Efficacy and Safety of Personalized Prophylaxis with Simoctocog Alfa in Adult Japanese Previously Treated Patients with Severe Hemophilia a

Background: It is recommended that hemophilia A patients with a severe phenotype are treated with regular prophylaxis in order to prevent bleeds, and ideally prophylaxis should be individualized. The NuPreviq study (GENA-21) conducted in Europe showed that pharmacokinetic (PK)-guided personalized prophylaxis with simoctocog alfa (Nuwiq Esplorhem Study Design and Progress: Evaluation®) provides excellent bleeding protection, with 83% of patients having zero spontaneous bleeds during 6 months of prophylaxis. The GENA-21b study conducted also in North America and Japan further assessed personalized prophylaxis with simoctocog alfa; patients in Japan who took part on the study were also eligible to enter a long-term extension study.

Aim: To assess the long-term efficacy and safety of simoctocog alfa in Japanese patients receiving personalized prophylaxis with simoctocog alfa.

Methods: GENA-21b was a prospective, open-label, multicenter, phase 3b study investigating the efficacy and safety of personalized prophylaxis with simoctocog alfa in previously treated adult patients with severe hemophilia A. Male patients ≥18 years of age with severe hemophilia A (FVIII:C <1%) who have been previously treated with any FVIII products for at least 150 exposure days were eligible for this study. The study consisted of three phases: a 72-hour initial PK evaluation phase, a 1-3-month standard prophylaxis phase, and a 6-month personalized prophylaxis phase. After 6 months of personalized prophylaxis, Japanese patients were eligible to enter an optional extension phase.

During the personalized prophylaxis phase, the dose and dosing interval were recommended for each patient based on their individual PK data. The primary outcome was the annualized bleeding rate (ABR) for total bleeds.

Results: 58 patients were enrolled in the GENA-21b study, including 11 Japanese patients. In the 6 months prior to entering the study, all 11 Japanese patients had received FVIII prophylaxis, with a mean (SD) weekly dose 91.9 (30.9) IU/kg and a mean (SD) ABR of 7.5 (11.7). Of the patients enrolled, 56 received personalized prophylaxis, including 10 Japanese patients. The mean (SD) terminal half-life, as measured using the one-stage assay was 17.2 (4.6) h in the 10 Japanese patients compared with 15.6 (3.9) in all 56 patients. During personalized prophylaxis with simoctocog alfa, the median (interquartile range [IQR]) ABR in the Japanese patients was 3.04 (0-7.69) for total bleeds, 0 (0-5.99) for spontaneous bleeds, and 0.98 (0-5.99) for joint bleeds. 70% of Japanese patients were treated twice weekly or less while on personalized prophylaxis, with a median weekly dose that was 14% lower than during standard prophylaxis (94 vs 106 IU/kg). 9 patients entered the extension phase and remained on simoctocog alfa prophylaxis for a further 2.1 years. During the extension phase, the median (IQR) total ABR was 16% lower than during the personalized prophylaxis phase (1.76 [0-6.30] vs 2.09 [0-5.99]). The median (IQR) ABRs for spontaneous bleeds were 0.81 (0-3.36) and for joint bleeds were 0.84 (0-1.74) during the extension phase. There were no treatment-related serious adverse events, no inhibitors, and no adverse events that lead to the discontinuation of simoctocog alfa.

Conclusions: Personalized prophylaxis with simoctocog alfa was efficacious in a sub-population of Japanese patients, and no treatment-related serious adverse events were reported during long-term prophylaxis. A high proportion of the patients were treated twice weekly or less. Notably, the mean ABRs decreased during long-term prophylaxis.

Shima:Takeda: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Speakers Bureau; Nara Medical University: Current Employment; UniQure: Consultancy; Bayer Yakuhin: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Fujimoto Seiyaku: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Ono Yakuhin: Speakers Bureau. Taki:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Takeda: Honoraria; CSL Behring: Honoraria; Bayer Yakuhin: Honoraria; Fujimoto: Honoraria; KM biologics Co.: Honoraria; Pfizer Japan: Honoraria. Shirayama:Chugai: Honoraria; Takeda: Honoraria; CSL Behring: Honoraria; Novo Nordisk Pharma: Honoraria; Fujimoto Pharmaceutical: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Matsushita:Sanofi: Honoraria; Fujimoto: Honoraria; Japan Blood Products: Honoraria; KM biologics Co.: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bayer Yakuhin: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex Corp.: Honoraria. Nishida:CSL Behring: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Sanofi: Honoraria; Bayer Yakuhin: Honoraria; Takeda: Honoraria; Novo Nordisk: Honoraria. Nagao:Takeda: Honoraria, Research Funding; Bayer Yakuhin: Honoraria, Research Funding; Sanofi: Honoraria; CSL Behring: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Fujimoto Pharmaceutical Corp: Honoraria; KM biologics Co.: Honoraria; Japan Blood Products Organization: Honoraria; Novo Nordisk Pharma: Honoraria; Pfizer Japan: Honoraria.