title: A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects.
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 white subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 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 ∼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 nonserious 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 white) were positive for anti-ACE910 antibodies (anti-drug antibodies [ADAs]). One subject tested positive for ADAs 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 white subjects and suggest that ACE910 will be an effective and convenient prophylactic treatment of hemophilia A. This trial was registered at www.clinicaltrials.jp as #JapicCTI-121934.
authors.affiliation: Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Tokyo, Japan; Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan;
authors.forename: Naoki
authors.initials: N
authors.lastname: Uchida
authors.affiliation: Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Tokyo, Japan; Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan;
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sambe
authors.affiliation: Translational Clinical Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan; and.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yoneyama
authors.affiliation: Translational Clinical Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan; and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Fukazawa
authors.affiliation: Translational Clinical Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan; and.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Kawanishi
authors.affiliation: Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Tokyo, Japan;
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics, Nara Medical University, Nara, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
mesh_terms: D000328:Adult; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000627:therapeutic use; D064368:Healthy Volunteers; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D020714:Maximum Tolerated Dose; D055815:Young Adult
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; C000608208:emicizumab; D005169:Factor VIII