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Keywords:

  • first-in-human;
  • half-life prolongation;
  • hemophilia A;
  • PEG ;
  • rFVIII

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.