Enhancing the pharmacokinetic properties of recombinant factorVIII: first-in-human trial of glycoPEGylated recombinant factorVIII in patients with hemophiliaA

Background N8-GP is a recombinant factorVIII (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 hemophiliaA who received one of three dose levels (25, 50 or 75Ukg1) 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 [(UmL1)/(Ukg1)]. The clearance was 1.79mL1h1kg1. The estimated time from dosing of 50Ukg1 N8-GP to a plasma activity of 1% was 6.5days (range: 3.67.9days). The mean terminal half-life of N8-GP was 19.0h (range: 11.627.3h), 1.6-fold longer than that of the patients' previous products. Conclusions A single dose of up to 75Ukg1 N8-GP was well tolerated in patients with hemophiliaA, 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 N8GP has the potential to reduce dosing frequency during prophylaxis.