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A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects

Naoki Uchida, Takehiko Sambe, Koichiro Yoneyama, Naoki Fukazawa, Takehiko Kawanishi, Shinichi Kobayashi and Midori Shima

Key points

  • Single subcutaneous dosing of ACE910 has a linear PK profile, a half-life of 4-5 weeks, and FVIII-mimetic procoagulant activity in humans.

  • ACE910 at doses up to 1 mg/kg is well tolerated and has no notable adverse hypercoagulable effect in healthy Japanese and Caucasian adults.

Abstract

ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 Caucasian subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; Caucasian: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of approximately 4 to 5 weeks. In FVIII-neutralized plasma, ACE910 shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. All adverse events were non-serious and did not lead to any subject's withdrawal. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects receiving ACE910 (1 Japanese and 1 Caucasian) were positive for anti-ACE910 antibodies (anti-drug antibodies; ADA). One subject tested positive for ADA both before and after ACE910 administration, whereas the other became ADA-positive after receiving ACE910. The PK and PD profiles of ACE910 were similar in healthy Japanese and Caucasian subjects, and suggest that ACE910 will be an effective and convenient prophylactic treatment for hemophilia A. This trial was registered at http://www.clinicaltrials.jp (JapicCTI-121934).

  • Submitted June 11, 2015.
  • Accepted October 27, 2015.