According to the results of a recent study, a novel variant of activated human factor VII Marzeptacog alfa (activated; MarzAA) was highly efficacious as prophylactic treatment in patients with severe congenital hemophilia with inhibitors, significantly decreasing bleed frequency and duration of bleeding episodes by approximately 90% each.
The investigators conducted a multicenter, open-label phase 2 trial (ClinicalTrials.gov Identifier: NCT03407651) to evaluate the safety and efficacy of daily subcutaneous administration of MarzAA as prophylaxis in adult patients with severe congenital hemophilia A or B with inhibitors; pharmacokinetics and pharmacodynamics were also evaluated.
To evaluate safety and efficacy, participants received a daily subcutaneous dose of MarzAA (30 μg/kg) for 50 days. In patients with spontaneous bleeding, the dose was sequentially escalated (60, 90, or 120 μg/kg) until reaching an effective dose. After 50 days at the final effective dose with no spontaneous bleeding, patients proceeded to a 30-day follow-up period. The primary endpoint was reduction in annualized bleeding rate, and secondary endpoints were safety, tolerability, and antidrug antibody formation.
A total of 11 male participants received MarzAA (hemophilia A, n=10; hemophilia B, n=1). The median age was 31 years (range, 18-47). At baseline, the mean annualized bleeding rate was 19.8 (range, 12.2-26.7), and the mean proportion of days with bleeding was 12.3% (range, 4-22).
All participants who completed the trial were adherent to all doses of MarzAA. No patients required blood transfusion, and none had been on a prophylactic treatment prior to the study. A total of 3 participants did not complete the trial (1 withdrew consent; 1 discontinued after 44 doses because of relocation; and 1 discontinued after experiencing a fatal serious adverse event unrelated to the study drug).
MarzAA significantly reduced the mean annualized bleeding rate from 19.8 to 1.6 (95% confidence interval [CI], 15.2-21.1; P =.009) and the mean proportion of days with bleeding from 12.3% to 0.8% (95% CI, 7.5-15.6; P =.009).
In the safety evaluation, treatment-emergent adverse events (TEAEs) varied with dose and included hyperglycemia (n=1), vomiting, (n=1), headache (n=1), and hypertension (n=1). Of 517 subcutaneous doses administered over the course of the study, 6 injection site reactions occurred in 2 participants. No antidrug antibodies were detected. A fatal serious adverse event (intracerebral hemorrhage due to untreated hypertension) occurred in 1 patient.
“This multicenter, open-label, phase 2 trial with MarzAA (NCT03407651) enrolled adults with severe congenital hemophilia A or B with an inhibitor,” the authors wrote. “The data demonstrated that an individualized dose of daily [subcutaneous] MarzAA can significantly decrease the frequency of bleeding and provide effective prophylaxis in people with hemophilia with inhibitors.”
Disclosure: This research was supported by Catalyst Biosciences, Inc. Please see the original reference for a full list of disclosures.
Mahlangu J, Levy H, Kosinova MV, et al. Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety. Res Pract Thromb Haemost. 2021;5(6):e12576. Published 2021 Aug 17. doi:10.1002/rth2.12576