In hemophilia A, emicizumab cuts bleeding; plasma-derived factor VIII less likely to trigger antibodies

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Innovations in hemophilia therapy

The studies by Peyvandi et al. and Shima et al. bring exciting news to patients with hemophilia. Peyvandi et al. report the influence of factor VIII product source on the cumulative incidence of inhibitors in children with severe hemophilia. Exclusive use of recombinant factor VIII through the highest-risk period increased the cumulative incidence of all inhibitors, compared with plasma-derived factor VIII. Factor VIII protein glycosylation and von Willebrand factor association play a role in endocytosis, clearance, and antigen presentation and are altered by recombinant technology, which lends plausibility to the implication of product source affecting inhibitor generation. The results may lead to valuable mechanistic insight into factor VIII immunogenicity.

In the second study, Shima et al. evaluate once-weekly administration of emicizumab in patients with severe hemophilia. The bifunctional antibody functions as a conformation replica of factor VIII, forming a thrombin-generating complex with factors IX and X. Emicizumab would likely not induce or be inhibited by factor VIII–neutralizing antibodies, and its subcutaneous bioavailability permits a once-weekly treatment regimen instead of intravenous infusion. The study reports impressive short-term decreases in annualized bleeding rates in both inhibitor-positive and inhibitor-negative patients. The next steps in testing more substantial and sustained thrombin generation required for the treatment of acute hemorrhage will be important for emicizumab.

If proven feasible as a therapeutic agent, emicizumab may play a role in mediating factor VIII immunogenicity. Early sustained treatment with emicizumab in children could ultimately affect the epidemiology of neutralizing antibodies.

The clinical and scientific ramifications of these two studies will take time to be fully realized but offer exciting potential as therapeutic options where new approaches to bypassing the factor VIII requirement have so far fallen short (N Engl J Med. 2016 May 25. doi: 10.1056/NEJMe1603419).

Dr. Donna DiMichele is the deputy director of the Division of Blood Diseases and Resources at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. These remarks were part of an editorial accompanying two reports in the New England Journal of Medicine. Dr. DiMichele reports personal fees from Chugai Pharmaceuticals outside the submitted work. She was an early founding member of the SIPPET study Steering Committee but resigned when she came to NIH in 2010.




Patients with severe hemophilia A treated with plasma-derived factor VIII, as compared with recombinant factor VIII, had a lower risk of developing neutralizing antibodies, based on a recent report from the randomized SIPPET trial published in the New England Journal of Medicine.

In a second study, also published in the journal, prophylactic treatment with the bispecific antibody emicizumab decreased bleeding in patients with or without neutralizing antibodies.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Of 125 patients with severe hemophilia A who were treated with plasma-derived factor VIII with von Willebrand factor, 29 (23.2%) developed inhibitors, compared with 47 of 126 patients (37.3%) treated with recombinant factor VIII. In the plasma-derived group, 20 (16.0%) had high-titer inhibitors compared with 30 (23.8%) in the recombinant group. Cox regression models showed an 87% higher rate of inhibitor development with recombinant factor VIII (hazard ratio, 1.87; 95% confidence interval, 1.17-2.96). For development of high-titer inhibitors, the HR was 1.69 (95% CI, 0.96-2.98).

Previous observational studies have suggested greater immunogenicity of recombinant vs. plasm-derived factor VIII, but the results remained inconclusive. Meta-analyses of studies have been hindered by differences in design, enrollment criteria, definition of hemophilia A, sample size, method of inhibitor detection, and intervals of follow-up testing, according to Dr. Flora Peyvandi of the IRCCS Maggiore Hospital, University of Milan and colleagues. “Our trial was specifically designed to compare the immunogenicity of factor VIII products. As a result of randomization, the main risk factors for inhibitor development were evenly distributed between the two factor VIII classes,” they wrote, adding, “The finding that native factor VIII products from human plasma are less immunogenic than those engineered by recombinant DNA technology in animal cell lines has the potential to affect treatment strategies and open new investigations to better understand the mechanisms of the immunogenicity of various factor VIII preparations.” (N Engl J Med. 2016 May 25. doi: 10.1200/JCO.2015.64.0730).

The Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) clinical trial randomized 251 patients with severe hemophilia A who received infusions of plasma-derived or recombinant factor VIII. The investigators found no association between risk of inhibitor development and race, intensity of treatment, or age at first treatment.

The second study, a 12-week dose-escalation trial of emicizumab, included 18 patients with severe hemophilia A, aged 12-59 years. Patients were assigned to one of three cohorts and received a once-weekly subcutaneous dose of 0.3, 1, or 3 mg per kilogram of body weight. During prophylactic emicizumab treatment, median annualized bleeding rates decreased from 32.5 (range, 8.1-77.1) to 4.4 (0.0-59.5) in cohort 1, from 18.3 (range, 10.1-38.6) to 0.0 (range, 0.0-4.3) in cohort 2, and from 15.2 (range, 0.0-32.5) to 0.0 (range, 0.0-4.2) in cohort 3. The annualized bleeding rate decreased regardless of factor VIII inhibitor status. Of 11 patients with factor VIII inhibitors, 8 (73%) had no bleeding episodes; 5 of 7 patients without factor VIII inhibitors (71%) had no bleeding episodes.

“This study showed that once-weekly subcutaneous administration of emicizumab as prophylaxis is safe and has the potential to reduce or prevent bleeding episodes in patients who have severe hemophilia A with or without factor VIII inhibitors,” wrote Dr. Midori Shima of Nara Medical University, Kashihara, Japan, and colleagues (N. Engl J Med. 2016 May 25. doi: 10.1056/NEJMoa1511769).

Emicizumab had an acceptable safety profile. In total, 43 adverse events were reported in 15 of 18 patients. All were mild, except two moderate events – an upper respiratory tract infection and a headache. Events thought to be treatment related included malaise, injection-site erythema, injection-site rash, diarrhea, increased C-reactive protein level, and increased blood creatine kinase level.

Dr. Peyvandi and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Grifols, Kedrion, and LFB. Dr. Shima and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Chugai Pharmaceuticals, which supported the study.

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