Enhancing the pharmacokinetic properties of recombinant factor VIII: first‐in‐human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. Issue 4 (11th April 2013) - Tiede, A.
Summary Background N8‐GP is a recombinant factor VIII (FVIII) with a site‐directed glycoPEGylation for the purpose of half‐life prolongation. Objectives To evaluate the safety and pharmacokinetic profiles of N8‐GP in comparison with those of the patients' previous FVIII products. Patients/Methods This dose‐escalation trial included previously treated patients with severe hemophilia A who received one of three dose levels (25, 50 or 75 U kg−1) of N8‐GP and FVIII product. Each dose escalation was preceded by safety and pharmacokinetic assessment. The trial was registered at www.clinicaltrials.gov (NCT01205724). Results Twenty‐six patients each received one dose of their previous FVIII product followed by the same, single dose of N8‐GP. N8‐GP, at any tested dose, was well tolerated, with a low frequency of adverse events. No new inhibitors against FVIII or N8‐GP and no binding antibodies against N8‐GP developed during the trial. The pharmacokinetics of N8‐GP were dose‐linear. The incremental recovery of N8‐GP was 0.025 [(U mL−1)/(U kg−1)]. The clearance was 1.79 mL−1 h−1 kg−1. The estimated time from dosing of 50 U kg−1 N8‐GP to a plasma activity of 1% was 6.5 days (range: 3.6–7.9 days). The mean terminal half‐life of N8‐GP was 19.0 h (range: 11.6–27.3 h), 1.6‐fold longer than that of the patients' previous products. Conclusions A single dose of up to 75 U kg−1 N8‐GP was well tolerated in patients with hemophilia A, with no safety concerns. N8‐GP had a prolonged half‐life, and FVIII:C activity remained at > 1% for longer than the patient's previous product. These results indicate that N8–GP has the potential to reduce dosing frequency during prophylaxis.