Safety and Efficacy of Turoctocog Alfa in Prevention and on-Demand Treatment of Bleeding Episodes in Patients with Hemophilia A

Background

Turoctocog alfa is a B-domain truncated recombinant factor VIII (rFVIII) product for the prevention and treatment of bleeds in patients with hemophilia A. The ongoing guardian™2 trial using turoctocog alfa consists of a main trial with planned visits, a surgery subtrial for patients who need to undergo surgery during the main trial, and an on-demand subtrial based on a regulatory requirement to collect data for at least 10 patients treated on-demand for 6 months. The guardian™2 trial is an open-label, prospective, international extension to pivotal trials in adults and adolescents (aged 12-65 years; guardian™1) and children (aged <12 years; guardian™3). Patients who completed the pharmacokinetic trials (NN7008-3600, NN7008-3893, or NN7008-4015), and new patients involved in the on-demand subtrial, also participated in guardian™2. We report an analysis of new long-term safety and efficacy data from the main guardian™2 trial and on-demand subtrial of turoctocog alfa.

Methods

Male patients with severe hemophilia A (FVIII ≤1%) without inhibitors (<0.6 Bethesda units [BU]) were enrolled from 19 countries. Turoctocog alfa was used prophylactically (20-50 IU/kg every second day or 20-60 IU/kg three times weekly) and on-demand (20-200 IU/kg/day) to treat bleeds. The primary safety endpoint was inhibitor development (≥0.6 BU/mL). All adverse events were reported. The main efficacy endpoints included hemostatic success when treating bleeds (excluding patients with missing evaluations), number of turoctocog alfa infusions required to stop bleeds, annualized bleeding rate (ABR), and consumption of turoctocog alfa. Safety and efficacy were assessed at the interim cut-off date, March 25, 2015.

Results

Prophylaxis and on-demand treatment were received by 199 and 19 patients, respectively (equivalent to 589 and 12.5 years of exposure to turoctocog alfa, respectively). Turoctocog alfa was used to treat 1508 bleeds in 162 patients receiving prophylaxis, and for 320 bleeds in 19 patients receiving on-demand treatment. No FVIII inhibitors, hypersensitivity, allergic reactions, or other safety concerns were reported in the main trial or on-demand subtrial for any patients. Treatment of bleeds was successful ('excellent' or 'good' response) in 90% of patients receiving prophylaxis and in 97% of those treated on-demand; the overall proportion of bleeds stopped with 1-2 injections was 90.7%, and 95.7% taking up to three injections. The median ABR (bleeds/patient/year) was 1.48 (mean Poisson estimated ABR: 2.56) for patients treated prophylactically, and 30.3 (mean Poisson estimated ABR: 25.56) for patients treated on-demand. Mean turoctocog alfa consumption (IU/kg/year/patient) was 5335 for patients on prophylaxis and 1707 for patients treated on-demand. Mean prophylactic dose was 32 IU/kg. Mean dose for treatment of bleed from start to stop was 61 IU/kg for patients on prophylaxis and 44 IU/kg for patients treated on-demand.

Conclusion

The latest data from the ongoing guardian™2 trial demonstrate the long-term safety and efficacy of turoctocog alfa for the prevention and treatment of bleeds in patients with severe hemophilia A. No FVIII inhibitors or other safety concerns have been reported. Compared with on-demand treatment, prophylaxis resulted in ~3-fold higher consumption of turoctocog alfa, and a 90% reduction in bleed rates.