Bleeding Phenotype with Various Bay 94-9027 Dosing Regimens: Subanalyses from the Protect VIII Study

Introduction: Factor VIII (FVIII) products with a longer half-life may allow for longer intervals between treatments for patients with hemophilia A and may facilitate prophylaxis tailored to an individual’s bleeding phenotype. BAY 94-9027, a PEGylated FVIII product, demonstrated an extended half-life in a phase 1 trial and was well tolerated and efficacious in a phase 2/3 study with dosing intervals up to every 7 days. In this subanalysis of the phase 2/3 trial, bleeding frequency calculated based on the BAY 94-9027 prophylactic dosing regimen during the study was compared with reported bleeding frequency in the 12 months before enrollment. Also, on-study annualized bleeding rates (ABRs) for joint, spontaneous, and trauma bleeds are presented by treatment group.

Methods: PROTECT VIII was a multinational, partially randomized, open-label, 36-week study in previously treated patients aged 12–65 years with severe hemophilia A and no history of FVIII inhibitors. Patients received BAY 94-9027 for 36 weeks either on demand or prophylactically. Patients were assigned to 1 of 3 prophylaxis dosing regimens based on the number of bleeds observed during a 10-week run-in period, during which all patients in the prophylaxis arm were treated with 25 IU/kg BAY 94-9027 2x/week. Patients with ≤1 breakthrough bleed during the 10-week period were randomized 1:1 to BAY 94-9027 45–60 IU/kg every 5 days or 60 IU/kg every 7 days. Patients with ≥2 breakthrough bleeds received 30–40 IU/kg BAY 94-9027 2x/week. ABR and annualized joint bleeding rate (AJBR) for the 12 months before the study (collected retrospectively at screening) were compared with values calculated in patients previously treated with prophylaxis who used BAY 94-9027 prophylaxis during the study (weeks 0–36 for the combined prophylaxis groups [including the 10-week period]; weeks 10–36 for the 3 assigned prophylaxis dosing regimens). ABRs for joint, spontaneous, and trauma bleeds during the study were analyzed for the on-demand and combined prophylaxis groups (weeks 0–36) and in relation to patients’ BAY 94-9027 dosing regimen (weeks 10–36).

Results: The intent-to-treat population comprised132 patients (prophylaxis, n=112; on demand, n=20). In patients previously treated with prophylaxis, median ABR and AJBR during BAY 94-9027 prophylaxis (weeks 0–36) were lower than corresponding prestudy values; ABR and AJBR during weeks 10–36 for every-5-day, every-7-day, and 2x/week BAY 94-9027 dosing were also lower than or comparable to prestudy values (Table). Median ABRs for joint, spontaneous, and trauma bleeds were lower for the combined prophylaxis groups (weeks 0–36) compared with the on-demand group (combined prophylaxis groups: 1.5, 1.4, and 0.0, respectively; on-demand group: 16.3, 14.3, and 9.1). In the prophylaxis arms (weeks 10–36), median ABRs for joint, spontaneous, and trauma bleeds were 2.1, 0.0, and 0.0 for 2x/week dosing; 1.9, 0.0, and 0.0 for every-5-day dosing; and 1.9, 1.9, and 0.0 for every-7-day dosing.

Conclusions: BAY 94-9027 prophylaxis resulted in lower ABRs and AJBRs during the 36-week study period compared with prestudy values in patients previously treated with prophylaxis. Subgroup analyses based on prophylactic dosing regimens (including dosing intervals of up to every 7 days) showed that patients who were randomized based on bleeding phenotype during the 10-week run-in period achieved bleeding control that was better than or comparable to their prestudy levels, highlighting the value of individualized phenotype-based dosing with BAY 94-9027. In addition, prophylaxis with BAY 94-9027 resulted in reduced joint, spontaneous, and trauma bleeds compared with on-demand treatment.