Once-weekly prophylaxis with glycoPEGylated recombinant factor VIII (N8-GP) in severe haemophilia A: Safety and efficacy results from pathfinder 2 (randomized phase III trial)

Abstract

Introduction: Turoctocog alfa pegol (N8-GP) is a site-specific, 40 kDa glycoPEGylated recombinant factor VIII (FVIII) product with an extended half-life. The comprehensive main phase of the pivotal pathfinder 2 trial showed N8-GP dosed every 4 days (Q4D) provided favourable safety and efficacy for preventing bleeds in 175 patients with haemophilia A.

Aim and methods: We investigated the safety and efficacy of N8-GP prophylaxis when administered weekly (Q7D) for 24 weeks to patients with low bleeding rates in the pathfinder 2 extension trial. Patients (≥12 years) with ≤2 bleeds during the preceding 6 months of the pathfinder 2 main phase were eligible for randomization to receive N8-GP 50 IU/kg Q4D or 75 IU/kg Q7D. Safety and efficacy endpoints were incidence of FVIII inhibitors and annualized bleeding rate (ABR), respectively.

Results: Fifty-five of 143 (38.5%) patients on prophylaxis who continued into the extension phase were randomized to receive 50 IU/kg Q4D (n = 17) or 75 IU/kg Q7D (n = 38). Nine patients in the Q7D cohort reverted to 50 IU/kg Q4D. No inhibitors were detected. In both cohorts, >50% of patients experienced no bleeds. Median ABR for overall, joint, spontaneous, traumatic and muscle was 0.00 for both cohorts. Overall estimated success rate for treating bleeding episodes was 87.5%; 94.7% of bleeds were controlled with ≤2 injections.

Conclusions: Weekly N8-GP was well tolerated and efficacious and may benefit selected "low bleeder" patients with haemophilia A.

Keywords: FVIII; N8-GP; efficacy; haemophilia A; once-weekly prophylaxis; safety.

Figure 1

Patient flow through pathfinder 2 extension phase for patients who received N8‐GP prophylaxis. ^aPatients who participated in the pathfinder 2 main phase and received N8‐GP prophylaxis. The last patient last visit of pathfinder 2 extension phase part 1 was 3 March 2015. ^bWithdrawn due to SAEs considered unlikely to be N8‐GP related. ^cReverted due to investigator's discretion (X‐ray changes showing worsened pre‐existent arthropathy [n = 1]) or bleeding episodes (n = 8). The patients withdrawn from randomization due to bleeding episodes were equally distributed over time; within first month (n = 2), second month (n = 2), third month (n = 2) and after 5 months (n = 2). n, number of patients; Q4D, every 4 d; Q7D, every 7 d; SAE, serious adverse event. Trial registered at http://www.clinicaltrials.gov (NCT01480180)

Figure 2

Bleeding details for patients randomized to receive N8‐GP 50 IU/kg Q4D or 75 IU/kg Q7D prophylaxis. The number of bleeds is reported above each bar. The total exposure time for the 50 IU/kg Q4D cohort was eight patient‐years and 15 patient‐years for the 75 IU/kg cohort. n, number of bleeds; Q4D, every 4 d; Q7D, every 7 d

Figure 3

Observed mean ABR for patients randomized to receive N8‐GP 50 IU/kg Q4D or 75 IU/kg Q7D prophylaxis by time since last N8‐GP dose. If the exact time of a bleed was not known, the bleed was grouped into a time interval. If a bleed could be grouped to more than one interval, it was grouped to the one closest to the last N8‐GP dose. *The N, NB and ABR for >4 d since N8‐GP last dose were not presented for 50 IU/kg Q4D patients due to the limited amount of the data observed for Q4D patients with more than 4 d since N8‐GP last dose. ABR, annualized bleeding rate (total number of bleeding episodes/total exposure time); n, number of patients; N/A, not applicable; NB, number of patients with bleeds; Q4D, every 4 d; Q7D, every 7 d