Reviewed by Dr. Nimish Shah 
Oldenburg J, et al. NEJM. 2017 July 10; Epub ahead of print

Hemophilia A is a bleeding disorder caused by deficiency of factor VIII activity. Current prophylaxis for severe bleeding events is IV infusion of factor VIII concentrate two to three times weekly, however this potentiates the development of alloantibodies that render factor VIII replacement ineffective in about a third of patients. In patients with hemophilia A with acquired inhibitors, treatment includes eradication of inhibitor through induction of immune tolerance or prophylaxis with bypassing treatments like recombinant factor VII or activated PCC, which are suboptimally effective. These patients experience high morbidity and decreased quality of life.

Emicizumab is a recently introduced recombinant humanized bispecific monoclonal antibody bridging activated factor IX and factor X to restore the function of factor VIII without inhibition by factor VIII alloantibodies.

The HAVEN 1 trial was a phase 3 open-label, international randomized study that assessed the efficacy, safety, and pharmacokinetics of emicizumab prophylaxis in patients with hemophilia A with inhibitors who had received episodic treatment or prophylaxis with bypassing treatments (n=109). Participants were randomly assigned to receive emicizumab 3.0 mg/kg body weight subcutaneously weekly for 4 weeks, followed by 1.5mg/kg weekly for at least 20 weeks. The control group received no injections. The primary outcome was the difference in the rate of treated bleeding events over at least 24 weeks between patients receiving emicizumab prophylaxis and those receiving no prophylaxis. The secondary endpoint included additional bleeding events as well as quality of life and validated scales of health status. Patients were also studied in an intraindividual, noninterventional analysis to compare bleeding rates between bypassing treatments/prophylaxis and emicizumab prophylaxis.

The annualized bleeding rate among those receiving emicizumab prophylaxis was significantly lower than among controls (2.9 events [95%CI 1.7-5.0] vs. 23.3 events [95%CI 12.3-43.9]; RR 0.13, p<0.001). Remarkably, while only 1 of 18 controls had 0 bleeding events, 22 of 35 (63%) participants with prior episodic bypassing agent treatment who received emicizumab had 0 bleeding events. Among those who had previously received episodic treatment or prior prophylaxis with bypassing agents, emicizumab treatment also resulted in significantly lower bleeding events with relative risk reductions of 95% and 79%, respectively. Those who received emicizumab prophylaxis also demonstrated significantly better health-related quality of life and health status scores. There were 198 adverse events in 103 treated patients, 15% of which were mild injection-site reactions. Twelve serious adverse reactions including thrombotic microangiopathy, cavernous sinus thrombosis, and skin necrosis-superficial thrombitis were reported in 9 participants who had received high cumulative doses of PCC while receiving emicizumab. One participant who developed TMA after receiving PCC died of rectal hemorrhage. Two participants had evidence of declining exposure to emicizumab, suggestive of antidrug antibodies.

The magnitude of effect of emicizumab in reducing severe bleeding rates is promising for Hemophilia A patients with inhibitors. However, the potential for serious adverse events including thrombotic microangiopathy is very concerning, especially since these developed with PCC salvage therapy, the use of which would be usual practice for breakthrough bleeding. The authors recognize that scant prior data suggest a synergistic thrombogenic effect when both agents are used, limiting the use of PCC while on emicizumab prophylaxis. The reduced effectiveness of emicizumab in two patients also raises the concern for long-term development of antidrug antibodies, though none were detected in this study. The non-blinded nature of this study may bias the positive effect on quality of life measures, however it is unlikely that the substantial reductions in bleeding rates were biased by this study design. Lastly, while the cost of recombinant and human-derived factors is high, it is likely that the cost of this novel agent will be more prohibitive. Overall, emicizumab may be a promising agent to use in Hemophilia A patients with antibodies to minimize morbidity and improve quality of life, however strict restrictions on salvage therapy for breakthrough bleeding will likely be necessary.