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Emicizumab prophylaxis reduces bleeds associated with hemophilia A without inhibitors
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Emicizumab prophylaxis significantly reduced the bleeding rate among people 12 and older with hemophilia A without factor VIII inhibitors, according to results of the multicenter, open-label, randomized phase 3 HAVEN 3 study published in The New England Journal of Medicine.
More than half of the patients who received emicizumab (Hemlibra, Genentech) experienced no treated bleeding events.
“In patients with hemophilia without inhibitors, emicizumab prophylaxis given subcutaneously weekly or every second week results in clinically meaningful reduction in bleed event rate,” Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre at University of the Witwatersrand and National Health Laboratory Service in Johannesburg, South Africa, told HemOnc Today. “Emicizumab has the potential to reduce the treatment burden associated with prophylaxis treatment and therefore reduce the hemophilia disease-related complications.”
Emicizumab — a bispecific humanized monoclonal antibody administered via subcutaneous injection — is approved for routine prophylaxis to prevent or reduce frequency of bleeding episodes among adults and children with hemophilia A with factor VIII inhibitors.
The FDA granted priority review to emicizumab for treatment of adults and children with hemophilia A without factor VIII inhibitors in June based on these study results.
The analysis included 152 patients aged 12 years or older with hemophilia A who did not have factor VIII inhibitors. Patients underwent prior treatment with factor VIII therapy, either on demand (n = 89) or as prophylaxis (n = 63).
Researchers randomly assigned patients who had been receiving on-demand factor VIII 2:2:1 to 1.5 mg/kg subcutaneous emicizumab prophylaxis per week (group A; n = 36); 3 mg/kg subcutaneous emicizumab prophylaxis every 2 weeks for at least 24 weeks (group B; n = 35); or no prophylaxis (group C; n = 18). Groups A and B both initially received four weekly 3-mg/kg loading doses of emicizumab prophylaxis before switching to their weekly or biweekly schedules.
The difference in rates of treated bleeding between the groups served as the study’s primary endpoint.
Researchers reported annualized bleeding rates of 1.5 events (95% CI, 0.9-2.5) in group A and 1.3 events (95% CI, 0.8-2.3) in group B, compared with 38.2 events (95% CI, 22.9-63.8) in group C.
Thus, emicizumab prophylaxis was associated with a 96% reduction in treated bleeds with weekly dosing and 97% reduction with dosing every 2 weeks compared with no prophylaxis (P < .0001).
In addition, 55.6% of those who received weekly prophylaxis and 60% of those who received prophylaxis every 2 weeks experienced no treated bleeds, whereas every patient in the no prophylaxis group experienced at least one treated bleed.
A separate study arm included 48 of 63 patients who previously received factor VIII prophylaxis in a noninterventional study. These patients received 3 mg/kg subcutaneous emicizumab prophylaxis every week for 4 weeks, followed by 1.5 mg/kg every week until study conclusion.
The annualized bleeding rate was 1.6 events (95% CI, 1.1-2.4) in this group, and 56% of the participants had 0 bleeding events.
Intraindividual analyses from this arm showed emicizumab led to a 68% reduction in treated bleeds (P < .0001).
Researchers observed 543 adverse events among 127 patients who received emicizumab. The most common adverse event was injection-site reaction, observed among 25% of patients.
No treatment-related serious adverse events were reported.
It remains a question whether emicizumab prophylaxis promotes factor VIII tolerance among previously untreated patients, according to Margaret V. Ragni, MD, MPH, professor of medicine and clinical translational science in the division of hematology/oncology at University of Pittsburgh Medical Center.
“If emicizumab prophylaxis allows children to avoid factor VIII exposure in early life and during severe bleeding events in which intense factor VIII exposure occurs (both of which are major risk factors for inhibitor formation), will inhibitors be prevented or delayed?” Ragni wrote in a related editorial.
Cost also is a concern.
“Although emicizumab therapy is cost-effective in patients with a hemophilia inhibitor, is emicizumab prophylaxis cost-effective in a patient without an inhibitor who has a better response to treatment, higher quality of life and fewer hospitalizations?” Ragni wrote. “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.” – by Melinda Stevens
For more information:
Johnny Mahlangu, MD, can be reached at Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, 7 York Rd., Parktown, 2194 Johannesburg, South Africa; email: johnny.mahlangu@nhls.ac.za.
Disclosures: Mahlangu reports grants or personal fees from Alnylam Pharmaceuticals, Bayer, Baxalta, CSL Behring, Roche and Shire. Please see the study for all other authors’ relevant financial disclosures. Ragni reports grants or personal fees from Alnylam, Bayer, BioMarin, Bioverativ, CSL Behring, MOGAM (Green Cross Corporation), NovoNordisk, Opko Biologics, Sangamo, Spark Therapeutics and Institute for Clinical & Economic Review, as well as nonfinancial support from Shire, outside the submitted work.
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