Emicizumab prophylaxis lowers bleeding rate in hemophilia A

Once-weekly emicizumab prophylaxis reduced the rate of bleeding events among patients with hemophilia A with inhibitors, according to results of the HAVEN 1 phase 3 clinical trial.

Factor VIII is deficient in patients with hemophilia A. Emicizumab (ACE910; Genentech/Roche, Chugai Pharmaceutical) is a bispecific monoclonal antibody that bridges activated Factor IX and Factor X to restore the function of activated Factor VIII.

“The reduction in bleeding events across all measures seen with emicizumab compared with either on-demand or prophylactic bypassing agents supports that it may be one of the most significant scientific innovations in the treatment of hemophilia A in over 30 years,” Johannes Oldenburg, MD, PhD, chairman and director of Institute of Experimental Haematology and Transfusion Medicine and medical director of Hemophilia Centre at University Clinic in Bonn, Germany, said in a press release.

The multicenter, open-label study evaluated the safety and efficacy of emicizumab prophylaxis in 109 male patients (median age, 28 years; range, 12-75 years) with hemophilia A with inhibitors to Factor VIII who previously received treatment with episodic or prophylactic bypassing agents.

Oldenburg and colleagues randomly assigned patients who had previously received episodic treatment with bypassing agents 2:1 to emicizumab prophylaxis (n = 35) — 3 mg/kg subcutaneous injections weekly for 4 weeks, followed by 1.5 mg/kg weekly thereafter — or no emicizumab prophylaxis (n = 18). Patients who had previously received prophylaxis with bypassing agents received emicizumab prophylaxis in a third group (n = 49). The study also included a fourth group (n = 7) of patients unable to enroll in the first three groups after they closed.

The difference in the rate of treated bleeding events over at least 24 weeks between patients who received emicizumab prophylaxis and those who did not served as the primary endpoint. After 24 weeks, patients assigned no prophylaxis could receive emicizumab.

Further, to evaluate intraindividual comparisons of previous outcomes with bypassing agents vs. outcomes with emicizumab prophylaxis, researchers designed a prospective, noninterventional study as part of the clinical development of emicizumab. That study collected real-world data on bleeding and safety outcomes in patients who received episodic or prophylactic treatment with bypassing agents per local clinical practice. These patients could subsequently participate in the HAVEN 1 trial if they met eligibility criteria.

Study findings

Results — published in The New England Journal of Medicine in conjunction with their presentation at the International Society on Thrombosis and Haemostasis Congress — showed an 87% reduction in treated bleeding events (RR = 0.13; P < .0001) among patients who received emicizumab prophylaxis compared with patients who received on-demand bypassing agents.

Patients experienced an annualized bleeding rate of 2.9 events (95% CI, 1.7-5) with emicizumab prophylaxis compared with 23.3 events (95% CI, 12.3-43.9) without prophylaxis.

Twenty-two patients (63%) assigned emicizumab prophylaxis compared with one (6%) assigned no prophylaxis experienced zero bleeding events.

After a median follow-up of 31 weeks, more patients who received emicizumab prophylaxis experienced zero treated spontaneous bleeds (68.6% vs. 11.1%), zero treated joint bleeds (85.7% vs. 50%), zero treated target joint bleeds (94.3% vs. 50%), and zero treated and nontreated bleeds overall (37.1% vs. 5.6%).

At 25 weeks, researchers measured health-related quality of life using two validated instruments — Haem-A-QoL and EQ-5D-5L — and observed clinical and significant improvements in patients assigned emicizumab prophylaxis.

Among 24 patients who had previously received prophylactic treatment with bypassing agents and participated in the noninterventional study, intraindividual comparisons showed emicizumab prophylaxis led to a significantly lower bleeding rate than previously bypassing-agent prophylaxis (annualized bleeding rate, 3.3 events vs. 15.7 events; difference, 79%; P < .001).

Overall, 198 adverse events occurred in 103 patients assigned emicizumab prophylaxis. The most common reported adverse events were mild injection-site reactions, with 28 events in 15 patients (15%). Thrombotic microangiopathy and thrombosis occurred in two patients each who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding.

Researchers detected no antidrug antibodies.

Emicizumab prophylaxis appeared to reduce bleeding rates and improve quality of life for these patients — a very challenging patient group — David Lillicrap, MD, professor in the department of pathology and molecular medicine at Queen’s University, wrote in a related editorial.

“The results of this phase 3 trial are extremely important for the hemophilia treatment community, which has battled the hemostatic calamity of Factor VIII inhibitor formation with the same bypassing therapies for the past 30 years,” Lillicrap wrote. “Additional studies are already in progress to determine the benefit of emicizumab prophylaxis in pediatric patients with hemophilia with inhibitors, and a study involving patients with hemophilia A without inhibitors is planned.”

HAVEN 2 study

Interim results from the HAVEN 2 study — also presented at the International Society on Thrombosis and Haemostasis Congress — in children aged younger than 12 years with hemophilia A with inhibitors who received emicizumab prophylaxis are comparable with the results from HAVEN 1, according to a press release.

After a median follow-up of 12 weeks, the study showed that one of 19 children who received emicizumab experienced a treated bleed.

“Managing hemophilia A with inhibitors to Factor VIII can be especially challenging for children and their caregivers,” study researcher Guy Young, MD, director of the Hemostasis and Thrombosis Program at Children’s Hospital Los Angeles and professor of pediatrics at University of Southern California Keck School of Medicine, said in the press release. “The HAVEN 2 interim results indicate that emicizumab may help prevent bleeding in children with inhibitors. Given the once-weekly subcutaneous dosing, it may also help alleviate some of the burden of hemophilia treatment for these children and their parents.”

Data from the HAVEN 1 and HAVEN 2 studies have been submitted for approval to the FDA, the release said. The FDA granted breakthrough therapy designation for emicizumab in adults and adolescents with hemophilia A with inhibitors in September 2015. – by Melinda Stevens

Disclosure: F. Hoffmann–La Roche and Chugai Pharmaceutical funded this study. Oldenburg reports grant support and personal fees from Baxalta, Bayer, Biotest, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer and Baxter, as well as personal fees from Biogen Idec, Chugai, Roche and Swedish Orphan Biovitrium outside the study. Young reports personal fees from Alnhylam, Bayer, Biogen, Kedrion, Novo Nordisk, Roche and Shire outside the study. Please see the full study for a list of all other researchers’ relevant financial disclosures. Lillicrap reports grants from Bayer, Bioverativ, CDL Behring and Octapharma.