Once-weekly prophylactic therapy with emicizumab (ACE910) was associated an 87% lower rate of treated bleeding than no prophylaxis among patients with hemophilia A with inhibitors in the open-label, phase III HAVEN 1 trial.
After a median 24 weeks of treatment (range, 3-48 weeks), the 35 patients who were randomly assigned to prophylactic emicizumab (3.0 mg per kg for 4 weeks, followed by 1.5 mg per kg) had an annualized bleeding rate of 2.9 events, compared with an annualized rate of 23.3 events among the 18 patients who received no prophylaxis. The difference was statistically significant, reported Johannes Oldenburg, MD, PhD, and his associates at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jul 10. doi: 10.1056/NEJMoa1703068).
In addition, 63% of patients who received prophylactic emicizumab had no bleeding events, compared with only 6% of the comparison group, said Dr. Oldenburg of Universitaetsklinikum Bonn, Germany. Emicizumab also was associated with a 79% lower rate of treated bleeds, compared with the historic rate among 24 patients who previously had been on prophylactic bypassing agents (P less than .001). No patient developed detectable antidrug antibodies.
The most common adverse events were injection site reactions (15% of patients), followed by headache, upper respiratory tract infection, arthralgia, and fatigue. Four patients developed thrombotic microangiopathy or cavernous sinus thrombosis and skin necrosis, all of whom had experienced breakthrough bleeding for which they had received multiple infusions of activated prothrombin complex concentrate at doses averaging more than 100 U per kg per day.
Patients with severe hemophilia A typically require prophylactic factor VIII infusions two to three times a week, but 30% develop neutralizing antibodies against factor VIII (inhibitors), which increases care burden, costs, and complication rates.
Emicizumab is a recombinant humanized bispecific monoclonal antibody that restores the function of missing active factor VIII by bridging activated factor IX and factor X, the investigators noted. A phase I study linked once-weekly emicizumab prophylaxis to markedly lower bleeding rates without dose-limiting toxicities (N Engl J Med 2016;374:2044-53). Subsequently, the phase III HAVEN 1 study (NCT02622321) compared once-weekly subcutaneous prophylactic emicizumab with on-demand (episodic) and prophylactic use of bypassing agents (BPAs) in 109 adults and adolescents (12 years and older) with hemophilia A with inhibitors. The primary endpoint was the difference in rates of treated bleeds between the groups. Patients had a median age of 28 years, all were male, and most had severe hemophilia at baseline. They typically had more than nine bleeding events in the 6 months before enrollment, with bleeding in more than one target joint and factor VIII titers of 180 Bethesda units per mL.
HAVEN 1 was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. Dr. Oldenburg and 13 coinvestigators disclosed ties to Chugai, Roche, and other pharmaceutical companies. The remaining coinvestigator had no disclosures.