Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety

Abstract Background Marzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia. Objectives To investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis. Methods This multicenter, open‐label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor. All subjects had a baseline annualized bleeding rate (ABR) of ≥12 events/year. Subjects received a single 18 μg/kg intravenous dose of MarzAA to measure 24‐hour pharmacokinetics (PK) and pharmacodynamics (PD), single 30 μg/kg SC dose to measure 48‐hour PK/PD, then daily SC 30 μg/kg MarzAA for 50 days. If spontaneous bleeding occurred, the dose was sequentially escalated to 60, 90, or 120 μg/kg, with 50 days at the final effective dose without spontaneous bleeding to proceed to a 30‐day follow‐up. The primary end point was reduction in ABR. Secondary end points were safety, tolerability, and antidrug antibody (ADA) formation. Results In the 11 subjects, the mean ABR significantly reduced from 19.8 to 1.6, and the mean proportion of days with bleeding significantly reduced from 12.3% to 0.8%. Of a total of 517 SC doses, six injection site reactions in two subjects were reported. No ADAs were detected. One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension. Conclusions The data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes.