Abstract: This is a summary of the results from two clinical studies of treatment for men with severe hemophilia A or B. The studies were published in the British Journal of Haematology. People with hemophilia either have low amounts of clotting factors or are missing certain clotting factors in their blood. The severity of hemophilia is found out by a blood test. There are medicines that people with hemophilia can take to replace the missing clotting factor. However, sometimes the body thinks the clotting factor used to treat hemophilia is a foreign substance and produces antibodies to destroy it (called inhibitors) which may slow down or stop blood clotting. What were the results? The studies showed that men with hemophilia had fewer bleed events while taking marstacimab than before this treatment. The results were similar for all doses of marstacimab tested. Overall, the side effects with marstacimab were generally acceptable. Two men had to stop taking marstacimab because of side effects in the short-term study. The most common side effects were high blood pressure and injection site reactions. Most of these reactions were mild or moderate. What do the results mean? These studies showed that marstacimab could help prevent bleeding in men with hemophilia A or B, with or without inhibitors. The results of this study may differ from those of other studies. Physicians should make treatment decisions based on all available evidence and not just on the results of a single study. Larger studies of marstacimab involving more people with hemophilia A or B have started.

Abstract: A phase 1b/2, three‐month study of marstacimab, a human monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), was conducted in participants with haemophilia A or B, with or without inhibitors. Participants assigned to four cohorts received escalating weekly doses based on inhibitor status (without inhibitors: 300 mg, a single 300‐mg loading dose with subsequent 150‐mg doses, or 450 mg; with inhibitors: 300 mg). Safety outcomes were treatment‐emergent adverse events (TEAEs), injection site reactions, clinical and laboratory parameter changes. Efficacy was assessed by annualised bleeding rates (ABRs). Pharmacokinetics and pharmacodynamics (PD) were also evaluated. Among 26 treated participants [haemophilia A without inhibitor, n  = 16 (61.5%); haemophilia A with inhibitor, n  = 7 (26.9%); haemophilia B, n  = 3 (11.5%)], 24 completed the study. Overall, 80.8% experienced TEAEs. ABR during treatment was significantly reduced versus an external on‐demand control group ( p   〈  0.0001) and versus pretreatment ABR ( p   〈  0.0001), with significant reductions observed across all dose cohorts. Marstacimab exposure generally increased in a dose‐related manner, with steady‐state concentration reached by day 57. Changes in pharmacodynamic biomarkers occurred across all dose cohorts. Marstacimab was safe and well tolerated. Clinically meaningful reductions in ABR and treatment‐related changes for all PD biomarkers indicated effective targeting of TFPI. ( Clinicaltrials.gov identifier, NCT02974855).

Abstract: Real‐world data on health‐related outcomes in persons with haemophilia A (PwHA) can provide useful information for improving patient care. The global, non‐interventional study (NIS; NCT02476942) prospectively collected high‐quality data in PwHA, including those without factor VIII (FVIII) inhibitors treated according to local routine clinical practice. Aim To report health‐related quality of life (HRQoL) and health status of adult/adolescent PwHA without FVIII inhibitors. Methods Participants were PwHA without FVIII inhibitors age ≥12 years; they remained on existing episodic treatment or prophylaxis. HRQoL was assessed by Haemophilia Quality of Life Questionnaire for Adults (Haem‐A‐QoL) or Haemophilia‐Specific Quality of Life Assessment for Children and Adolescents Short Form (Haemo‐QoL‐SF II). Health status was assessed through EuroQol 5‐Dimensions 5‐Levels (EQ‐5D‐5L) index utility score and visual analogue scale (EQ‐VAS). Results Ninety‐four participants enrolled; median age was 34.0 years (range 12–76). Forty‐five received episodic treatment and 49 received prophylaxis for a median time of 27.7 weeks and 30.4 weeks, respectively. Mean (standard deviation) baseline Haem‐A‐QoL total scores were 40.1 (17.0) for the episodic group and 26.6 (14.6) for the prophylaxis group, indicating impairments in HRQoL, which remained consistent over time. Mean EQ‐5D‐5L IUS scores were similar between treatment regimens (0.8 episodic; 0.9 prophylaxis) and consistent over time. The mean EQ‐VAS scores were similar between treatment regimens, and lower on days when bleeding occurred (79.0 vs 85.0 for episodic treatment; 77.0 vs 82.0 for prophylaxis, respectively). Conclusions Adult and adolescent PwHA without FVIII inhibitors had HRQoL impairments regardless of whether they were treated with episodic or prophylactic standard care with FVIII.

Abstract: Emicizumab is a subcutaneously (SC) administered prophylactic agent for persons with haemophilia A (PwHA). As part of its clinical development, a new instrument was required to measure treatment satisfaction. Aim Describe development of the Satisfaction Questionnaire with Intravenous or Subcutaneous Hemophilia Injection (SQ‐ISHI) and its subsequent testing with HAVEN 3 study participants to measure patient satisfaction with emicizumab. Methods To develop the SQ‐ISHI, we conducted four rounds of in‐person interviews at five qualitative research facilities. Participants aged ≥12 years with moderate or severe haemophilia A, receiving intravenous factor VIII (FVIII) prophylaxis, provided feedback to optimize content understanding, ease of completion and item relevance. The final SQ‐ISHI was completed by HAVEN 3 participants who previously received FVIII prophylaxis; baseline scores were compared with those at Week 21 or 25 of emicizumab prophylaxis. Results Sixty‐three HAVEN 3 participants were eligible to complete the questionnaire and rate their satisfaction on a scale of 0 (‘not at all satisfied’) to 10 (‘extremely satisfied’). Mean ‘overall satisfaction’ with previous FVIII prophylaxis at baseline was 6.9 (95% confidence interval [CI]: 6.2 to 7.7) increasing to 8.8 (95% CI: 8.4 to 9.3) at follow‐up (Week 21/25 of treatment with emicizumab). The greatest improvement was observed in satisfaction with treatment half‐life (mean score at baseline: 5.8 [95% CI: 4.9 to 6.6] vs 8.6 [95% CI: 8.0 to 9.2] at follow‐up). Conclusion These results demonstrate that emicizumab prophylaxis leads to greater treatment satisfaction compared with FVIII prophylaxis, reflecting in part the low treatment burden of emicizumab associated with its infrequent, SC administration.

Abstract: Prophylaxis is the globally accepted standard of care for persons with haemophilia and presents many advantages over episodic treatment. The prophylaxis benefits include bleed reduction, reduction in musculoskeletal complications and improvement in the quality of life. The currently evolving novel therapies for the management of haemophilia has ushered a new era characterized by improved prophylaxis targets and outcomes. These redefined targets and outcomes have necessitated the need to also redefine prophylaxis. In this state‐of‐the‐art review, we redefine prophylaxis in the modern era by revisiting its definition, presenting data to support higher trough levels to achieve with prophylaxis and introducing steady‐state haemostasis as a possible new target for prophylaxis.

Abstract: Background: Prolongation technology has recently been employed to advance the treatment in hemophilia. Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) with a significantly extended half-life in hemophilia B adults (Negrier et al. Blood 2011), up to 111 h, as compared to currently available treatment options. The pivotal phase 3 trial, paradigm™2, demonstrated that the prophylactic protection of 40 U/kg N9-GP once weekly significantly reduced the risk of bleeding as well as successfully controlled the bleeding episodes (Collins et al. JTH (Suppl.2) 2013). It also demonstrated a potential to improve clinical outcomes, reduce joint damage and improve quality of life with fewer injections. The phase 3 extension trial, paradigm™4, was designed to investigate the safety and efficacy of long-term treatment with N9-GP in severe and moderately severe hemophilia B patients. Aims: The primary objective of this trial was to evaluate immunogenicity of N9-GP. Key secondary objectives were to assess therapeutic and prophylactic efficacy and safety of N9-GP. Methods: 71 hemophilia B patients above 12 years of age with ≤2% FIX activity, with no history of inhibitors, at least 150 exposures days (ED) to other FIX products, and who completed the pivotal phase 3 trial, paradigm™2, or the pivotal surgery trial, paradigm™3, were included. The trial was approved by local IRB/REC and all participants signed an informed consent before any trial related activity. Patients were allowed to change the treatment regimen at trial start or during the trial based on their clinical manifestation and investigator recommendation; options included on-demand treatment, or once weekly prophylaxis with 10 or 40 U/kg N9-GP. Immunogenicity was evaluated as the primary endpoint; incidence of inhibitory antibodies against FIX defined as titer ≥0.6 Bethesda Units (BU). Efficacy endpoints included frequency of bleeds among prophylaxis patients, hemostatic response to N9-GP infusion based on a 4-point categorical scale, as well as FIX activity as a surrogate marker. Results: A total of 71 patients were treated for at least 12 months, 67 of whom received a prophylactic regimen of N9-GP either 10 U/kg or 40 U/kg once weekly; there were considerable movements between treatment arms, with approximately one third of the patients moving from on-demand or 10 U/kg at the start of this extension trial, up to 40 U/kg, with a smaller proportion moving from 40 U/kg to 10 U/kg, or from 10 U/kg to on-demand. None of the patients in the trial developed inhibitors. There were no differences relating to adverse events or standard safety parameters between the treatment groups. In paradigm™4 a total of 94.6% of all bleeding episodes were successfully treated, with 87.9% of all bleeding episodes treated with a single infusion. Among patients on prophylaxis, a median (IQR) annualized bleeding rate of 1.1 (0.0 – 2.2) episodes per year was observed. There was a higher proportion of traumatic bleeding episodes in the patients on 40 U/kg N9-GP compared with patients on 10 U/kg N9-GP (57.1% vs. 28.6%, respectively), though the annualized bleeding rates were similar in both prophylactic groups, with median (IQR) ABR of 0.0 (0.0 – 1.0) and 0.0 (0.0 – 1.1) in 10 U/kg and 40 U/kg N9-GP, respectively. For spontaneous bleeds only, the median (IQR) annualized bleeding rate was 1.1 (0.0 – 2.2) and 0.0 (0.0 – 1.0) among patients treated with 10 U/kg and 40 U/kg N9-GP, respectively. Conclusion: The outcome of the trial confirmed the results from paradigm™2 that N9-GP appeared to have a safe and well-tolerated profile with good prophylactic protection and control of bleeding. Disclosures Young: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: N9-GP is not yet FDA approved. Information provided will discuss phase 3 clinical trial data.. Collins:Novo Nordisk: Consultancy, Honoraria. Tehranchi:Novo Nordisk A/S: Employment, Shareholder Other. Chuansumrit:Novo Nordisk: Honoraria. Hanabusa:Baxter Healthcare, Novo Nordisk, Bayer, Pfizer, Biogen Idec and KaketsuKen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lentz:Novo Nordisk: Consultancy, Research Funding. Mahlangu:Biogen Idec, Novo Nordisk, Biotest: Speakers Bureau; Amgen, Bayer, Novo Nordisk, Pfizer, Genentech: Membership on an entity's Board of Directors or advisory committees; Bayer, Biogen Idec, Novo Nordisk: Research Funding. Mauser-Bunschoten:Sanquin, CSL Behring, Bayer, Baxter, Griffols, LFB, Novo Nordisk: Speakers Bureau; Sanquin, CSL Behring: Research Funding; Baxter: Consultancy; Novo Nordisk: Registration trial, Registration trial Other. Negrier:Novo Nordisk, Baxter, Bayer, CSL Behring, LFB and Pfizer: Consultancy, Honoraria, Research Funding. Oldenburg:Baxter, Bayer, Biogen Idec, Biotest, CSL-Behring, Grifols, Novo Nordisk, Octapharma, Swedish Orphan Biovitrum and Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Santagostino:Pfizer, Bayer, Baxter, Novo Nordisk, CSL Behring, Grifols, Biotest: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Zak:Novo Nordisk A/S: Employment.

Abstract: Background: rVIII-SingleChain, a novel recombinant Factor VIII, has been designed as a B-domain truncated construct with a covalent bond between the heavy and light chain, aiming for a higher binding affinity to von Willebrand Factor. rVIII-SingleChain has a lower clearance, longer half-life and larger area under the curve compared to octocog alfa (Advate®). This sub-study of the AFFINITY program investigated the safety and efficacy of rVIII-SingleChain to control hemostasis in adult and adolescent patients (12 - 65 years of age) with severe Hemophilia A undergoing major surgery. rVIII-SingleChain was used either as continuous infusion or as a bolus injection. Methods: The study was approved by the relevant ethics committees and national authorities and conducted according to GCP and the Declaration of Helsinki. 13 patients underwent a total of 16 major surgical procedures (a surgical procedure that required general, spinal or regional anesthesia). Dosing was guided by the WFH recommendations. In 8 patients, rVIII-SingleChain was used as continuous infusion and in 8 patients rVIII-SingleChain was used as a bolus injection. Results: The following procedures were performed using continuous infusion: knee replacement (5), cholecystectomy, lengthening of the achilles tendon combined with surgical correction of the right toes, and open reduction and internal fixation of right ankle fracture. Furthermore, circumcision (3), extraction of wisdom teeth, abdominal hernia repair, elbow replacement, ankle arthroplasty, and hardware removal of the right ankle were performed after administering a bolus injection of rVIII-SingleChain. In the 8 procedures that were covered by bolus injection rVIII-SingleChain median pre- and intraoperative consumption was 79.2 IU/kg, and in the 8 procedures that were covered by continuous infusion, rVIII-SingleChain median pre- and intraoperative consumption was 92.5 IU/kg. Investigators rated the efficacy of rVIII-SingleChain during surgery as excellent (defined as hemostasis not clinically significant different from normal) in all cases but one (knee replacement under continuous infusion), in which it was rated as good (defined as hemostasis normal or mildly abnormal in terms of quantity and/or quality e.g., slight oozing). After the procedure, patients returned to routine treatment after a median of 9 days. No related AEs or SAEs were observed during the surgery period. Conclusion: rVIII-SingleChain provides very effective and safe control of hemostasis during a wide range of surgical procedures when dosed either by continuous infusion or by bolus injection. Consumption of factor on the day of surgery seems to be comparable in both treatment regimens. Disclosures Mahlangu: NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Baker:Daiichi Sankyo: Research Funding; CSL Behring: Research Funding; Portola Pharmaceuticals: Research Funding; Astellas: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: conference travel support, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support , Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support; Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: conference travel support; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Other: conference travel support. Leissinger:Biogen: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Santagostino:Pfizer: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Biotest: Speakers Bureau; Octapharma: Speakers Bureau; Kedrion: Speakers Bureau; Biogen/Sobi: Membership on an entity's Board of Directors or advisory committees. Bensen-Kennedy:CSL Behring: Employment. St. Ledger:CSL Behring: Employment. Veldman:CSL Behring: Employment. Pabinger:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

Abstract: BAY 81-8973 (Kovaltry ® ) is an unmodified, full-length recombinant factor VIII (rFVIII) approved for the prevention and treatment of bleeding episodes in patients with hemophilia A. The amino acid sequence for BAY 81-8973 is identical to that of sucrose-formulated rFVIII (rFVIII-FS; Kogenate ® FS/KOGENATE ® , Bayer), but the two products differ in their manufacturing approaches. The manufacture of BAY 81-8973 includes several modifications and enhancements, such as the introduction of the gene for human heat shock protein 70, a molecular chaperone protein that facilitates folding of proteins; no addition of human- or animal-derived proteins in the cell culture, purification process, or final formulation; and use of a 20-nm filter to remove any potential aggregates and pathogens. BAY 81-8973 was extensively studied in the LEOPOLD clinical development program, which enrolled participants of all age groups (children, adolescents, and adults) with severe hemophilia A. The pharmacokinetic profile of BAY 81-8973 was shown to be noninferior to, and for some variables more favorable than, rFVIII-FS and another commercial full-length rFVIII product. BAY 81-8973 was shown to be efficacious when used for prophylaxis, on-demand treatment, and perioperative hemostasis. The efficacious prophylaxis dose of BAY 81-8973 was approximately 20–40 IU/kg given two or three times per week, which achieved low annualized bleeding rates. Either the one-stage or the chromogenic assay provides accurate measurements for postinfusion monitoring of BAY 81-8973 levels, with no product-specific calibration standard needed. The incidence of treatment-related adverse events was ⩽7% across all LEOPOLD studies, and no previously treated patient developed anti-BAY 81-8973 inhibitors in the completed primary studies.