Results of a phase 1 study suggest the bispecific monoclonal antibody (mAb) emicizumab (ACE910) may be safe and effective for patients with severe hemophilia A, whether or not they have factor VIII (FVIII) inhibitors.
A weekly injection of emicizumab decreased annualized bleeding rates (ABRs), and 13 of the 18 patients studied did not experience any bleeding while on treatment.
In addition, researchers said the mAb had an acceptable safety profile.
These results were published in NEJM. The study was funded by Chugai Pharmaceutical Co., Ltd., which is co-developing emicizumab with Genentech.
Emicizumab is engineered to simultaneously bind factors IXa and X. The mAb mimics the cofactor function of FVIII and is designed to promote blood coagulation in hemophilia A patients regardless of whether they have developed inhibitors to FVIII. As it is distinct in structure from FVIII, emicizumab is not expected to lead to the formation of FVIII inhibitors.
This phase 1 study of emicizumab enrolled both healthy subjects and hemophilia A patients. Results in the healthy subjects were previously published in Blood.
All 18 patients had severe hemophilia A, and 11 had FVIII inhibitors. They were 12 to 58 years of age, and all were Japanese.
The patients received once-weekly subcutaneous injections of emicizumab for 12 successive weeks at one of the following dose levels: 0.3 mg/kg (cohort 1), 1 mg/kg (cohort 2), or 3 mg/kg (cohort 3).
There were 6 patients in each cohort. Cohorts 1 and 2 each had 4 patients with inhibitors, and there were 3 patients with inhibitors in cohort 3.
Efficacy
Whether or not they had inhibitors, patients experienced a decrease in ABR with emicizumab. Median ABRs decreased from 32.5 to 4.4 in cohort 1, 18.3 to 0.0 in cohort 2, and 15.2 to 0.0 in cohort 3.
The annualized bleeding rate decreased from baseline in 17 of the patients. The remaining patient, who was in cohort 3 and did not have FVIII inhibitors, had an annualized bleeding rate of 0.0 both at baseline and while receiving emicizumab.
Thirteen patients did not have any bleeding episodes during treatment—8 of 11 patients with inhibitors and 5 of 7 patients without them.
There were 21 bleeding episodes, all of which were successfully treated with FVIII or a bypassing agent. Eighteen these episodes resolved with 1 or 2 doses.
Fourteen of the bleeding episodes occurred in 1 patient. They were attributed to very high levels of physical activity and hemophilic arthropathy.
Safety
There were 43 adverse events in 15 patients. The researchers said all events were of mild or moderate intensity.
Adverse events that were considered related to emicizumab included injection-site erythema (n=1), increase in blood creatinine kinase (n=1), diarrhea (n=1), injection-site pruritus (n=1), injection-site rash (n=1), and malaise (n=1).
One patient discontinued emicizumab due to injection-site erythema, as the patient experienced this event twice.
There was no evidence of clinically relevant coagulation abnormalities. And there were no thromboembolic events, even when emicizumab was given concomitantly with FVIII products or bypassing agents as episodic treatment for breakthrough bleeds.
None of the patients developed anti-emicizumab antibodies during the 12 weeks of dosing.
One patient had a positive test for anti-emicizumab antibodies at baseline and had a transient increase in the C-reactive protein level on day 3, but this did not affect the pharmacokinetics or pharmacodynamics of emicizumab.
