Patients With Hemophilia A, With or Without Factor VIII, Benefitted from Emicizumab in HAVEN Trials

Trial results show that patients with hemophilia A with or without factor VIII inhibitors treated with emicizumab-kxwh every 4 weeks can have clinically meaningful control of bleeding.

Drug maker Genentech has announced the full results from the phase 3 HAVEN 3 and HAVEN 4 trials of emicizumab-kxwh (Hemlibra) in patients with hemophilia A at the World Federation of Hemophilia (WFH), held in Glasgow, Scotland from May 20-24, 2018. The results show that patients with hemophilia A with or without factor VIII inhibitors treated with emicizumab-kxwh every 4 weeks can have clinically meaningful control of bleeding.

In November 2017, the FDA first approved the drug for the treatment of hemophilia A for routine prophylaxis in adult and pediatric patients with factor VIII inhibitors based on the results from the HAVEN 1 and HAVEN 2 trials.

“Hemlibra is the first medicine to show superior efficacy to prior factor VIII prophylaxis, the current standard of care therapy, as demonstrate by a statistically significant reduction in treated bleeds in the HAVEN 3 study intra-patient comparison,” said Johnny Mahlangu, MB BCh, FCPath, MMed, faculty of health sciences, University of the Witwatersrand and NHLS, in a statement.

The HAVEN 3 trial is a randomized, multicenter, open-label, phase 3 study to evaluate the efficacy, safety, and pharmacokinetics of emicizumab-kxwh prophylaxis versus no prophylaxis (episodic versus on demand factor VIII treatment, respectively) in patients with hemophilia A without factor VIII inhibitors, and included 152 patients with hemophilia A who were aged 12 or older and were previously treated with factor VIII therapy either as needed or for prophylaxis. Patients who had been previously treated with on demand factor VIII were randomized 2:2:1 to receive:

  • Subcutaneous emicizumab-kxwh prophylaxis at 3mg per week for 4 weeks, followed with 1.5 mg per week for the length of the study (Arm A)
  • Subcutaneous emicizumab-kxwh prophylaxis at 3 mg per week for 4 weeks, followed by 3 mg biweekly for at least 24 weeks (Arm B)
  • No prophylaxis

Patients who were previously treated with factor VIII prophylaxis received subcutaneous emicizumab-kxwh prophylaxis at 3 mg per week for 4 weeks, followed by 1.5 mg per week until the end of the study (Arm D).

Per protocol, any episodic treatment of breakthrough bleeds with factor VIII therapy was permitted. Researchers found that patients that received emicizumab-kxwh prophylaxis every week or every 2 weeks showed a 96% (P <.0001) and 97% (P <.0001) reduction in treated bleeds, respectively, compared to those who received no prophylaxis.

Notably, in an intra-patient comparison, patients that had previously participated in a prospective non-interventional study, once-weekly emicizumab-kxwh prophylaxis showed superior efficacy compared to prior factor VIII prophylaxis, which is the standard of care for people with hemophilia A without factor VIII inhibitors, demonstrated by a 68% reduction (P <.0001) in treated bleeds.

HAVEN 4 is a single-arm, multicenter, open-label phase 3 study of subcutaneous emicizumab-kxwh dosed every 4 weeks. The study included 48 patients aged 12 or older with hemophilia A with or without factor VIII inhibitors who had previously been treated with either factor VIII or bypassing agents.

The trial was separated into a pharmacokinetic run-in and an expansion cohort. All patients in the pharmacokinetic run-in (n = 7) had received previous on-demand treatment. This cohort received subcutaneous emicizumab-kxwh at 6 mg in order to fully characterize the profile after a single dose in 4 weeks. This period was followed with 6 mg every 4 weeks for at least 24 weeks.

Conversely, patients in the expansion arm (n = 41) received subcutaneous emicizumab-kxwh prophylaxis at 3 mg per week for 4 weeks, followed with 6 mg every 4 weeks for at least 24 weeks. In addition, episodic treatment of breakthrough bleeds with factor VIII therapy or bypassing agents (depending on the patients factor VIII inhibitor status) was permitted per study protocol.

Researchers found that patients with or without factor VIII inhibitors who received emicizumab-kxwh every 4 weeks had a median annualized bleeding rate for treated bleeds of 0.0 (interquartile range, 0.0-2.1) with 56.1% (95% CI: 39.7%-71.5%) of people experiencing 0 treated bleeds and 90.2% (95% CI: 76.9%-97.3%) experiencing 3 or fewer treated bleeds.

Data from both the HAVEN 3 and HAVEN 4 trials are being submitted to regulatory agencies around the globe to support product approval.