Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients

Abstract

Current factor VIII (FVIII) products display a half-life (t(1/2)) of ∼ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG(1) to extend circulating rFVIII t(1/2). This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t(1/2), 1.49- to 1.56-fold lower clearance, and 1.48- to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ∼ 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377.

Figure 1

Study design. The phase 1/2a study was a dose-escalation, sequential design to evaluate the safety and PK of rFVIIIFc compared with rFVIII after a single intravenous dose of either 25 IU/kg (low-dose cohort) or 65 IU/kg (high-dose cohort).

Figure 2

Group mean plasma FVIII activity PK profiles for low-dose and high-dose cohorts. The plasma FVIII activity (one-stage aPTT assay) versus time curve after a single intravenous injection of rFVIIIFc or rFVIII are shown for (A) 25 IU/kg (low-dose cohort; n = 6) and (B) 65 IU/kg (high-dose cohort; n = 10 [rFVIII]; n = 9, [rFVIIIFc]). Results presented are group mean ± SEM.

Figure 3

Effect of VWF Ag levels on CL and t_1/2 of FVIII activity after injection of rFVIII or rFVIIIFc. Correlation between VWF Ag levels and (A) the weight-adjusted CL of rFVIII (R² = 0.5415, P = .0012) and rFVIIIFc (R² = 0.5492, P = .0016) and (B) the t_1/2 of rFVIII (R² = 0.7923, P < .0001) and rFVIIIFc (R² = 0.6403, P = .0003). Each dot represents an individual subject.