In the phase III HAVEN-1 study, preventive treatment with emicizumab significantly reduced bleeding rates, compared with no treatment in patients with hemophilia A with inhibitors. Lead author Johannes Oldenburg, MD, PhD, from the UniversitÃ¤tsklinikum Bonn in Germany, presented the findings at the 2017 Congress of the International Society on Thrombosis and Haemostasis, and the New England Journal of Medicine simultaneously published the results.
Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that bridges activated factor IX and factor X to restore the function of activated factor VIII (FVIII). "These data may support a genuine paradigm shift in the management of [this patient group]," Dr. Oldenburg said.
The open-label, multicenter, randomized HAVEN-1 trial began on November 17, 2015, and enrolled 109 male patients (â‰¥12 years old; median age = 28 years; range = 12-75 years) from 43 centers in 14 countries. Patients were included if they had congenital hemophilia A, had a history of a high titer of FVIII inhibitor, and were receiving episodic or prophylactic treatment with bypassing agents.
Patients were assigned to one of four treatment groups:
- arm A: patients who received prior episodic treatment with bypassing agents and received subcutaneous emicizumab 3.0 mg/kg once-weekly for four weeks, followed by 1.5 mg/kg thereafter (n=35)
- arm B: patients who only received episodic treatment with bypassing agents (n=18)
- arm C: patients who received prophylactic treatment with bypassing agents and received emicizumab 3.0 mg/kg (n=49)
- arm D: patients who were unable to join arms A, B, or C before enrollment closed and received emicizumab 3.0 mg/kg (n=7)
Patients who were randomly assigned to group B could receive emicizumab prophylaxis after 24 weeks.
The median emicizumab exposure for all patients was 24 weeks (range = 3.0-47.9 weeks); in arm A, it was 29.5 weeks (range = 3.3-47.9 weeks).
At data cutoff (October 25, 2016), the study had met its primary efficacy endpoint (a comparison of the annualized bleeding rate [ABR] between arms A and B). The ABR was 2.9 events in arm A and 23.3 events in arm B, representing a significant difference of 87 percent in favor of emicizumab prophylaxis (p<0.001).
Most patients in arm A (n=22; 63%) had zero bleeding events (median ABR = 0; range = 0-3.7), and only one patient (6%) in group B had zero bleeding events.
Additionally, for patients who received prior prophylaxis (arm C), the researchers noted a significantly lower bleeding rate with emicizumab (ABR = 3.3; 95% CI 1.3-8.1), compared with bypassing agent prophylaxis (ABR = 15.7; 95% CI 11.1-22.3), representing a difference of 79 percent (p<0.001).
A total of 198 adverse events (AEs) were reported in 103 patients, the most common of which was injection site reaction (28 events in 15 patients).
Overall, 12 serious AEs were reported in nine participants (9%). Thrombotic microangiopathy and thrombosis were reported in two patients each – all of whom had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding concurrent with emicizumab. This finding "may limit the usefulness of this bypassing agent in patients who bleed while receiving emicizumab prophylaxis," the authors noted.
"Proportionally fewer participants had AEs in groups B and D than in groups A and C," the authors wrote. "However, observation periods were also shorter [in arms B and D]." The shorter follow-up (<24 weeks) in these arms made it difficult to draw conclusions between the treatment groups, and the study was further limited by its open-label design and potential selection bias in arms C and D.
The study was supported by F. Hoffmann-La Roche and Chugai Pharmaceuticals, which is the manufacturer of emicizumab.
The authors report no conflicts.
- Oldenburg J, Mahlangu JN, Kim B, et al. Efficacy, safety and pharmacokinetics (PK) of emicizumab (ACE910) prophylaxis (Px) in persons with hemophilia A with inhibitors (PwHAwI): randomized, multicenter, open-label, phase 3 study (HAVEN 1). Abstract ASY 01.1. Presented at the International Society of Thrombosis and Haemostasis 2017 Congress, June 8-13, 2017; Berlin, Germany.
- Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017 July 17. [Epub ahead of print]