Photo by Linda Bartlett
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for ACE910 to prevent bleeding in hemophilia A patients age 12 and older who have factor VIII inhibitors.
ACE910 is the first factor VIIIa-mimetic bispecific antibody to be investigated for the prophylactic treatment of hemophilia A.
Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.
The breakthrough therapy designation for ACE910 was granted based on results of a phase 1 study of ACE910 in patients with severe hemophilia A.
About ACE910
ACE910 is an investigational, humanized, bispecific monoclonal antibody engineered to simultaneously bind factors IXa and X. ACE910 thereby mimics the cofactor function of factor VIII and is designed to promote blood coagulation in hemophilia A patients, regardless of whether they have developed inhibitors to factor VIII.
ACE910 is administered subcutaneously once weekly. As it is distinct in structure from factor VIII, it is not expected to lead to the formation of factor VIII inhibitors.
ACE910 was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Genentech.
ACE910 research
Results of the phase 1 trial suggested that once-weekly, subcutaneous administration of ACE910 can reduce annualized bleeding rates (ABRs) in adults and adolescents with severe hemophilia A, with or without factor VIII inhibitors.
At ISTH 2015 (abstract AS017), researchers presented data on 18 Japanese patients with severe hemophilia A (factor VIII: C<1%, ages 12 to 58 years).
Patients received once-weekly subcutaneous ACE910 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.
The patients were followed for 5.6 months to 18.5 months.
Efficacy
Whether or not they had inhibitors, patients experienced a decrease in ABR with ACE910. The changes in ABR per treatment cohort and according to inhibitor status are as follows:
| Treatment/patient type | N | ABR reduction | Median ABR change |
| Cohort 1 (0.3 mg/kg) without inhibitors | 2/6 | 22.8%-82.7% | 32.5→1.7 |
| Cohort 1 (0.3 mg/kg) with inhibitors | 4/6 | 49.3%-100% | |
| Cohort 2 (1 mg/kg) without inhibitors | 2/6 | 79.6%-100% | 18.3→0 |
| Cohort 2 (1 mg/kg) with inhibitors | 4/6 | 87.0%-100% | |
| Cohort 3 (3 mg/kg) without inhibitors | 3/6 | 0%*-100% | 15.2→0 |
| Cohort 3 (3 mg/kg) with inhibitors | 3/6 | 93.0%-100% |
*One patient did not report bleeding episodes at baseline or during the study.
Safety
There were 93 adverse events. The researchers said all events were of mild or moderate intensity. One patient discontinued ACE910 due to mild injection-site redness.
There were no thromboembolic events, even when ACE910 was given concomitantly with factor VIII products or bypassing agents as episodic treatment for breakthrough bleeds.
Three patients developed anti-ACE910 antibodies, but they did not affect ACE910 pharmacokinetics or pharmacodynamics.
Genentech is planning to initiate a phase 3 trial of ACE910 in patients with hemophilia A and factor VIII inhibitors by the end of 2015, a phase 3 trial in patients without inhibitors in 2016, and a trial in pediatric patients with hemophilia A in 2016.
