On October 4, 2018, the Food and Drug Administration approved emicizumab-kxwh injection (HEMLIBRA, Genentech, Inc.) for prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients (ages newborn and older) with hemophilia A (congenital factor VIII deficiency) with or without factor VIII (FVIII) inhibitors.
Hemlibra was first approved in 2017 for patients with hemophilia A with FVIII inhibitors.
The current approval was based on two clinical trials: HAVEN 3 (NCT02847637) and HAVEN 4 (NCT03020160). This approval expanded the indication for patients with hemophilia A without FVIII inhibitors and provided for new dosing regimens for patients with and without FVIII inhibitors.
In HAVEN 3, a randomized, multicenter, open-label trial, 89 patients with severe hemophilia A without FVIII inhibitors who previously received episodic (on demand) treatment with FVIII were randomized (2:2:1) to receive Hemlibra prophylaxis 1.5 mg/kg once every week (Arm A), 3 mg/kg once every two weeks (Arm B), or no prophylaxis (Arm C). Patients were stratified by 24-week bleed rate prior to trial entry (< 9 or ≥ 9 bleeds). Patients received Hemlibra prophylaxis for a minimum of 24 weeks.
The HAVEN 3 primary efficacy endpoint was the annualized bleed rate (ABR) for treated bleeds. Hemlibra prophylaxis in Arm A resulted in a 96% reduction in ABR compared with Arm C (ABR ratio=0.04; p<0.0001). Hemlibra prophylaxis in Arm B also led to a 97% reduction in ABR compared with Arm C (ABR ratio=0.03; p<0.0001). HAVEN 3 met all bleed-related secondary endpoints (all bleeds, treated spontaneous bleeds, treated joint bleeds and treated target joint bleeds).
HAVEN 4 was a single-arm, multicenter, open-label trial in 48 adult and adolescent males with hemophilia A with or without FVIII inhibitors who previously received either episodic (on demand) or prophylactic treatment with FVIII or bypassing agents. Patients in the expansion cohort (n=41) received Hemlibra prophylaxis 6 mg/kg once every four weeks for at least 24 weeks. The ABR for treated bleeds was 2.4 (95% CI: 1.38, 4.28) and the median ABR was 0.0 (interquartile range: 0.00, 2.08).
The prescribing information includes a warning that thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving Hemlibra prophylaxis. Patients should be monitored for the development of thrombotic microangiopathy and thrombotic events if aPCC is administered. aPCC should be discontinued and Hemlibra dosing should be suspended if there is evidence of thrombotic microangiopathy or an acute thrombotic event. The most common adverse reactions reported (incidence ≥10%) were injection site reactions, headache, and arthralgia.
The recommended loading dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks for all approved prophylactic dosing regimens. In addition to the already approved weekly dose of 1.5 mg/kg, the new Hemlibra maintenance dosing regimens include 3 mg/kg by subcutaneous injection once every 2 weeks and 6 mg/kg by subcutaneous injection every 4 weeks.
FDA granted Hemlibra priority review and breakthrough therapy designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
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