Treatment with emicizumab was associated with lower bleeding rates, compared with no prophylaxis, in patients with hemophilia A without inhibitors, according to findings from the phase III, open-label HAVEN 3 study published in the New England Journal of Medicine. Emicizumab also is administered via subcutaneous injection, making it a less burdensome alternative to regular prophylactic intravenous infusions of factor VIII (FVIII), the study’s lead author, Johnny Mahlangu, MBBCh, MMed, of the University of the Witwatersrand and National Health Laboratory Service in Johannesburg, South Africa, told ASH Clinical News.
“Subcutaneous injection of emicizumab every week or two weeks results in better compliance with prophylaxis, which is the current standard of care,” he said, “and the reduction in bleed rates will reduce the arthropathy associated with hemophilia.”
Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that bridges activated factor IX and factor X to restore the function of activated FVIII. Once-weekly emicizumab has been proven effective for patients with hemophilia A and inhibitors, but in this analysis, investigators evaluated its safety and efficacy in patients ≥12 years of age without inhibitors who were undergoing episodic or prophylactic FVIII infusions.
A total of 152 patients (age range = 14.4-50.6 years) were enrolled and randomized to one of three treatment arms:
- group A: emicizumab 1.5 mg/kg once weekly (n=36)
- group B: emicizumab 3.0 mg/kg every two weeks (n=35)
- group C: no prophylaxis with an option to receive emicizumab every two weeks after ≥24 weeks (n=18)
In groups A and B, patients received four initial loading doses of emicizumab at 3.0 mg/kg per week.
An additional group, D, was reserved for 48 participants who were unable to join the other arms because they were receiving adequate prophylactic FVIII at the time of enrollment; these patients were assigned to receive once-weekly emicizumab as maintenance and could continue FVIII prophylaxis until the second loading dose of emicizumab.
In the instances of breakthrough bleeding events, investigators administered additional FVIII. Patients reported bleeding events, as well as the administration of treatment throughout the study, using an electronic handheld device.
The annualized bleeding rates among each group were:
- group A: 1.5 events (range = 0.9-2.5 events)
- group B: 1.3 events (range = 0.8-2.3 events)
- group C: 38.2 events (range = 22.9-63.8 events)
Compared with no prophylaxis, therefore, emicizumab prophylaxis significantly lowered bleeding rates (TABLE). Participants in the once-weekly group were 96 percent less likely to experience a bleeding event (rate ratio [RR] = 0.04; 95% CI 0.02-0.08; p<0.001) and participants in the biweekly group were 97 percent less likely (RR=0.03; 95% CI 0.02-0.07; p<0.001).
Emicizumab prophylaxis also was associated with a significantly lower incidence of treated bleeding events, compared with no prophylaxis (primary endpoint). Over a ≥24-week treatment period, all members of group C reported at least one treated bleeding event, while 56 percent of people receiving once-weekly emicizumab and 60 percent of people receiving biweekly emicizumab reported no treated bleeding events.
In group D, the annualized bleeding rates (ABRs) for those receiving once-weekly emicizumab vs. FVIII prophylaxis were 1.5 events (range = 1.0-2.3) and 4.8 events (range = 3.2-7.1), respectively, “a result that indicated a 68-percent lower rate in favor of emicizumab prophylaxis (RR=0.32; 95% CI 0.20-0.51; p<0.001),” the authors reported.
At enrollment, target joints (major joints in which ≥3 bleeding events occurred over a 24-week period) were reported by 76 of 89 participants (85%) who had been receiving episodic therapy with FVIII and by 26 of 63 participants (41%) who had been receiving prophylactic therapy with FVIII. During emicizumab treatment, these numbers appeared to decrease, with three of 71 participants in groups A and B reporting target joints.
“Emicizumab had a favorable safety profile with no unexpected safety signals,” the researchers added. Among the 127 participants who received emicizumab, a total of 543 adverse events (AEs) were reported, the most common of which was low-grade injection-site reaction (n=38; 25%). There were no patient deaths during the study, and no thromboembolism, thrombotic microangiopathy, or inhibitor development events occurred.
There were 14 serious AEs, which included: bleeding events (n=4), infection (n=3), musculoskeletal disorder (n=3), cardiac disorder (n=1), loosening of an orthopedic device (n=1), psychiatric disorder (n=1), and trauma (n=1). However, none of these were considered related to emicizumab treatment.
As a secondary endpoint of the analysis, participants completed the 100-point Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) every 12 weeks to measure how emicizumab prophylaxis affected their quality of life. Compared with patients in group C, those in groups A and B had higher Haem-A-QoL scores (representing greater impairment), although these comparisons were not statistically significant. However, of the 95 eligible participants who completed a treatment preference survey, 89 (94%) preferred emicizumab, the investigators noted.
A limitation of the analysis was the relatively short follow-up period, which precludes the ability to determine the longer-term impact of emicizumab prophylaxis in this patient population. Dr. Mahlangu also noted that data from “real-life experience with emicizumab is important in validating these results.”
The authors report financial relationships with Roche and Chugai Pharmaceutical Co., which supported the study.
Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018;379:811-22.