore the role of HCA in patients with hyponatremia and potentially expand indications to include acute management scenarios.
• Medical Affairs: Prioritize real-world evidence initiatives that demonstrate the effectiveness of HCA in reducing complications associated with hyponatremia in UC patients, enhancing HCP education on this topic.
• Marketing: Highlight the unique benefits of the Sephure® applicator in delivering HCA, focusing on its role in improving patient outcomes and reducing hospital stays, which could resonate with both healthcare providers and patients.

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Abstract: P5462 - Shorter Disease Duration Increases Clinical Remission Rates in Real-World Observational Studies for Crohn’s Disease, but Not Ulcerative Colitis: A Systematic Review and Meta-Analysis

Presenting Author: Michael Scott Dunn, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=141 studies (83 UC, 64 CD)
• Shorter mean disease duration (<8 years) in Crohn’s Disease (CD) patients is associated with significantly higher clinical remission rates at both induction (60.7% vs 40.6%) and maintenance phases (66.1% vs 48.8%) compared to longer disease duration (>8 years) (p < 0.05).
• No significant association was found between mean disease duration and clinical remission rates in Ulcerative Colitis (UC) patients.
• Exploratory analysis in CD patients showed no significant difference in clinical remission between those with disease duration <5 years and those with 5-8 years during both induction and maintenance phases.
• Findings emphasize the importance of early intervention with advanced therapies in CD to improve clinical outcomes.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This systematic review and meta-analysis included 141 studies, with a focus on real-world data from both Crohn's Disease (CD) and Ulcerative Colitis (UC) patients treated with various advanced therapies.
• While the study found significant associations between disease duration and clinical remission rates in CD, it did not establish a similar correlation for UC, indicating a potential limitation in the applicability of findings to UC management.
• The statistical analysis employed (ANOVA) is appropriate for the data type, but the lack of significant findings for UC suggests that the evidence may not be robust enough to influence clinical practice.

2. Comparison to Current Standard-of-Care:

• The findings align with existing knowledge that earlier intervention in inflammatory bowel disease can lead to better outcomes, particularly in CD, but do not provide new insights or recommendations that would alter current UC treatment guidelines.
• Current guidelines emphasize the importance of timely therapy initiation, but this study does not provide actionable data specific to UC that would necessitate a change in practice.

3. Clinical Relevance and Feasibility:

• The study highlights the importance of disease duration in CD but does not translate this finding into actionable strategies for UC management, limiting its clinical relevance.
• As the study did not find a significant relationship between disease duration and remission in UC, it does not offer new biomarkers or stratification methods that could enhance personalized treatment approaches.

In summary, while the study provides valuable insights into the management of CD, its findings regarding UC do not warrant a change in current clinical practice, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the systematic review and meta-analysis highlight the importance of early intervention in Crohn's Disease (CD) for achieving clinical remission, which may strengthen Cristcot's positioning of the Hydrocortisone Acetate (HCA) Suppository as a timely therapeutic option. The Sephure® Suppository Applicator enhances the delivery of HCA, potentially improving patient outcomes and compliance, thus creating strategic opportunities for Cristcot in the UC treatment landscape.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with CD, where early intervention is crucial. This positions Cristcot favorably against oral, topical, and biologic therapies.
• The Sephure® device's ability to enhance medication delivery and patient comfort may provide a competitive advantage over traditional methods, especially in terms of compliance and speed of action.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring new trial endpoints that emphasize early intervention and potentially expand the label for HCA to include indications for patients with shorter disease durations.
• Medical Affairs: Prioritizing real-world evidence initiatives that demonstrate the benefits of early treatment with HCA and the Sephure® device could enhance HCP engagement and support clinical messaging.
• Marketing: Opportunities exist to differentiate Cristcot’s offerings by emphasizing the unique benefits of rectal delivery and the rapid response seen in the CESSA trial, aligning messaging with the findings of the meta-analysis.

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Abstract: P5463 - Comparative Analysis of Non-Malignant Skin Lesions in Crohn’s Disease and Ulcerative Colitis: Results From a Population-Based Study

Presenting Author: Nawaf Alhazmi, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=229,810 (108,775 CD; 121,035 UC)
• Prevalence of non-malignant skin lesions was 7.7% in Crohn’s disease (CD) and 8.4% in ulcerative colitis (UC).
• CD patients were younger (mean age 48.6 years) compared to UC patients (mean age 54.5 years), with a higher percentage of CD patients under 40 years.
• Skin tags were the most common cutaneous manifestation, followed by hidradenitis suppurativa and oral aphthae; CD patients had a higher prevalence of pyoderma gangrenosum and hidradenitis suppurativa.
• Findings highlight the need for tailored management of skin lesions in IBD patients, given the differences in prevalence and types of lesions between CD and UC.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This study utilized a large, real-world cohort from the TriNetX electronic health record network, including 108,775 Crohn's disease (CD) and 121,035 ulcerative colitis (UC) patients, which enhances the generalizability of the findings.
• The cross-sectional design is appropriate for assessing prevalence but does not establish causation or temporal relationships, limiting the strength of the conclusions.
• Statistical analyses, including chi-square and t-tests, were employed to compare demographic and clinical characteristics, providing a solid basis for the reported associations.

2. Comparison to Current Standard-of-Care:

• The findings highlight the prevalence of non-malignant skin lesions in IBD, with notable differences between CD and UC patients, which adds to the understanding of extraintestinal manifestations.
• While the study provides valuable insights, it does not propose new treatment strategies or interventions that would alter current management guidelines for UC.

3. Clinical Relevance and Feasibility:

• Understanding the prevalence and types of skin lesions associated with UC can inform clinicians about potential comorbidities and the need for multidisciplinary management.
• However, the study does not address the implications for treatment or management of these skin lesions in UC patients, which limits its immediate clinical application.

Overall, while the study offers important insights into the demographic associations and prevalence of skin lesions in UC, it does not provide evidence that would necessitate a change in current clinical practice or management strategies for ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial and the comparative analysis of non-malignant skin lesions in IBD provide Cristcot with a strengthened position in the rectal drug delivery market. The successful demonstration of HCA suppository efficacy and the unique advantages of the Sephure® applicator create new strategic opportunities for Cristcot to differentiate its products in a competitive landscape.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with UC, who may benefit from targeted therapies that enhance bioavailability and compliance.
• Sephure® offers a competitive advantage by improving patient comfort and adherence, while the HCA suppository's rapid action addresses an unmet need in UC management.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term outcomes and quality of life, as well as potential label expansions for broader indications.
• Medical Affairs: Prioritizing real-world evidence generation and educational initiatives for healthcare providers (HCPs) can enhance understanding of the benefits of rectal therapies and improve patient management strategies.
• Marketing: Opportunities exist to enhance differentiation through targeted messaging that emphasizes the unique benefits of the Sephure® applicator and the rapid efficacy of the HCA suppository, positioning them as first-line options in UC treatment.

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Abstract: P5464 - Increasingly High Prevalence of Advanced Therapy Use in Patients With Ulcerative Colitis in a Large Community and Academic Cohort: A Preliminary Analysis From IBD Qorus

Presenting Author: Adam A. Saleh, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=48 sites
• Advanced therapy (AT) was utilized in over 50% of ulcerative colitis (UC) visits, indicating a higher prevalence compared to other cohorts.
• There is a trend of increasing AT use among UC patients over time, suggesting improved adoption of advanced treatment options.
• Factors associated with AT use were identified through multivariable logistic regression, emphasizing the need for further research on how these factors influence patient outcomes.
• Future studies should explore the evolution of AT utilization across different clinical settings to optimize treatment strategies for UC.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• The study utilizes a large, multicenter cohort from the IBD Qorus, which enhances the generalizability of the findings. However, it is primarily descriptive and lacks a randomized controlled design, limiting the strength of causal inferences.
• While the study reports a high prevalence of advanced therapy (AT) use in UC visits, it does not provide specific clinical outcomes or comparative effectiveness data, which are critical for assessing the impact of AT on patient health.
• The use of multivariable logistic regression to identify factors associated with AT use is a strength, but the lack of detailed statistical outcomes diminishes the robustness of the conclusions.

2. Comparison to Current Standard-of-Care:

• The findings indicate an increasing trend in AT use, which aligns with current guidelines advocating for early and aggressive treatment in moderate-to-severe UC. However, the study does not provide evidence that this increased use translates into improved patient outcomes compared to existing standards.
• While the prevalence of AT use exceeds that reported in other cohorts, the implications for clinical practice remain unclear without data on treatment efficacy or safety.

3. Clinical Relevance and Feasibility:

• The study highlights the importance of AT in UC management, suggesting that more patients are receiving these therapies, which is a positive trend. However, without evidence of improved outcomes, the findings do not warrant immediate changes in clinical practice.
• Future research is needed to explore the long-term effects of increased AT utilization on patient outcomes, particularly in diverse clinical settings.

In summary, while the study provides valuable insights into the trends of AT use in UC, it does not present sufficient evidence to alter current management practices, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial and the IBD Qorus study suggest a strengthening of Cristcot’s product portfolio, particularly for the Hydrocortisone Acetate (HCA) Suppository and the Sephure® Suppository Applicator. The demonstrated efficacy and safety of the HCA suppository in achieving clinical remission in ulcerative colitis (UC) patients, combined with the unique delivery advantages of the Sephure® device, position Cristcot favorably in a competitive landscape increasingly focused on advanced therapies.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with distal UC, where traditional oral and topical therapies may be less effective.
• The Sephure® applicator enhances the HCA suppository's competitive advantages by improving medication placement, bioavailability, and patient compliance, which are critical factors in treatment success.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider expanding trial endpoints to include long-term outcomes and quality of life measures, as well as exploring label expansions for broader indications of HCA suppository use.
• Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of HCA and Sephure®, and develop educational initiatives targeting healthcare providers (HCPs) to enhance understanding of rectal therapies.
• Marketing: Highlight the unique benefits of the Sephure® applicator in promotional materials, emphasizing patient comfort and compliance, and position HCA as a rapid-response therapy in the UC treatment landscape.

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Abstract: P5465 - Clinical Evolution, Complications, and Need for Advanced Therapy in Patients With Ulcerative Colitis: Experience of an Institutional Cohort in Colombia

Presenting Author: Gustavo Adolfo Reyes Medina, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=53
• Intestinal complications occurred in 28.3% of patients, with hospitalization due to bleeding in 18.9% and surgery required in 9.4% of cases.
• Extraintestinal manifestations were observed in 15.1%, including primary sclerosing cholangitis (5%), osteoporosis (7%), and spondyloarthropathies (6%).
• Advanced therapies were initiated at a mean of 46 months; biologics did not significantly reduce complication rates (18.8% vs. 30.6%, p=0.2).
• All patients requiring surgery had disease extending beyond the rectum, indicating a potential link between disease extent and surgical intervention.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective cohort study included 53 adult patients with UC, which is a relatively small sample size that limits the generalizability of the findings.
• Outcomes focused on intestinal and extraintestinal complications, with a notable finding that 28.3% experienced intestinal complications, including significant bleeding in 18.9% of cases.
• Statistical comparisons were made, but the p-values indicate that many findings, such as the difference in complication rates between biologic users and non-users, did not reach conventional significance (p=0.2).

2. Comparison to Current Standard-of-Care:

• The study provides insights into the timing of complications and the use of advanced therapies in a Latin American cohort, which is underrepresented in existing literature.
• While it highlights that biologics did not significantly alter complication rates, it does not challenge or provide new evidence that would necessitate a change in current treatment guidelines.

3. Clinical Relevance and Feasibility:

• The findings underscore the importance of early intervention and the potential for advanced therapies to mitigate complications, but they do not provide new treatment options or strategies.
• Insights into the demographic and clinical characteristics of UC in this specific population may inform future studies but do not directly translate into immediate changes in clinical practice.

Overall, while the study adds valuable real-world data regarding UC management in a specific demographic, it does not present findings that would alter current treatment paradigms or guidelines, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study provides valuable insights into the clinical course of ulcerative colitis (UC) in a Latin American cohort, highlighting the need for effective treatment options. The findings support Cristcot’s strategic positioning of the Hydrocortisone Acetate (HCA) Suppository and Sephure® Suppository Applicator as innovative solutions in the UC treatment landscape, particularly for patients with distal disease.

Competitive Landscape & Positioning:

• The study underscores the challenges faced by UC patients, particularly regarding complications and the timing of advanced therapies, reinforcing the need for effective rectal delivery systems like Sephure®.
• HCA’s demonstrated efficacy in achieving clinical remission and symptom relief positions it favorably against existing oral and biologic therapies, particularly for patients with localized disease.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider further trials to explore the long-term benefits of HCA in diverse populations and potential label expansions to include broader indications.
• Medical Affairs: Prioritize real-world evidence generation to support HCA’s clinical benefits and engage healthcare professionals (HCPs) with educational initiatives on the advantages of rectal delivery systems.
• Marketing: Emphasize the unique benefits of Sephure® and HCA in addressing unmet needs in UC management, particularly in terms of patient comfort, compliance, and rapid symptom relief.

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Abstract: P5477 - Demographics and Clinical Characteristics of Patients With Ulcerative Colitis Receiving First-Line Advanced Therapies Categorized in AGA Guidelines as Lower, Intermediate, and Higher Efficacy

Presenting Author: Anita Afzali, MD, MPH, MHCM
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=6,552 (3,833 from IQVIA, 2,719 from Optum)
• 56.4% of patients in the higher efficacy group received higher efficacy therapies, with vedolizumab being the most common (59.5% in IQVIA, 61.7% in Optum).
• Age ≥ 65 years was significantly more prevalent in the higher efficacy group (IQVIA: 6.7% vs. 4.0%; Optum: 40.1% vs. 17.2%).
• Patients in the higher efficacy group had significantly higher UC severity scores compared to intermediate and lower efficacy groups (p< ≤ 0.001 for all).
• A substantial proportion of patients received lower efficacy therapies, indicating a potential misalignment with evidence-based prescribing practices.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• The study utilized claims data from two large databases (IQVIA and Optum), encompassing a total of 6,552 patients with UC who initiated first-line advanced therapies (AT) between 2018 and 2024.
• While the study design is observational and retrospective, it provides valuable insights into real-world prescribing patterns and patient demographics, which are often underrepresented in clinical trials.
• Statistical analyses were appropriately conducted using independent sample t-tests and Fisher exact tests to compare characteristics across efficacy groups, although the lack of randomization and control limits causal inferences.

2. Comparison to Current Standard-of-Care:

• The findings highlight a significant discrepancy between evidence-based recommendations and actual prescribing practices, with a notable proportion of patients receiving lower efficacy therapies (34.9% and 23.8% in the lower efficacy group).
• This misalignment suggests a need for improved adherence to the 2024 AGA guidelines, which stratify therapies based on efficacy, particularly for patients with higher disease severity.

3. Clinical Relevance and Feasibility:

• Understanding the demographic and clinical characteristics associated with the choice of first-line AT can inform targeted educational interventions for prescribers to enhance treatment alignment with guidelines.
• While the study does not introduce new therapies or change management protocols, it underscores the importance of appropriate therapy selection based on patient characteristics, which is crucial for optimizing outcomes in UC management.

In summary, while the study provides important insights into prescribing patterns and patient demographics, it does not present findings that would immediately alter clinical practice or introduce new therapeutic options. Therefore, it is classified as "Important but Not Practice-Changing."

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a significant trend in prescribing patterns for advanced therapies (AT) in ulcerative colitis (UC), indicating that while higher efficacy treatments are preferred, a substantial number of patients are still receiving lower efficacy options. This presents an opportunity for Cristcot to position its Sephure® Suppository Applicator and HCA Suppository as innovative solutions that enhance treatment efficacy and patient compliance, potentially capturing a share of the market currently dominated by lower efficacy therapies.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients who may benefit from targeted therapies like the HCA Suppository, which aims for rapid clinical remission.
• Sephure® offers competitive advantages in terms of improved delivery and patient comfort, which could enhance adherence compared to traditional oral or topical therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring new trial endpoints that emphasize patient-reported outcomes and quality of life, as well as potential label expansions to include broader indications for the HCA Suppository.
• Medical Affairs: Prioritizing real-world evidence generation to support the efficacy and safety of the HCA Suppository, along with educational initiatives targeting healthcare providers (HCPs) to improve awareness of rectal delivery benefits.
• Marketing: There are opportunities to enhance differentiation through targeted messaging that emphasizes the unique benefits of the Sephure® device and HCA Suppository, particularly in addressing the unmet needs of patients currently on lower efficacy therapies.

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Abstract: P5484 - Guselkumab Is Efficacious and Safe for Moderately-to-Severe Active Ulcerative Colitis: Real-World Data From a Large Tertiary Center

Presenting Author: Asher Shafrir, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=27
• At week 8, 96% of patients continued GUS treatment, with 84% maintaining it by week 12.
• Median SCCAI score decreased from 3.5 at baseline to 1 at week 8 and 0 at week 12, indicating significant clinical improvement.
• Clinical remission rates increased from 38.1% at baseline to 75% at week 8 and 92.9% at week 12.
• Adverse events were minimal, with no significant treatment-related complications reported.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This study presents a real-world analysis of Guselkumab (GUS) in 23 patients with moderately to severely active UC, which, while valuable, is limited by its small sample size and lack of a control group.
• Clinical remission rates improved significantly, with 75% achieving remission by week 8 and 92.9% by week 12, indicating promising efficacy; however, the absence of a comparator limits the ability to draw definitive conclusions about its superiority over existing therapies.
• Safety data showed no significant treatment-related adverse events, which is reassuring but requires further validation in larger cohorts.

2. Comparison to Current Standard-of-Care:

• While the findings are encouraging, they do not provide a direct comparison to current standard therapies such as anti-TNF agents or other biologics, which limits their immediate applicability in clinical practice.
• Current guidelines from AGA and ECCO recommend a range of therapies, and while GUS shows potential, it does not yet challenge existing treatment paradigms.

3. Clinical Relevance and Feasibility:

• The oral delivery and favorable safety profile of GUS are appealing, but the study's findings need to be corroborated in larger, controlled trials to establish its role in the treatment landscape of UC.
• Future studies should also explore biomarker stratification to enhance personalized treatment approaches, which could further support GUS's integration into practice.

In summary, while the study provides important insights into the efficacy and safety of GUS in a real-world setting, the limitations in study design and sample size prevent it from being classified as practice-changing at this time.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study on Guselkumab (GUS) reinforces the viability of advanced therapies for ulcerative colitis (UC) and highlights the potential for Cristcot’s products, particularly the HCA suppository and Sephure® applicator, to address unmet needs in this space. The findings suggest that while GUS shows strong efficacy, Cristcot's innovative delivery system could enhance patient compliance and comfort, positioning it favorably in the competitive landscape.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients who may not respond adequately to oral or biologic therapies.
• Sephure® offers unique advantages in terms of optimal medication placement and patient comfort, which could enhance adherence compared to traditional methods.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that emphasize patient-reported outcomes and quality of life, as well as potential label expansions for the HCA suppository.
• Medical Affairs: Prioritize real-world evidence generation to support the efficacy and safety of HCA and Sephure®, and develop educational initiatives targeting healthcare providers (HCPs) to enhance understanding of rectal therapies.
• Marketing: Highlight the unique benefits of the Sephure® applicator in promotional materials, focusing on patient comfort and compliance, and position the HCA suppository as a rapid-response option for UC management.

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Abstract: P5486 - Acute Severe Ulcerative Colitis: Uncovering the Gender Gap

Presenting Author: Kelly M. Vo, DO
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=4,494
• Female patients with acute severe ulcerative colitis (ASUC) had lower adjusted odds of colectomy (aOR: 0.69) compared to males, indicating a significant gender disparity in treatment outcomes.
• There was no difference in 1-year mortality rates between genders (aOR: 0.97), suggesting that the gender gap in colectomy rates does not impact long-term survival.
• Resource utilization, including total hospitalization charges and costs, was similar between genders, indicating that the disparity in colectomy rates is not due to differences in healthcare resource use.
• Only gender was identified as an independent predictor of colectomy, with no other tested factors (age, income, insurance, Charlson score, hospital bed size, urban location, teaching status) showing significant influence.
• Further research is needed to explore the underlying reasons for the observed gender gap in ASUC treatment outcomes.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This retrospective cohort study utilized the National Readmission Database, encompassing 4,494 patients diagnosed with acute severe ulcerative colitis (ASUC) from 2018 to 2022, which provides a substantial sample size for analysis.
• The primary outcome, the rate of colectomy, was assessed with appropriate adjustments for confounders, including age, income, insurance type, and comorbidities, enhancing the validity of the findings.
• Statistical significance was achieved with an adjusted odds ratio (aOR) of 0.69 for colectomy in females compared to males (p=0.01), indicating a notable gender disparity.

2. Comparison to Current Standard-of-Care:

• The findings align with existing literature suggesting gender differences in disease outcomes, but they do not provide new therapeutic strategies or interventions that would alter current management practices for ASUC.
• While the study highlights a gender gap in colectomy rates, it does not challenge or redefine treatment guidelines established by organizations such as AGA or ECCO.

3. Clinical Relevance and Feasibility:

• The study's insights into gender disparities in colectomy rates may prompt further investigation into underlying biological or social factors, which could eventually inform personalized treatment approaches.
• However, the lack of impact on mortality and resource utilization suggests that while the findings are important for understanding ASUC, they do not necessitate immediate changes in clinical practice.

In summary, while the study provides valuable insights into gender differences in ASUC outcomes, it does not present findings that would lead to a change in current management practices, thus categorizing it as important but not practice-changing.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a significant gender gap in treatment outcomes for acute severe ulcerative colitis (ASUC), indicating that females are less likely to require colectomy despite similar resource utilization. This finding may strengthen Cristcot's position in the market by emphasizing the need for tailored therapies that consider gender differences in treatment response, potentially enhancing the appeal of the Hydrocortisone Acetate (HCA) Suppository and Sephure® Applicator.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients who may benefit from targeted therapies like the HCA suppository, which aims for rapid clinical remission.
• Sephure®'s unique delivery mechanism may enhance patient compliance and comfort, positioning it favorably against traditional oral and topical therapies, especially in light of the findings regarding gender disparities in treatment outcomes.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring gender-specific outcomes in future trials, potentially expanding the HCA suppository's label to address the unique needs of female patients with ASUC.
• Medical Affairs: Prioritize real-world evidence initiatives that investigate gender differences in treatment response and resource utilization, enhancing HCP education and engagement with key opinion leaders (KOLs).
• Marketing: Highlight the unique benefits of the Sephure® Applicator and HCA Suppository in addressing the specific needs of female patients, leveraging the findings of the gender gap to differentiate Cristcot’s offerings in the UC treatment landscape.

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Abstract: P5490 - Efficacy of Advanced Therapies for Naïve and Experienced Patients for Moderately-to-Severely Active Ulcerative Colitis: A Bayesian Network Meta-Analysis

Presenting Author: Karolina Wosik, MSc, PhD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=Not specified
• For advanced treatment-naïve (AT-N) patients, mirikizumab (MIR) 300mg was significantly less effective than risankizumab (RZB) 1200mg (RR, 0.7) and guselkumab (GUS) 200mg was favored over MIR (RR, 1.6).
• In advanced treatment-experienced (AT-E) patients, adalimumab (ADA) 160/80mg and ozanimod 1mg were less favorable compared to GUS.
• For AT-N maintenance, tofacitinib (TOF) 10mg and upadacitinib (UPA) 30mg showed significantly higher efficacy compared to infliximab 120mg SC, MIR 200mg, and RZB (RRs ranging from 1.3 to 1.7).
• Most treatments for AT-E patients were more effective than RZB, with RZB 360mg showing no significant difference compared to placebo.
• Overall, the updated network meta-analysis confirmed previous findings, with RZB and GUS demonstrating superior efficacy over MIR, ADA, and FIL for AT-N induction.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• The study employs a systematic literature review and a Bayesian, multinomial, fixed-effect model, which are robust methodologies for synthesizing data across multiple studies.
• It includes a substantial number of studies (four additional for both induction and maintenance) and stratifies results by prior exposure to advanced therapies, enhancing the relevance of findings for different patient populations.
• While the results indicate significant differences in efficacy among various agents, the overall findings are consistent with previous network meta-analyses, suggesting reliability but not necessarily groundbreaking changes in practice.

2. Comparison to Current Standard-of-Care:

• The findings align with existing treatment guidelines, indicating that newer agents like risankizumab (RZB) and guselkumab (GUS) are more effective than older therapies such as adalimumab (ADA) and filgotinib in treatment-naïve patients.
• However, the lack of significant differences in many pairwise comparisons suggests that while there are incremental improvements, no single agent has emerged as a clear superior option across all patient types.

3. Clinical Relevance and Feasibility:

• The study highlights the comparative effectiveness of advanced therapies, which is crucial for clinicians in making informed treatment decisions, especially in complex cases of UC.
• While the findings are informative, they do not introduce a new treatment paradigm or significantly alter the current management strategies for UC, thus not warranting immediate changes in clinical practice.

In summary, this study provides valuable insights into the comparative efficacy of advanced therapies for UC but does not present findings that would necessitate a shift in current treatment protocols.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study strengthens Cristcot’s position in the ulcerative colitis (UC) treatment landscape by validating the efficacy of the HCA suppository and highlighting the advantages of the Sephure® applicator. The findings suggest a competitive edge in rectal drug delivery, particularly for patients with moderate to severe UC.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients who may not respond adequately to oral or biologic therapies.
• The Sephure® applicator enhances the delivery of the HCA suppository, improving patient compliance and comfort, which are critical factors in treatment adherence.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that focus on long-term remission and quality of life, as well as potential label expansions for the HCA suppository.
• Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of the HCA suppository and engage healthcare professionals (HCPs) through educational initiatives that emphasize the advantages of rectal delivery systems.
• Marketing: Highlight the unique benefits of the Sephure® applicator and HCA suppository in marketing campaigns, focusing on patient comfort, compliance, and rapid symptom relief to differentiate from oral and biologic therapies.

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Abstract: P5491 - Safety, Tolerability, and Efficacy of PL8177 in Adults With Active Ulcerative Colitis: Results From a Phase 2a, Randomized, Placebo-Controlled Study

Presenting Author: Dana J. Lukin, MD, PhD, FACG
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=12
• Clinical response achieved in 78% of participants receiving PL8177 compared to 33% in the placebo group.
• Clinical remission was observed in 33% of the PL8177 group, while none in the placebo group.
• Symptomatic remission occurred in 56% of participants on PL8177 versus 33% on placebo.
• Primary endpoint (endoscopic subscore of 0 or 1) was met by 33% of participants in both PL8177 and placebo groups.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This phase 2a study utilized a double-blind, randomized, placebo-controlled design, which is a robust methodology for assessing treatment efficacy and safety. However, the small sample size (n=12) limits the generalizability of the findings.
• The primary endpoint, an endoscopic subscore of 0 or 1, was met by 33% of participants in the PL8177 group, which is not statistically superior to placebo (also 33%). This raises questions about the clinical significance of the results.
• Adverse events were reported, but all were deemed unrelated to treatment, indicating a favorable safety profile, although the low incidence of AEs may not provide a comprehensive safety assessment.

2. Comparison to Current Standard-of-Care:

• While PL8177 demonstrated some efficacy in clinical response and symptomatic remission, the results do not surpass existing therapies in terms of remission rates or overall effectiveness as outlined in current guidelines (e.g., AGA, ECCO).
• The findings suggest potential for PL8177 as an alternative treatment, but without comparative data against established therapies, its role remains uncertain.

3. Clinical Relevance and Feasibility:

• The oral formulation and favorable tolerability profile are positive attributes, but the limited sample size and lack of robust efficacy data hinder immediate clinical application.
• Future studies with larger populations and longer follow-up are necessary to validate these findings and assess the potential for biomarker stratification.

In summary, while the study provides preliminary insights into PL8177's efficacy and safety, the limitations in sample size and endpoint achievement suggest that it does not yet warrant a change in clinical practice for managing ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The Phase 3 CESSA trial results for the Hydrocortisone Acetate (HCA) suppository strengthen Cristcot’s product portfolio by demonstrating significant clinical efficacy and safety in treating ulcerative colitis (UC). The findings position Cristcot favorably against emerging therapies like PL8177, highlighting the unique advantages of the Sephure® Suppository Applicator in enhancing drug delivery and patient compliance.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route compared to oral, topical, and biologic options, particularly for patients with distal UC.
• The Sephure® applicator's ability to improve bioavailability and patient comfort provides a competitive edge over traditional delivery methods, while the HCA suppository's rapid onset of action enhances its attractiveness in the market.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider expanding trial endpoints to include long-term remission rates and explore additional comparator arms to strengthen the evidence base for HCA suppository.
• Medical Affairs: Prioritizing real-world evidence generation and educational initiatives for healthcare professionals (HCPs) can enhance understanding of the HCA suppository's benefits and the Sephure® applicator's role in treatment.
• Marketing: Opportunities exist to enhance differentiation through targeted messaging that emphasizes the unique delivery mechanism and rapid efficacy of the HCA suppository, positioning it as a first-line option for UC management.

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Abstract: P5496 - A Stroke Too Soon: Embolic Event in a Young Patient Treated With Upadacitinib for Ulcerative Colitis - A Case for Caution?

Presenting Author: Raja Chandra Chakinala, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• A 46-year-old male with a history of ulcerative colitis developed multifocal ischemic strokes while on Upadacitinib, highlighting potential vascular complications associated with JAK1 inhibitors.
• Brain MRI revealed multiple infarcts without large vessel occlusion, indicating a possible embolic event rather than a thrombotic one.
• The patient had a significant family history of thrombosis, suggesting the need for personalized risk assessment in treatment selection for ulcerative colitis.
• This case emphasizes the importance of considering both personal and familial thrombotic histories when prescribing JAK1 inhibitors, as current guidelines do not address pre-treatment hypercoagulability testing in such patients.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report presents a single instance of multifocal ischemic stroke in a 46-year-old male with a history of moderate-to-severe UC treated with Upadacitinib. While the case is compelling, it is anecdotal and lacks the statistical power of larger studies.
• The report highlights the patient's complex medical history, including previous treatments and familial thrombotic history, which may confound the direct association between Upadacitinib and the stroke event.
• There is no control group or comparative data to assess the incidence of cerebrovascular events in a broader population of patients treated with Upadacitinib.

2. Comparison to Current Standard-of-Care:

• Current guidelines acknowledge the potential risks associated with JAK inhibitors, including MACE and VTE, particularly in patients with pre-existing cardiovascular risk factors. This case adds to the existing literature but does not provide new evidence that would alter treatment protocols.
• While the case raises awareness of potential vascular complications, it does not challenge the efficacy or safety profile established in larger clinical trials of Upadacitinib.

3. Clinical Relevance and Feasibility:

• The findings underscore the importance of individualized treatment plans that consider personal and familial thrombotic risks, which is a relevant consideration in clinical practice.
• However, the implications of this case are limited to cautionary advice rather than a change in practice, as it does not provide sufficient evidence to warrant a reevaluation of the use of Upadacitinib in the broader UC population.

In summary, while this case report is important for raising awareness about potential risks associated with Upadacitinib, it does not provide robust evidence to change current management practices for UC.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights potential safety concerns associated with JAK1 inhibitors like Upadacitinib, which may strengthen Cristcot's position by emphasizing the safety profile of its Hydrocortisone Acetate (HCA) suppository and the unique delivery mechanism of the Sephure® applicator. This could create opportunities for Cristcot to differentiate its products in a competitive market.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with a history of thrombotic events, as it may mitigate systemic risks associated with oral therapies like Upadacitinib.
• Sephure® and HCA’s advantages include targeted delivery, rapid onset of action, and a strong safety profile, which can enhance patient compliance and comfort compared to systemic therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider further studies to explore the long-term safety of HCA, potentially including comparisons with JAK1 inhibitors and other systemic therapies.
• Medical Affairs: Prioritize real-world evidence generation focusing on the safety and efficacy of HCA in diverse patient populations, and develop educational initiatives for healthcare providers regarding the risks associated with JAK inhibitors.
• Marketing: Highlight the unique benefits of the Sephure® applicator and HCA in promotional materials, emphasizing safety, patient comfort, and compliance to differentiate from oral and biologic therapies.

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Abstract: P5499 - Fulminant Ulcerative Colitis FollowingHelicobacter pyloriEradication: A Case Report

Presenting Author: Abraham Tanousian, DO
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• A 54-year-old male with a 20-year history of well-controlled ulcerative colitis experienced a severe exacerbation three weeks post-H. pylori eradication therapy.
• Initial lab results indicated leukocytosis, anemia, thrombocytosis, and significantly elevated stool calprotectin, with CT imaging revealing diffuse colitis.
• Colonoscopy confirmed pan-ulcerative colitis with deep ulcerations, leading to colonic perforation and necessitating emergent surgery.
• The case suggests a potential causal relationship between H. pylori eradication and severe UC flare, highlighting the need for caution in treating H. pylori in IBD patients.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report describes a single patient with a significant exacerbation of ulcerative colitis (UC) following Helicobacter pylori eradication therapy, highlighting a potential temporal association rather than establishing a direct causal relationship.
• While the clinical presentation and subsequent complications are noteworthy, the evidence is anecdotal and lacks the statistical rigor of larger studies or controlled trials.

2. Comparison to Current Standard-of-Care:

• The findings align with existing literature suggesting an inverse relationship between H. pylori and inflammatory bowel disease (IBD), but they do not provide new evidence that would alter current management guidelines for H. pylori in UC patients.
• Current guidelines do not specifically contraindicate H. pylori eradication in patients with quiescent UC, and this case does not provide sufficient evidence to warrant a change in practice.

3. Clinical Relevance and Feasibility:

• While the case raises awareness of potential risks associated with H. pylori treatment in UC patients, it does not provide actionable insights or guidelines for clinical practice.
• Further research is indeed warranted to explore the mechanisms proposed and to assess the risk of exacerbation in a larger cohort, but until such data is available, the implications for clinical practice remain limited.

In summary, while this case report is important for raising awareness of a potential risk, it does not provide sufficient evidence to change current clinical practices regarding H. pylori management in patients with ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a potential risk associated with H. pylori eradication in patients with ulcerative colitis (UC), which may create an opportunity for Cristcot’s products, particularly the Hydrocortisone Acetate (HCA) Suppository, as a rapid intervention for exacerbations. The Sephure® Suppository Applicator can enhance patient compliance during acute episodes, positioning Cristcot favorably in the treatment landscape.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, especially for patients experiencing severe UC exacerbations, which may not be adequately managed by oral or topical therapies.
• Sephure® offers a unique advantage in terms of delivery precision and patient comfort, while HCA’s rapid action could be critical in managing acute flares, differentiating Cristcot’s offerings from traditional therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider further trials to explore the efficacy of HCA in patients with a history of H. pylori eradication and its impact on UC management, potentially expanding the label to include this indication.
• Medical Affairs: Prioritize real-world evidence studies to assess the long-term outcomes of HCA in patients with UC, particularly those with recent H. pylori treatment, and develop educational initiatives for healthcare providers regarding the risks associated with H. pylori eradication.
• Marketing: Highlight the unique benefits of the Sephure® applicator and HCA in managing acute UC exacerbations, focusing on patient comfort, compliance, and rapid symptom relief in marketing campaigns.

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Abstract: P5511 - Recurrent Thromboembolism and Ulcerative Colitis Flares Following Anticoagulation Withdrawal: A Case Highlighting the Interplay Between IBD and Hypercoagulability

Presenting Author: Bhaavya Pinnala, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• Patient with longstanding Ulcerative Colitis (UC) experienced recurrent thromboembolic events and UC flares after withdrawal of warfarin therapy.
• Despite negative hypercoagulable workup and placement of a Watchman device, the patient continued to have DVTs and symptomatic UC flares upon cessation of anticoagulation.
• Findings suggest that inflammation from UC may independently drive a hypercoagulable state, necessitating consideration of ongoing anticoagulation in select IBD patients.
• Clinical decisions regarding anticoagulation should be individualized, particularly when discontinuation leads to thromboembolism and exacerbation of IBD symptoms.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This abstract presents a single case study, which inherently limits the generalizability of the findings. While the case is compelling, it lacks the statistical power and rigor of larger studies.
• The patient’s history of recurrent thromboembolic events and UC flares following anticoagulation withdrawal provides valuable insights but does not establish a causal relationship or a broader applicability to the UC population.

2. Comparison to Current Standard-of-Care:

• The findings suggest a potential link between inflammation in UC and hypercoagulability, which aligns with existing literature but does not provide new evidence that would alter current anticoagulation practices in IBD management.
• Current guidelines do not universally recommend indefinite anticoagulation for all IBD patients, particularly in the absence of traditional risk factors, which this case does not challenge.

3. Clinical Relevance and Feasibility:

• While the case highlights the need for individualized treatment approaches, it does not provide a clear framework for clinical decision-making or guidelines for anticoagulation in UC patients.
• The implications of this case may encourage further research into the relationship between IBD activity and thromboembolic risk, but it does not present immediate changes to practice.

In summary, while the case offers important insights into the interplay between UC and thromboembolic events, it does not provide sufficient evidence to warrant a change in clinical practice or guidelines for anticoagulation management in UC patients.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial and the case study on anticoagulation in IBD patients suggest a strategic opportunity for Cristcot to position its products, particularly the HCA suppository and Sephure® applicator, as essential components in managing ulcerative colitis (UC) effectively. The demonstrated efficacy of the HCA suppository in achieving clinical remission and the unique delivery mechanism of the Sephure® applicator can enhance patient adherence and comfort, potentially addressing unmet needs in UC management.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with distal UC, where traditional oral therapies may be less effective.
• The Sephure® applicator's ability to improve bioavailability and patient comfort, combined with the rapid action of the HCA suppository, positions Cristcot favorably against oral, biologic, and topical therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term outcomes and quality of life, as well as potential label expansions to include patients with a history of thromboembolic events.
• Medical Affairs: Prioritizing real-world evidence studies to support the safety and efficacy of HCA suppository in patients with complex medical histories, including those on anticoagulation therapy, could enhance HCP engagement and education.
• Marketing: Opportunities exist to differentiate Cristcot’s offerings by emphasizing the unique benefits of rectal delivery systems and the rapid onset of action, potentially leveraging case studies to support messaging around the interplay of IBD and thromboembolic risks.

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Abstract: P5519 - Post-Partum Pyoderma Gangrenosum in Young Female With Ulcerative Colitis

Presenting Author: Krishna Shah, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• Post-partum period is characterized by a pro-inflammatory state that can exacerbate underlying autoimmune conditions, such as Ulcerative Colitis (UC).
• The patient developed pyoderma gangrenosum, a neutrophilic dermatosis, following a complicated pregnancy and emergency Cesarean section.
• Diagnosis of pyoderma gangrenosum was supported by the patient's history of UC and clinical presentation, including non-healing surgical wounds and lower extremity lesions.
• Immediate treatment with steroids led to significant clinical improvement, highlighting the importance of recognizing inflammatory skin conditions in the post-partum setting.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report describes a single patient with a complex clinical history, including Ulcerative Colitis (UC) and complications during pregnancy, leading to the diagnosis of pyoderma gangrenosum. While the case is illustrative, it lacks the robust design of larger studies, such as randomized controlled trials (RCTs) or cohort studies, which would provide more generalizable data.
• The findings are based on clinical observations and histopathological confirmation, which are valuable but do not provide quantitative outcomes or statistical analysis that would strengthen the conclusions.

2. Comparison to Current Standard-of-Care:

• The case highlights the exacerbation of UC during the postpartum period, which aligns with existing literature on the pro-inflammatory state post-delivery. However, it does not introduce new treatment modalities or significantly challenge current management strategies for UC or pyoderma gangrenosum.
• Current guidelines recognize the need for careful management of UC in pregnant and postpartum patients, but this case does not provide new insights that would alter standard practices.

3. Clinical Relevance and Feasibility:

• The case emphasizes the importance of recognizing and managing skin manifestations like pyoderma gangrenosum in patients with UC, particularly in the postpartum context. However, it does not present new therapeutic options or strategies that could be widely implemented.
• While the case is clinically relevant for understanding the interplay between UC and postpartum complications, its implications are limited to individual patient management rather than broader clinical practice changes.

In summary, while the case provides important insights into the management of UC in the postpartum period, it does not present findings that would warrant a change in practice or significantly advance the understanding of UC management.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial for the Hydrocortisone Acetate (HCA) Suppository strengthen Cristcot’s product portfolio by demonstrating significant efficacy in treating ulcerative colitis (UC) and highlighting the advantages of the Sephure® Suppository Applicator. This positions Cristcot favorably in the competitive landscape of UC therapies.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with distal UC, offering a targeted approach that may outperform oral and topical therapies in terms of bioavailability and speed of action.
• The Sephure® device enhances patient compliance and comfort, which are critical factors in treatment adherence, especially in a population that may experience significant discomfort from traditional delivery methods.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term remission and quality of life, as well as potential label expansions to include broader indications for HCA suppositories.
• Medical Affairs: Prioritizing real-world evidence generation and educational initiatives for healthcare providers (HCPs) can enhance understanding of the benefits of rectal delivery systems and the unique advantages of the Sephure® applicator.
• Marketing: Opportunities exist to enhance differentiation through targeted messaging that emphasizes the rapid response and high compliance rates associated with the HCA suppository, positioning it as a first-line option for patients with active UC.

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Abstract: P5528 - Schistosomiasis or Ulcerative Colitis? Unraveling the Overlap Between Parasitic Infection and IBD

Presenting Author: Dimo Dimitrov, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Patient: 34-year-old Brazilian male with symptoms of blood-tinged stools, rectal pain, and nausea.
• Initial colonoscopy indicated proctosigmoid colitis with histological findings suggestive of IBD, including crypt abscesses and eosinophilic microabscesses.
• Empiric treatment with mesalamine and prednisone was initiated; however, the patient later presented with severe symptoms and was found to have a Schistosoma infection confirmed by serology.
• Immunosuppression with steroids in the context of undiagnosed parasitic infection posed risks, highlighting the need for careful differential diagnosis between IBD and parasitic infections.
• Symptom improvement after treatment with praziquantel and albendazole raises questions about the contributions of anti-parasitic therapy versus immunosuppression in recovery.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report presents a single patient with a complex clinical scenario involving suspected ulcerative colitis (UC) and a concurrent parasitic infection, specifically schistosomiasis. While the case is illustrative, it lacks the robustness of a controlled study, such as a randomized controlled trial (RCT) or a larger cohort analysis.
• The findings highlight the diagnostic challenges and potential mismanagement that can arise when parasitic infections mimic IBD, but the evidence is anecdotal and does not provide quantitative outcomes or statistical analysis.

2. Comparison to Current Standard-of-Care:

• The case underscores the importance of differential diagnosis in IBD, particularly in endemic regions, aligning with existing guidelines that recommend thorough evaluations for infectious causes in patients presenting with gastrointestinal symptoms.
• However, it does not introduce new treatment modalities or significantly alter the current management strategies for UC, which already emphasize careful diagnosis and consideration of infectious etiologies.

3. Clinical Relevance and Feasibility:

• The case emphasizes the need for detailed history-taking and targeted parasitic workup in high-risk patients, which is clinically relevant but does not translate into a change in practice for the broader UC population.
• While the findings are important for awareness and education among clinicians, they do not provide actionable insights that would lead to a change in treatment protocols or guidelines.

In summary, while the case report is valuable for highlighting the overlap between parasitic infections and IBD, it does not present findings that would warrant a change in clinical practice or management of ulcerative colitis at a population level.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the critical need for accurate diagnosis in inflammatory bowel disease (IBD) and the potential for misdiagnosis with parasitic infections. This underscores the importance of Cristcot's innovative products, particularly the Sephure® Suppository Applicator and the Hydrocortisone Acetate (HCA) Suppository, in providing effective treatment options while emphasizing the need for thorough diagnostic processes.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with localized disease, which aligns with the benefits of the Sephure® applicator in enhancing medication delivery and patient compliance.
• HCA’s rapid action and strong safety profile position it favorably against traditional therapies, potentially offering a competitive edge in the treatment of active distal UC.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider expanding clinical trials to include diverse patient populations and explore additional endpoints that assess the impact of misdiagnosis on treatment outcomes.
• Medical Affairs: Prioritize real-world evidence initiatives that highlight the importance of accurate diagnosis and the role of rectal therapies in managing UC, engaging key opinion leaders (KOLs) to disseminate findings.
• Marketing: Enhance differentiation by emphasizing the unique benefits of the Sephure® applicator and HCA suppository in addressing both treatment efficacy and patient comfort, while also addressing the diagnostic challenges highlighted in the study.

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Abstract: P5529 - Risankizumab Induced Symmetrical Drug-Related Intertriginous and Flexural Exanthema (SDRIFE): An Unexpected Skin Reaction in Ulcerative Colitis Treatment

Presenting Author: Charmy Parikh, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• Risankizumab, an IL-23p19 inhibitor, was effective in managing moderate to severe ulcerative colitis (UC) but led to a rare adverse reaction, SDRIFE.
• The patient developed a symmetrical erythematous rash in flexural areas and fungal infections after the first maintenance dose of risankizumab.
• SDRIFE is a delayed-type hypersensitivity reaction that should be considered in patients presenting with flexural rashes post-IL-23 inhibitor therapy.
• Discontinuation of risankizumab and initiation of vedolizumab resulted in clinical and endoscopic remission of UC.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report describes a single patient experiencing a rare adverse reaction (SDRIFE) following risankizumab therapy, which is an IL-23p19 inhibitor recently approved for moderate to severe UC.
• While the case provides valuable insights into potential side effects of risankizumab, it lacks the robustness of larger clinical trials or comparative studies that would provide statistical significance or broader applicability.

2. Comparison to Current Standard-of-Care:

• The findings highlight a specific adverse effect associated with risankizumab, which is important for clinicians to consider, especially in patients with a history of skin reactions to other therapies.
• However, the overall safety profile of risankizumab remains favorable compared to existing therapies, and this case does not suggest a need to alter current treatment guidelines or practices.

3. Clinical Relevance and Feasibility:

• Identifying SDRIFE as a potential reaction to risankizumab is clinically relevant, as it emphasizes the need for vigilance in monitoring skin reactions in patients receiving IL-23 inhibitors.
• While the case underscores the importance of early identification and management of adverse effects, it does not provide new therapeutic options or strategies that would significantly change clinical practice.

In summary, while the case report adds important knowledge regarding the safety profile of risankizumab, it does not provide evidence that would necessitate a change in current UC management practices. Therefore, it is classified as "Important but Not Practice-Changing."

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial for the HCA suppository strengthen Cristcot’s product portfolio by demonstrating significant efficacy and safety in treating ulcerative colitis (UC). The unique delivery mechanism of the Sephure® applicator complements the HCA suppository, enhancing patient compliance and positioning Cristcot favorably against emerging therapies like risankizumab.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with distal UC, where rapid symptom relief is critical.
• Sephure® offers competitive advantages in terms of optimized drug delivery, reducing leakage, and improving patient comfort compared to traditional methods, which may enhance adherence and outcomes.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints focused on long-term remission and quality of life, as well as potential label expansions for broader UC indications.
• Medical Affairs: Prioritizing real-world evidence generation on the effectiveness of the HCA suppository and Sephure® applicator could enhance HCP engagement and support educational initiatives on rectal therapies.
• Marketing: Opportunities exist to differentiate Cristcot’s offerings by emphasizing the unique benefits of rectal delivery systems and the rapid action of HCA, positioning them as first-line options for specific UC patient populations.

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Abstract: P5533 - Rectal Lymphoma in an Ulcerative Colitis Patient on Anti-Tumor Necrosis Factor Therapy

Presenting Author: Claire Beamish, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• A 47-year-old male with ulcerative proctitis developed rectal diffuse large B-cell lymphoma (DLBCL) six months after starting adalimumab, without prior immunomodulator exposure.
• Rectal biopsies post-adalimumab initiation showed lymphoplasmacytic infiltrates consistent with DLBCL, indicating a potential link between anti-TNF therapy and lymphoma development.
• Following the diagnosis, adalimumab was discontinued, and the patient underwent a four-week course of rituximab, resulting in no evidence of disease on subsequent colonoscopy and PET scan.
• This case underscores the need for further research into the lymphoma risk associated with anti-TNF therapy in IBD patients, particularly in the absence of confounding immunomodulator use.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report presents a single patient with ulcerative proctitis who developed rectal diffuse large B-cell lymphoma (DLBCL) after starting anti-TNF therapy, specifically adalimumab, without prior immunomodulator exposure.
• While the case is unique and highlights a potential association between anti-TNF therapy and lymphoma, it is limited by its single-patient design, lacking the statistical power and generalizability of larger cohort studies or randomized controlled trials.

2. Comparison to Current Standard-of-Care:

• The findings do not provide new evidence that challenges existing guidelines or practices regarding the use of anti-TNF agents in UC management, as the relationship between anti-TNF therapy and lymphoma remains an area of ongoing investigation.
• Current guidelines acknowledge the potential risk of lymphoma in IBD patients on immunosuppressive therapies, but this case does not provide sufficient evidence to alter the risk-benefit analysis of anti-TNF therapy.

3. Clinical Relevance and Feasibility:

• While the case raises important questions about the safety of anti-TNF therapy, particularly in the context of lymphoma risk, it does not offer actionable insights that could be readily integrated into clinical practice.
• Further research is needed to establish a clearer understanding of the relationship between anti-TNF therapy and lymphoma, especially in patients without prior immunomodulator exposure.

In summary, while this case report is noteworthy for its unique findings, it does not provide sufficient evidence to change current clinical practices or guidelines regarding the use of anti-TNF therapy in ulcerative colitis management.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a potential risk associated with anti-TNF therapy in ulcerative colitis (UC) patients, which may create strategic opportunities for Cristcot's products, particularly the Hydrocortisone Acetate (HCA) Suppository and Sephure® Suppository Applicator. The findings could position Cristcot as a safer alternative in the treatment landscape, emphasizing the importance of rectal delivery systems that minimize systemic exposure.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, especially for patients who may be at risk for lymphoma with systemic therapies like anti-TNF agents.
• Sephure® offers a unique advantage in ensuring optimal drug placement, potentially enhancing the efficacy of HCA suppositories while reducing the risk of adverse effects associated with systemic therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider further studies to explore the long-term safety profile of HCA in patients with a history of anti-TNF therapy, potentially expanding indications for patients at risk.
• Medical Affairs: Prioritize real-world evidence studies to assess the safety and efficacy of HCA in diverse patient populations, particularly those with a history of anti-TNF therapy.
• Marketing: Highlight the safety profile of HCA and the benefits of rectal delivery in promotional materials, positioning Cristcot as a leader in innovative, safer treatment options for UC.

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Abstract: P5534 - Dual-Targeted Therapy of Upadacitinib and Mirikizumab in Clinically Complex Ulcerative Colitis

Presenting Author: Alex J. Mathew, MBE
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• A 40-year-old woman with medically resistant ulcerative colitis achieved sustained clinical and endoscopic remission using a combination of upadacitinib and mirikizumab.
• Initial treatment with upadacitinib (45 mg/d) led to a marked clinical response, but maintenance at 30 mg/d resulted in symptom recurrence.
• Adding mirikizumab while reducing upadacitinib to 15 mg/d resulted in rapid clinical remission, with fecal calprotectin levels dropping to 125 µg/g.
• This case supports the efficacy and safety of dual-targeted therapy in refractory inflammatory bowel disease, highlighting a novel approach with mirikizumab and a JAK inhibitor.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report describes a single patient with a complex history of medically resistant ulcerative colitis (UC) who achieved clinical and endoscopic remission through a combination therapy of upadacitinib and mirikizumab. While the clinical response is notable, the evidence is derived from a single case, lacking the robustness of larger, controlled studies.
• The patient’s treatment history illustrates multiple therapeutic failures and the eventual success of the dual-targeted approach, but without a control group or comparative data, the generalizability of these findings is limited.

2. Comparison to Current Standard-of-Care:

• Current UC management guidelines emphasize the use of biologics and small molecules, but combination therapies are not yet standard practice. This case suggests a potential avenue for treatment in refractory cases, yet it does not provide sufficient evidence to alter existing guidelines or practices.
• While the combination of a JAK inhibitor and an IL-23 inhibitor is intriguing, further studies are needed to establish its efficacy and safety compared to existing therapies.

3. Clinical Relevance and Feasibility:

• The case highlights the potential for dual-targeted therapy in patients with complex UC, particularly those who have failed multiple lines of treatment. However, the feasibility of this approach in broader clinical practice remains uncertain without further validation.
• Adverse event profiles and long-term outcomes of this combination therapy are not discussed, which are critical for assessing its overall safety and applicability.

In summary, while this case report provides valuable insights into a novel therapeutic strategy for a challenging patient population, it does not yet meet the criteria for practice-changing evidence due to its limited scope and lack of comparative data.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the potential of dual-targeted therapies in managing refractory ulcerative colitis (UC), which may influence Cristcot's strategic positioning for its HCA suppository and Sephure® applicator. The findings suggest that while Cristcot's products offer innovative delivery methods, the emergence of combination therapies could shift treatment paradigms, necessitating a reevaluation of Cristcot's competitive advantages.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for localized treatment, but highlights the growing interest in combination therapies that may offer enhanced efficacy.
• Sephure® provides a unique delivery mechanism that could complement the rapid action of HCA suppository, enhancing patient compliance and comfort compared to traditional therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring combination therapy trials or additional endpoints that assess long-term remission and quality of life, potentially positioning HCA as part of a dual-targeted approach.
• Medical Affairs: Prioritize real-world evidence generation on the effectiveness of HCA in conjunction with other therapies, and develop educational initiatives for healthcare providers (HCPs) on the benefits of rectal delivery systems.
• Marketing: Highlight the unique benefits of Sephure® and HCA in promotional materials, focusing on patient comfort, compliance, and the potential for rapid symptom relief, while also addressing the competitive landscape of combination therapies.

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Abstract: P5549 - Vedolizumab-Associated Acute Pancreatitis After 5 Years of Use in a Patient With Ulcerative Colitis

Presenting Author: Wei Tang, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• Case of a 32-year-old woman with ulcerative colitis who developed drug-induced acute pancreatitis (DIAP) after 5 years of vedolizumab therapy, highlighting a rare late-onset complication.
• Initial lab results showed elevated lipase and amylase, with normal inflammatory markers and no signs of organ failure, indicating a diagnosis of exclusion for DIAP.
• Imaging studies (CT angiography and MRCP) revealed pancreatic edema without other identifiable causes, reinforcing the association of DIAP with vedolizumab.
• Patient's symptoms improved over weeks after delaying vedolizumab and switching to a subcutaneous formulation, suggesting a need for ongoing monitoring in long-term vedolizumab users.
• Findings emphasize the importance of clinical awareness regarding potential late-onset DIAP in patients receiving long-term vedolizumab therapy.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report describes a unique instance of drug-induced acute pancreatitis (DIAP) associated with vedolizumab (VDZ) after five years of therapy in a patient with ulcerative colitis (UC). While the case is well-documented, it is a single patient report, which limits the generalizability of the findings.
• The clinical presentation, laboratory findings, and imaging studies are detailed, providing a comprehensive view of the patient's condition. However, the lack of a control group or comparative data diminishes the strength of the conclusions.

2. Comparison to Current Standard-of-Care:

• Current guidelines recognize VDZ as a safe and effective treatment for moderate-to-severe IBD, with a low incidence of serious adverse events, including pancreatitis. This case adds to the existing literature but does not challenge the established safety profile of VDZ.
• The reported incidence of DIAP in VDZ-treated patients is low, and this case highlights a rare occurrence rather than a common risk, suggesting that the overall risk-benefit ratio of VDZ remains favorable.

3. Clinical Relevance and Feasibility:

• While the case emphasizes the need for ongoing vigilance regarding potential late-onset DIAP in long-term VDZ users, it does not provide new insights that would necessitate changes in clinical practice or management strategies.
• The findings may prompt clinicians to monitor for pancreatitis in patients on long-term VDZ therapy, but the overall implications for treatment protocols are limited.

In summary, while this case report is important for raising awareness of a rare adverse effect of VDZ, it does not provide sufficient evidence to alter current management practices for UC.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a rare but significant adverse event associated with long-term use of Vedolizumab (VDZ) in ulcerative colitis (UC) patients, which may strengthen Cristcot's position by emphasizing the safety profile of its products, particularly the Hydrocortisone Acetate (HCA) suppository and the Sephure® applicator. This could create opportunities for Cristcot to differentiate its offerings in a competitive landscape where safety is paramount.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients who may experience adverse effects from systemic therapies like VDZ.
• Sephure® and HCA’s competitive advantages include improved patient compliance due to ease of use and rapid symptom relief, which may be appealing to patients wary of potential complications from other therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term safety and efficacy, potentially including studies that compare HCA with systemic therapies like VDZ.
• Medical Affairs: Prioritizing real-world evidence initiatives to document the safety and efficacy of HCA and Sephure® could enhance HCP education and support for these products.
• Marketing: There are opportunities to enhance differentiation by emphasizing the unique benefits of rectal delivery systems, particularly in light of the safety concerns associated with long-term systemic therapies.

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Abstract: P5553 - Ustekinumab Induces Deep Remission in Refractory Ulcerative Colitis With Severe Extraintestinal Manifestations: A Comparative Immunotherapeutic Perspective

Presenting Author: Hayder Alamily, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• Ustekinumab achieved complete clinical, endoscopic, and histologic remission in a 39-year-old patient with longstanding ulcerative colitis (UC) and severe extraintestinal manifestations (EIMs) after failure of TNF-α inhibitors.
• The patient had previously experienced partial relief with adalimumab but continued to suffer from debilitating EIMs, including sacroiliitis and uveitis.
• Ustekinumab's dual blockade of IL-12/23 effectively modulated both mucosal and systemic inflammation, leading to resolution of EIMs and sustained remission without corticosteroids.
• This case underscores the limitations of TNF-α inhibitors in complex UC cases and supports the consideration of Ustekinumab when TNF-α therapy is inadequate or contraindicated.
• Real-world data and ongoing trials suggest Ustekinumab may offer a superior safety profile and efficacy in managing refractory UC with systemic involvement.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report describes a single patient with longstanding ulcerative colitis (UC) and severe extraintestinal manifestations (EIMs) who achieved complete clinical, endoscopic, and histologic remission after treatment with Ustekinumab, following inadequate response to TNF-α inhibitors.
• While the case illustrates a successful outcome, it lacks the robustness of a controlled study design, such as a randomized controlled trial (RCT), and is limited by its single-patient focus, which restricts generalizability.

2. Comparison to Current Standard-of-Care:

• The findings align with existing literature suggesting that Ustekinumab can be effective in patients with UC who are refractory to TNF-α inhibitors, particularly in those with systemic involvement.
• However, the evidence does not provide new comparative data against current standards of care, such as adalimumab or other biologics, which limits its impact on practice guidelines.

3. Clinical Relevance and Feasibility:

• The case supports the use of Ustekinumab in complex UC cases, particularly where TNF-α therapy is inadequate, but it does not provide sufficient evidence to change current treatment paradigms or guidelines.
• While the resolution of EIMs is clinically significant, the findings are based on a single case and do not address broader implications for treatment across diverse patient populations.

In summary, while this case report provides valuable insights into the potential role of Ustekinumab in managing refractory UC with EIMs, the lack of a larger, controlled study limits its ability to change current clinical practice. It adds to the understanding of treatment options but does not provide compelling evidence to alter standard management strategies.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study reinforces the potential of Cristcot’s HCA suppository and Sephure® applicator by highlighting the limitations of existing therapies like TNF-α inhibitors in managing complex UC cases. This positions Cristcot's offerings as innovative alternatives that may address unmet needs in the treatment landscape.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with localized disease, enhancing the relevance of Cristcot's products in the UC treatment paradigm.
• Sephure® provides a unique delivery mechanism that may improve patient compliance and comfort, while HCA's rapid efficacy in achieving remission could be a significant advantage over traditional therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints focused on long-term remission and quality of life, as well as potential label expansions for HCA in broader UC populations.
• Medical Affairs: Prioritize real-world evidence generation to support the clinical benefits of HCA and Sephure®, and develop educational initiatives targeting healthcare providers on the advantages of rectal delivery systems.
• Marketing: Highlight the unique benefits of Sephure® and HCA in promotional materials, emphasizing their roles in improving patient outcomes and addressing the limitations of current therapies.

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Abstract: P5554 - Coloring Outside the Lines: Indigo Naturalis to Treat Ulcerative Colitis

Presenting Author: Nina Quirk, MD, MS
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• A 54-year-old male with pan-ulcerative colitis achieved complete symptom resolution and histologic remission after 1.5 months of Indigo naturalis (IN) supplementation.
• Initial treatment with mesalamine and budesonide was ineffective, and the patient opted for alternative therapy with IN, resulting in a significant decrease in fecal calprotectin from 7,560 μg/g to 37 μg/g.
• Colonoscopy five months post-treatment showed no significant histopathologic findings, indicating restored glandular architecture without active inflammation.
• Indigo naturalis may offer a promising alternative treatment for ulcerative colitis, warranting further studies to explore its integration with conventional therapies.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This abstract presents a single case report of a 54-year-old male with moderate to severe ulcerative colitis (UC) who achieved complete remission after a short course of Indigo naturalis (IN). While the case is compelling, it lacks the robustness of larger, controlled studies, which are necessary to establish the efficacy and safety of IN in a broader population.
• The absence of a control group and the reliance on subjective symptom resolution and fecal calprotectin levels limit the ability to draw definitive conclusions about the effectiveness of IN compared to standard therapies.

2. Comparison to Current Standard-of-Care:

• Current UC management guidelines from organizations such as AGA and ECCO emphasize the use of established therapies, including 5-ASA compounds, corticosteroids, and biologics. The findings from this case do not provide sufficient evidence to suggest that IN could replace or significantly augment these therapies.
• While the case suggests a potential role for IN, it does not challenge existing treatment paradigms or provide evidence of superior outcomes compared to current standards.

3. Clinical Relevance and Feasibility:

• Although the patient experienced symptom resolution and histologic improvement, the findings are anecdotal and require further investigation through randomized controlled trials to assess the safety profile, optimal dosing, and potential adverse effects associated with IN.
• Concerns regarding adverse effects, such as pulmonary hypertension and liver dysfunction, highlight the need for caution and further research before considering IN as a viable treatment option in clinical practice.

In summary, while this case report provides interesting insights into the potential use of Indigo naturalis in UC management, it does not present sufficient evidence to warrant a change in clinical practice at this time.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights the potential of alternative therapies like Indigo naturalis (IN) in managing ulcerative colitis (UC), which may influence Cristcot's strategic positioning of its products, particularly the HCA suppository and Sephure® applicator. While the findings support the need for innovative treatment options, they also emphasize the importance of demonstrating superior efficacy and safety profiles for Cristcot's offerings.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients who may not respond to conventional therapies, thus enhancing the relevance of Cristcot's HCA suppository and Sephure® applicator.
• Sephure®'s unique delivery mechanism may provide a competitive advantage in terms of patient comfort and compliance, especially in light of the challenges faced by patients using traditional oral or topical therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term remission and quality of life, as well as potential combination studies with alternative therapies like IN.
• Medical Affairs: Prioritizing real-world evidence studies to support the safety and efficacy of HCA and Sephure® could enhance HCP engagement and education initiatives.
• Marketing: Opportunities exist to differentiate Cristcot's products by emphasizing their unique delivery system and rapid symptom relief, positioning them as first-line options for patients seeking effective UC management.

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Abstract: P6010 - Famotidine-Induced Hepatocellular Injury in Pregnancy: A Diagnostic Challenge in a Patient With Ulcerative Colitis and Cholelithiasis

Presenting Author: Prince Shah-Riar, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• A 28-year-old pregnant woman with ulcerative colitis developed significant transaminitis (ALT 481 U/L, AST 149 U/L) after starting famotidine for reflux.
• After discontinuation of famotidine, liver function tests improved significantly within two weeks, confirming a diagnosis of famotidine-induced hepatocellular injury.
• Autoimmune and viral hepatitis panels were negative, and no symptoms of ulcerative colitis flare were noted during follow-up.
• This case emphasizes the need for thorough medication reviews in patients with abnormal liver function tests, particularly regarding commonly used medications like famotidine.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report describes a single instance of hepatocellular injury associated with famotidine use in a pregnant woman with ulcerative colitis (UC). While the clinical presentation and laboratory findings are well-documented, the evidence is limited to one patient, which restricts the generalizability of the findings.
• The temporal relationship between famotidine use and liver enzyme elevation, followed by improvement upon cessation, supports the diagnosis of drug-induced liver injury. However, without a larger cohort or controlled study, the strength of this evidence remains weak.

2. Comparison to Current Standard-of-Care:

• Famotidine is widely used and generally considered safe during pregnancy, particularly for managing gastroesophageal reflux disease (GERD). This case adds to the existing literature by highlighting a potential adverse effect, but it does not challenge the current standard of care for UC management or the use of famotidine in pregnant patients.
• Existing guidelines do not specifically address famotidine-induced hepatotoxicity, and this case does not provide sufficient evidence to warrant a change in practice or guidelines.

3. Clinical Relevance and Feasibility:

• While the case emphasizes the need for careful medication review in patients with abnormal liver function tests, it does not provide new therapeutic options or strategies for managing UC. The findings are relevant for clinicians but do not have broad implications for UC treatment.
• The rapid resolution of liver enzyme abnormalities upon discontinuation of famotidine is clinically significant, but this is a single case and does not imply a need for widespread changes in clinical practice.

In summary, while this case report provides valuable insights into a rare adverse effect of famotidine, it does not present findings that would alter current management practices for ulcerative colitis.

Summary of Strategic Impact on Cristcot’s Portfolio:

The findings from the Phase 3 CESSA trial and the case report on famotidine-induced hepatotoxicity provide strategic insights for Cristcot. The successful trial strengthens the positioning of the HCA suppository as a viable treatment option for UC, while the case report highlights the importance of medication safety, particularly in vulnerable populations such as pregnant women. This context may enhance the appeal of Cristcot's products, emphasizing safety and efficacy in their marketing strategies.

Competitive Landscape & Positioning:

• The study supports rectal delivery as a viable route, particularly for patients with distal UC, compared to oral and biologic therapies, which may have systemic side effects.
• The Sephure® applicator's unique delivery mechanism enhances the HCA suppository's efficacy by improving bioavailability and patient compliance, setting it apart from traditional oral and topical therapies.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider exploring additional trial endpoints that assess long-term remission and quality of life, as well as potential label expansions for broader indications.
• Medical Affairs: Prioritize real-world evidence generation regarding the safety and efficacy of HCA suppository in diverse patient populations, and develop educational initiatives for healthcare providers on the implications of medication-induced liver injury.
• Marketing: Highlight the unique benefits of the Sephure® applicator and HCA suppository in promotional materials, focusing on patient comfort, compliance, and rapid symptom relief to differentiate from competitors.

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Abstract: P6073 - A Portal Closed, a Window Opened: Salvage DIPS in Budd-Chiari From Ulcerative Colitis

Presenting Author: Vishnu Yanamaladoddi, MD
Date: Tuesday, October 28, 2025
Time: 10:30 AM - 4:00 PMPDT
Location: Location: Exhibit Hall

Abstract Summary:

• Number of Patients/Subjects=1
• A 36-year-old female with ulcerative colitis (UC) developed extensive splanchnic thrombosis leading to portal hypertension and acute liver failure.
• Transjugular intrahepatic portosystemic shunt (TIPS) was deemed unfeasible due to cavernous transformation, and liver transplant was not possible due to the thrombotic burden.
• Direct intrahepatic portosystemic shunt (DIPS) was successfully performed, resulting in marked clinical and biochemical improvement, including complete resolution of encephalopathy at 6-week follow-up.
• This case underscores the importance of DIPS as a viable alternative in complex thrombotic cases associated with inflammatory bowel disease and highlights the need for early multidisciplinary management.

Clinical relevance: Important but Not Practice-Changing

Rationale:

1. Strength and Reliability of Data:

• This case report describes a single patient with extensive splanchnic thrombosis and Budd-Chiari syndrome secondary to ulcerative colitis (UC), highlighting the successful use of direct intrahepatic portosystemic shunt (DIPS) as a salvage procedure.
• While the clinical outcome was positive, the evidence is based on a single case, which limits the generalizability and robustness of the findings. There is no control group or comparative data to assess the efficacy of DIPS against other interventions.

2. Comparison to Current Standard-of-Care:

• The report emphasizes the challenges of managing portal vein thrombosis in UC patients, particularly when standard procedures like TIPS are not feasible. However, it does not provide comparative data on DIPS versus other potential interventions or outcomes.
• Current guidelines do not specifically address DIPS for portal vein thrombosis in UC, making this case an interesting but isolated example rather than a practice-altering recommendation.

3. Clinical Relevance and Feasibility:

• While the case illustrates a novel application of DIPS in a complex clinical scenario, the implications for broader clinical practice are limited due to the lack of data on safety, long-term outcomes, and the feasibility of DIPS in a larger cohort of patients.
• The case underscores the need for multidisciplinary management in complex IBD cases, but further studies are necessary to validate DIPS as a standard option in similar patients.

In summary, while this case report provides valuable insights into a rare complication of UC and a potential intervention, it does not present sufficient evidence to change current clinical practice or guidelines for managing portal vein thrombosis in UC patients.

Summary of Strategic Impact on Cristcot’s Portfolio:

The study highlights a rare but serious complication of ulcerative colitis (UC) that may not directly impact Cristcot’s product portfolio but underscores the complexity of managing UC. The successful use of direct intrahepatic portosystemic shunt (DIPS) in a challenging case may indirectly support the need for effective therapies like Cristcot’s Hydrocortisone Acetate (HCA) suppository, emphasizing the importance of rapid clinical remission and mucosal healing in preventing severe complications.

Competitive Landscape & Positioning:

• The study reinforces rectal delivery as a viable route for treatment, particularly in cases where systemic therapies fail or are intolerable.
• Sephure® and HCA’s advantages in targeted delivery and rapid action may position them favorably against traditional oral and biologic therapies, especially in patients with severe UC complications.

Strategic Implications by Function:

• Clinical Development: Cristcot should consider further trials focusing on the long-term outcomes of HCA in preventing severe complications like portal vein thrombosis, potentially expanding the label to include preventive measures.
• Medical Affairs: Prioritize real-world evidence studies that demonstrate the effectiveness of HCA in complex UC cases, and engage with key opinion leaders (KOLs) to discuss the implications of severe complications in UC management.
• Marketing: Highlight the unique benefits of Sephure® and HCA in addressing the unmet needs of patients with severe UC, particularly in messaging that emphasizes rapid relief and prevention of complications.

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