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Encouraging Results from a First-in-Human Trial of ACE910 to Treat Severe Hemophilia A

December 30, 2021

While patients with severe hemophilia A have a higher risk of bleeding complications than patients with moderate or mild hemophilia A, an investigational bispecific antibody that mimics factor VIII (FVIII) could be a safe and effective treatment for these patients, according to results of a first-in-human trial recently published in Blood. The pharmacokinetic and pharmacodynamics profile of ACE910 suggest that the drug has the potential to reduce bleeding frequency in patients with severe hemophilia A to that of patients with mild hemophilia A, even at less-frequent dosing than existing FVIII and bypassing drugs.

"An important goal of hemophilia A treatment is maintenance of FVIII:C ≥1 percent, which reduces bleeding risk, particularly at the joints," the authors, led by Naoki Uchida, MD, from Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics in Tokyo, Japan, wrote. "To achieve this, intravenous recombinant or plasma-derived FVIII agents with short half-lives (8-12 hours) must be administered frequently as prophylactic therapy, [incurring] a considerable physical and mental burden on patients and their families."

In September 2015, ACE910 received breakthrough designation from the U.S. Food and Drug Administration for the prophylactic treatment of patients with hemophilia A severe hemophilia A (<1% residual FVIII coagulant activity [FVIII:C]) with FVIII inhibitors.

In this phase I, single-center, double-blind, randomized, placebo-controlled, dose-escalation study, Dr. Uchida and colleagues enrolled 64 healthy patients (ages 20-44 years) with severe hemophilia A from Japanese and Canadian centers. Patients were randomized to receive a single subcutaneous injection of ACE910 (0.001, 0.01, 0.1, 0.3, or 1 mg/kg; n=6 per dose group) or placebo (n=2 per dose group). Part A of the study examined safety and pharmacokinetics of ACE910 among Japanese patients, while Part B enrolled Canadian subjects (all Caucasian).

Patients were observed for four weeks (0.001 or 0.01 mg/kg), 16 weeks (0.1 mg/kg), 20 weeks (0.3 mg/kg), or 24 weeks (1 mg/kg) until the study end.

The half-life of ACE910 averaged 28.3 to 34.4 days, "dramatically longer than current drugs (FVIII agents: 8-12 hours; recombinant FVIIa: 2.3-6.0 hours; activated prothrombin complex concentrate: 4-7 hours) and drugs recently approved or under development (≤19 hours)," Dr. Uchida and authors reported.

Absorption of ACE910 after subcutaneous administration was confirmed (measured by plasma ACE910 concentrations) and increased in a dose-proportional manner, peaking one to two weeks after administration. "ACE910 showed a linear dose-exposure profile in both Japanese and Caucasian subjects, [with] maximum plasma concentration ranging from 0.0675 to 5.92 μg/mL (0.01-1 mg/kg)."

Dr. Uchida and colleagues observed that ACE910 was "well tolerated" at all dose groups. Fifteen adverse events (AEs) were reported in 13 of 48 (27.1%) subjects receiving ACE910, compared with six AEs in four of 16 (25.0%) subjects receiving placebo. All of the reported AEs were mild, except for one moderate AE of nasopharyngitis in a Caucasian subject who received ACE910 0.1 mg/kg.

The incidence of AEs did not increase dose-dependently and did not differ between Japanese and Caucasian subjects, and none of these AEs led to study withdrawal.

ACE910 also showed no evidence of clinically relevant hypercoagulation at any dose level.

With a longer half-life than other hemophilia treatments, ACE910 demonstrated greater hemostatic potency that would require less frequent injections. "Weekly dosing of 1 mg/kg ACE910 is expected to provide constant hemostatic activity equivalent to approximately 10 percent FVIII:C," the investigators wrote. "ACE910 may change the treatment paradigm from the current approach of maintaining trough levels of FVIII:C above 1 percent to a new approach of maintaining a constant hemostatic activity corresponding to a mild hemophilia A level."

The authors noted some limitations of this study, including that these healthy volunteers received only a single subcutaneous dose up to 1 mg/kg, a dose specifically chosen to minimize the potential risk of hypercoagulability when ACE910 is administered in the presence of normal FVIII activity.


Uchida N, Sambe T, Yoneyama K, et al. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2015 December 1. [Epub ahead of print]


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