Spotlight on emicizumab in the management of hemophilia A: patient selection and special considerations

Abstract

Emicizumab is a factor (F)VIIIa-mimicking bispecific antibody recognizing FIXa and FX molecules. In the phase 1/2 clinical studies, once-weekly subcutaneous administration of emicizumab has shown a favorable safety profile with encouraging efficacy in the patients with hemophilia A (PwHA) irrespective of the presence of anti-FVIII inhibitors. Moreover, in the following phase 3 studies, emicizumab treatment by once-weekly, bi-weekly or tetra-weekly administration have been still well-tolerated, but some thromboembolic events or thrombotic microangiopathy were observed associated with the concomitant use of activated prothrombin complex concentrates (aPCC) for breakthrough bleeds. Since approved for routine prophylaxis in PwHA in the US, EU, and Japan, a compass on patient selection for emicizumab treatment and special considerations on the practical situations such as concomitant treatment by bypassing agents (BPAs) or clotting factor concentrates (CFCs) with less thrombotic risk, inhibitor eradication by immune tolerance induction (ITI) should be provided. There is no doubt that emicizumab is an alternate first-line therapy for any existing BPA as hemostatic treatment for PwHA with inhibitor, but we should be more cautious in combination with aPCC on breakthrough bleeds under emicizumab prophylaxis because of thrombotic risk. For severe PwHA without inhibitor, since most patients are under CFCs prophylaxis, switching from CFCs to emicizumab should be considered when the advantage of emicizumab prophylaxis surpasses that of CFCs prophylaxis from the viewpoint of hemostatic effect by treatment, physical activity according to the life stage, health condition of the joints, adherence and complication. There are pros and cons on the timing of introduction of emicizumab for cases scheduled to start ITI or cases of ongoing ITI. Introduction of emicizumab to previously untreated patients and nonsevere PwHA without inhibitor is also required to discuss in consideration of risk of inhibitor development and unforeseen safety issues.

Keywords:

• hemophilia
• emicizumab
• inhibitor
• noninhibitor
• bypassing agent

Author contributions

All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

KN is an inventor of the patents relating to emicizumab. KY and KN are engaged in clinical studies sponsored by Chugai and F. Hoffmann-La Roche. KY teaches a course endowed by Shire Japan Co. Ltd. KY also reports nonfinancial support from Chugai Pharmaceutical, F. Hoffmann-La Roche, and Shire Japan Co. Ltd., during the conduct of the study. KN reports grants and personal fees, from Shire, Japan Co. Ltd., Novo Nordisk, Bioverativ, and Bayer, during the conduct of the study. KN also receives personal fees from Chugai Pharmaceutical. In addition, KN has a patent pending with Chugai. The authors report no other conflicts of interest in this work.