The U.S. Food and Drug Administration (FDA) approved emicizumab-kxwh (Hemlibra) for prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients, including newborns, with hemophilia A with or without factor VIII (FVIII) inhibitors.
Emicizumab is a humanized bispecific factor IXa- and factor X-directed antibody for patients with congenital FVIII deficiency.
It was first approved in 2017 for hemophilia A patients with FVIII inhibitors.
The current approval expands the indication to include patients without FVIII inhibitors and provides new dosing regimens.
The FDA based the current approval on the HAVEN 3 and HAVEN 4 trials.
HAVEN 3 (NCT02847637)
This multicenter trial randomized 89 patients with severe hemophilia A without FVIII inhibitors to receive emicizumab prophylaxis at one of 3 dose levels: 1.5 mg/kg once weekly (ARM A), 3 mg/kg once every two weeks (Arm B), or no prophylaxis (Arm C). Patients had previously received on-demand treatment with FVIII.
Before the start of the trial, investigators stratified patients by 24-week bleed rate—fewer than 9 bleeds and 9 or more bleeds.
Patients were treated with emicizumab for a minimum of 24 weeks.
Patients in Arm A experienced a 96% reduction in annualized bleed rate (ABR) compared to patients with no prophylaxis (ABR ratio=0.04; P<0.0001).
Patients in Arm B had a 97% reduction in ABR compared to patients with no prophylaxis (ABR ratio=0.03; P<0.0001).
The trial met all bleed-related secondary endpoints, such as all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds.
HAVEN 4 (NCT03020160)
This was a single-arm multicenter trial in 48 adult and adolescent males with hemophilia A with or without FVIII inhibitors. The patients had previously received on-demand or prophylactic treatment with FVIII or bypassing agents.
The study was conducted in two parts: a run-in of 7 patients to determine the pharmacokinetics after a single 6 mg/kg dose in four weeks. This was followed by the same dose once every four weeks for at least 24 weeks.
The second part was an expansion cohort of 41 patients who received emicizumab at 3 mg/kg once weekly for the first four weeks followed by 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 recommended loading dose is 3 mg/kg once weekly for the first four weeks for all prophylactic regimens.
The prescribing information for emicizumab includes a warning about thrombotic microangiopathy and thromboembolism.
These events were reported on average when 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 emicizumab prophylaxis.
According to the warning box, patients should be monitored for these events if aPCC is administered. If symptoms occur, aPCC should be discontinued and emicizumab dosing suspended.
The most common adverse reactions reported for emicizumab with an incidence ≥10% were injection site reactions (22%), headache (15%), and arthralgia (15%).
Emicizumab is manufactured by Genentech, Inc., a member of the Roche Group.
Additional data on emicizumab can be found in an earlier Roche media release.