Extended Interval Prophylaxis with Bay 94-9027 for > 4 Years Leads to Median Spontaneous Annualized Bleeding Rates < 1 in the Protect VIII Extension

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. This analysis provides an updated assessment of the frequency of spontaneous bleeds with BAY 94-9027 prophylaxis during the PROTECT FVIII trial and its extension of more than 4 years.

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 or joint 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). Following completion of the main PROTECT VIII trial, patients could enter an extension, continuing BAY 94-9027 prophylaxis on either their regimen or switch regimens at the beginning or at any time during the extension. Prophylaxis patients who switched regimen at any time later than 7 days after the beginning of the extension period, were analyzed together in a variable frequency group. Annualized bleeding rates (ABRs) of spontaneous and trauma bleeds were calculated.

Results: The intent-to-treat population in the PROTECT VIII study extension included 121 subjects (prophylaxis, n = 107; on demand, n = 14) of the 134 previously treated with BAY 94-9027 in the main study. At data cut-off (31 January 2018), patients in the prophylaxis arms had spent a median (range) of 3.9 (0.8; 5.4) years on-study (main and extension studies combined; a median of 3.2 years were in the extension), with 223 (23; 563) ED. Median dose of BAY 94-9027 prophylaxis during the extension study was 47.8 IU/kg/infusion, with total FVIII consumption of 3488 IU/kg/year. The overall adherence was 100%. At data cut-off or last visit, 34, 45 and 28 patients were in the 2xW, E5D and E7D treatment arms, respectively. During the extension period, median spontaneous ABR (Q1; Q3) was 0.7 (0.0; 2.9) in patients receiving BAY 94-9027 prophylaxis; 2×W (n = 23, 0.8 [0.0; 3.1]), E5D (n = 33, 0.7 [0.0; 2.9]), E7D (n = 23, 0.2 [0.0; 0.8]), or at a variable frequency (n = 28, 1.8 [0.7; 4.3]). This was consistent with median spontaneous ABRs (Q1; Q3) in the main study of 0.0 (0.0; 4.0), 0.0 (0.0; 4.0) and 1.9 (0.0; 6.3) for patients receiving BAY 94-9027 infusions 2×W (n = 24), E5D (n = 43), or E7D (n = 43), respectively; and with spontaneous ABRs for the last 12 months of the extension study of 1.5 (0.0; 2.0), 1.0 (0.0; 3.0) and 0.0 (0.0; 0.0) for these treatment groups (1.0 [1.0; 2.12] in the variable group). Rates of trauma bleeding were consistent across the study periods, with a median ABR of 0.0 in each prophylaxis group in the main study (0.0 [0.0; 2.0] for all prophylaxis patients), 0.3 (0.0; 1.3) for all prophylaxis patients in the extension and 0.0 (0.0; 1.0) for all prophylaxis patients in the last 12 months of the extension.

Conclusions: Most patients were treated every 5 or 7 days with BAY 94-9027. Median spontaneous ABR remained < 1 with prophylaxis for > 4 years in all treatment groups (2×W, E5D and E7D).