Efficacy and Safety of Bay 94-9027 Is Sustained for 5 Years: Outcomes in 33 Patients in the Protect VIII Extension Study

Introduction

BAY 94-9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 × 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial and its extension. We present an analysis of efficacy and safety outcomes in patients from PROTECT VIII who had completed at least 5 years of treatment as of 31 January 2018.

Methods

PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 FVIII exposure days (ED). Prophylaxis patients received BAY 94-9027 25 IU/kg twice weekly for a 10-week run-in period. Patients with ≤ 1 spontaneous, joint or muscle bleed during this period were randomized to 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg twice-weekly (2×W). Twenty patients received BAY 94-9027 on demand as they had been prior to study. Following completion of the main PROTECT VIII study, patients could enter an extension, continuing BAY 94-9027 on any regimen used in the main study; 121 patients entered the extension, of whom 107 were on the prophylactic arm. Prophylaxis patients who switched regimen after the first 7 days of being in the extension were analyzed in a combined variable frequency (VAR) group. Annualized bleeding rate (ABR) and joint ABR were analyzed, along with safety outcomes.

Results

At the cut-off date, 33 patients had completed 5 years of treatment with BAY 94-9027 (2×W, n = 3; E5D, n = 10; E7D, n = 6; VAR, n = 14). Median number of infusions (range) was 363 (272-546), and median (range) annual factor consumption was 3385 (2732-5053) IU/kg. Median (range) ABR was 2 (0-15) in the full 5-year period, and 1 (0-12) for the final year. Corresponding joint ABRs were 1 (0-7) and 0 (0-7). Over the 5-year period, study drug-related adverse events (AE)s occurred in 6 patients (18.2%); no patients had a study drug-related serious AE. There were no discontinuations for AEs. No patients had confirmed FVIII inhibitors (titre ≥0.6 Bethesda units).

Conclusions

Thirty-three patients have received BAY 94-9027 prophylaxis for 5 years. The previously demonstrated efficacy of BAY 94-9027 was maintained across this period; in the last year of the extension median ABR was 1 and a third of patients were entirely free from bleeds. Consistent with the established safety profile of FVIII and with prior analyses of PROTECT VIII, there were few study drug-related AE and no evidence of any long-term toxicity of PEGylated product exposure. Taken together, these data support the use of BAY 94-9027 as a long-term treatment option for patients with hemophilia A.