Preliminary Results Suggest Less-Frequent Emicizumab Dosing Feasible in Patients With Hemophilia A

In November 2017, the U.S. Food and Drug Administration (FDA) approved once-weekly dosing of the recombinant bispecific monoclonal antibody emicizumab for patients with hemophilia A with inhibitors, based on results from the phase III HAVEN 1 and HAVEN 2 trials that showed emicizumab reduced bleeding rates by 87 percent (compared with standard bypassing agents).

At the 2017 ASH Annual Meeting, investigators shared preliminary results from the ongoing, multicenter, open-label, phase III HAVEN 4 study that suggest that less-frequent, once-monthly emicizumab dosing is feasible.

Lead author Víctor Jiménez-Yuste, PhD, of La Paz University Hospital in Madrid, Spain, and researchers examined the pharmacokinetic profile of emicizumab 6 mg/kg (delivered every 4 weeks for at least 24 weeks) in seven patients included in the run-in phase of the HAVEN 4 trial. (The FDA-approved dosing for this patient population is emicizumab 3 mg/kg by subcutaneous injection once-weekly for the first 4 weeks, followed by 1.5 mg/kg once-weekly).

Patients included in this analysis were >12 years old and had been receiving on-demand treatment with factor VIII replacement therapy or bypassing agents. By April 10, 2017 (data cutoff), seven patients with severe hemophilia A were enrolled in the pharmacokinetic run-in cohort; four patients did not have inhibitors.

Investigators measured pharmacokinetics and peak concentration levels of emicizumab after a minimum follow-up of six weeks (median = 8 weeks; range not provided), then compared those measurements with a pharmacokinetic model based on clinical data from patients receiving 1.5 mg/kg once-weekly dosing.

All individual observed pharmacokinetic profiles were within the 95 percent prediction interval computed by this model, and “emicizumab 6 mg/kg exhibited a pharmacokinetic behavior that was consistent with prior predictions, leading to an expected steady-state concentration average similar to the clinically confirmed dosing regimen,” the authors reported. Pharmacokinetic parameters after single emicizumab 6 mg/kg administration were consistent with values observed in previous studies with emicizumab (see TABLE).

Five patients reported 14 adverse events (AEs), including one grade 3 serious AE (worsening of hypertension). No AEs were deemed related to the study drug, and the investigator did not detect anti-drug antibodies.

Six of seven patients had no bleeds while receiving once-monthly emicizumab. One patient experienced three spontaneous nose bleeds on days 12, 14, and 21, which did not require treatment.

The analysis is limited by the small patient population and short follow-up, Dr. Jiménez-Yuste noted, adding that the HAVEN 4 study is now fully enrolled (n=48, including the pharmacokinetic run-in cohort). Emicizumab also is being studied in patients with hemophilia A without inhibitors in the ongoing HAVEN 3 study.

The authors report financial relationships with Roche and Genentech, the manufacturer of emicizumab.


Jiménez-Yuste V, Shima M, Fukutake K, et al. Emicizumab subcutaneous dosing every 4 weeks for the management of hemophilia A: preliminary data from the pharmacokinetic run-in cohort of a multicenter, open-label, phase 3 study (HAVEN 4). Abstract #86. Presented at the 2017 American Society of Hematology Annual Meeting, Atlanta, GA, December 9, 2017.