Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A

Abstract

This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week.

Trial registration: ClinicalTrials.gov NCT01181128.

Figure 1

Subject disposition. After screening, all subjects on a prophylactic regimen prior to study entry were to enter into arm 1; subjects on an episodic regimen prior to study entry were to enter into arm 1 or be randomized into either arm 2 or 3, with randomization stratified based on individual annualized bleeding episodes in the prior 12 months. Of the 30 subjects enrolled in the arm 1 sequential pharmacokinetics (PK) group, 28 had evaluable PK profiles for both rFVIII and rFVIIIFc; repeated PK analysis for rFVIIIFc was performed at weeks 12 to 24. Of the 164 subjects in the 3 arms combined, 4 subjects (2.4%) experienced AEs that led to discontinuation of rFVIIIFc treatment and/or withdrawal from the study: rash in 1 subject (assessed as related to rFVIIIFc treatment), femur fracture in 1 subject (assessed as unrelated to rFVIIIFc treatment), death in 1 subject (fatal outcome of polysubstance overdose and completed suicide, assessed as unrelated to rFVIIIFc treatment), and arthralgia in 1 subject (assessed as related to rFVIIIFc treatment, but subject was recorded to have discontinued the study due to withdrawal of consent). Of the 3 subjects who discontinued for ”other” reasons, 1 subject was incarcerated, 1 subject was traveling and could not ensure proper temperature conditions for study treatment, and 1 subject was not willing to reveal the reason for wanting to complete the early termination visit.

Figure 2

FVIII activity vs time profile for rFVIIIFc and rFVIII, 50 IU/kg intravenous injection. Data presented are observed FVIII activity (mean ± standard error) for each treatment group at nominal times. Dashed lines indicate 1 IU/dL (1%) and 3 IU/dL (3%) trough levels. Pharmacokinetic (PK) parameters were assessed after the first dose of rFVIII or rFVIIIFc for 28 evaluable subjects with data available for both rFVIIIFc and rFVIII. The terminal half-life of rFVIIIFc was significantly longer than that of rFVIII (geometric mean: 19.0 vs 12.4 hours, respectively; P < .001). Clearance (95% CI) was significantly lower for rFVIIIFc (2.0 [1.7-2.2] mL/h/kg) vs rFVIII (3.0 [2.7-3.4] mL/h/kg); P < .001. Dose-normalized area under the curve (95% CI) was 51.2 (45.0-58.4) and 32.9 (29.3-36.9) IU × h/dL per IU/kg for rFVIIIFc and rFVIII, respectively (P < .001). Times to 1 and 3 IU/dL above baseline (95% CI) were 4.9 (4.4-5.5) and 3.7 (3.3-4.1) days for rFVIIIFc vs 3.3 (3.0-3.7) and 2.5 (2.2-2.7) days for rFVIII, respectively (P < .001). h, hours.

Figure 3

Subgroup analyses of ABRs. Subgroup analyses results were consistent with the primary analyses, showing a reduction in bleeding rates in all prophylaxis subgroups compared with episodic therapy. Arm 1 was the only subgroup with a sufficient number of subjects to display results graphically. The box and whiskers represent the median, 25% to 75% range, and 10% to 90% range, respectively; circles represent individual subject outliers.