Key clinical point: In hemophilia A without factor VIII inhibitors, emicizumab therapy is superior to factor VIII prophylaxis.
Major finding: Treatment with emicizumab resulted in 68% fewer bleeding events, compared with factor VIII prophylaxis (P less than .001).
Study details: HAVEN 3 was a randomized, open-label phase 3 trial involving 152 patients who had hemophilia A without inhibitors.
Disclosures: The study was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The authors reported support from Bayer, Baxalta, CSL Behring, and others.
Mahlangu et al. N Engl J Med. 2018;379:811-22.
The HAVEN 3 trial by Mahlangu et al. showed that emicizumab can significantly decrease the incidence of bleeding events in patients with hemophilia A, but questions remain about impacts on factor VIII tolerance and the role of emicizumab in long-term management, according to Margaret V. Ragni, MD.
The HAVEN 3 results showed that emicizumab was highly effective for hemophilia A patients who did not have inhibitors. In addition, thrombosis or thrombotic microangiopathy did not occur in the trial, as breakthrough bleeding was treated with factor VIII concentrate instead of prothrombin concentrate, which was used in previous trials.
“The absence of thrombosis with factor VIII concentrate is probably related to the fact that factor VIII has an affinity for binding factors IXa and X that is 10 times as high as that of emicizumab, so it displaces emicizumab, thereby avoiding potential additive toxicity,” Dr. Ragni wrote.
A survey conducted in the trial showed that patients preferred emicizumab over factor VIII, but Dr. Ragni noted that “there was no direct comparison, nor was the basis specified for the preference, such as a simpler route of administration or a reduction in the incidence of joint bleeding events or pain severity.”
Questions surrounding joint disease, efficacy for acute bleeding, and cost should be addressed before emicizumab replaces factor VIII therapy as standard of care. Additionally, the relationship between emicizumab and inhibitor immune tolerance remains unclear. One trial participant exhibited recurrence of anti-factor VIII antibody, “a finding that suggests incomplete inhibitor suppression by emicizumab prophylaxis.”
“Until more is known, it will be important for discussions between providers and patients to focus on risk, benefit, cost, and participation in observational studies and clinical trials,” Dr. Ragni wrote.
Margaret V. Ragni, MD , is with the division of hematology/oncology at the University of Pittsburgh. Dr. Ragni reported funding from Bayer, Biomarin, NovoNordisk, and others. These comments are adapted from an accompanying editorial ( N Engl J Med. 2018;379:880-2 ).