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

Abstract

Key Points• Single subcutaneous dosing of ACE910 has a linear PK profile, a half-life of 4 to 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 white adults.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 5 6 per dose group) or placebo (n 5 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of ∼4 to 5 weeks. In FVIIIneutralized 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 (antidrug 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

Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors

“…24 The postemicizumab aPTT at steady state averaged 24.0 to 32.5 seconds and was within or shorter than the reference range of 25.4 to 37.2 seconds derived from healthy Japanese participants under the same assay conditions. 22 Results from the current study, where a majority of patients experienced bleeding events even with such apparently normalized aPTT, suggest that aPTT measurements overestimate the hemostatic activity of emicizumab. Nevertheless, monitoring aPTT may allow for the detection of neutralizing ADA development, as evidenced by data from 1 healthy participant in the first-in-human study.…”

“…Nevertheless, monitoring aPTT may allow for the detection of neutralizing ADA development, as evidenced by data from 1 healthy participant in the first-in-human study. 22 In contrast to aPTT, there may be a potential relationship between plasma emicizumab concentrations and reductions in bleeding rate, as suggested by the PK and ABR findings in patients who had emicizumab dose up-titration.…”

“…Hemorrhage 489 nmol/L, respectively, which were derived from healthy Japanese participants. 22 All data collected after dose up-titrations were excluded; the number of patients for this summary was 6 per cohort. Data points where the number of patients with quantifiable measurement was $2 and not less than half of the number of observed patients were plotted.…”

“…The assay methods for the PK, PD, and ADAs have been described previously. 22 Coagulation factor use was allowed to treat breakthrough bleeding or bleeding related to procedure/surgery. The number of breakthrough bleeding episodes requiring coagulation factor treatment was an exploratory efficacy end point of the study.…”

“…21 In its first-in-human phase 1 study, emicizumab demonstrated a long half-life of 4 to 5 weeks, and single subcutaneous doses of #1 mg/kg had favorable safety and tolerability in healthy participants. 22 Subsequently, in the first-in-patient 12-week, phase 1 study, once-weekly subcutaneous emicizumab at 0.3, 1, or 3 mg/kg was well tolerated and substantially reduced annualized bleeding rates (ABRs) in patients with severe hemophilia A both with and without inhibitors. 23 Currently, an extension of the first-in-patient 12-week study is ongoing.…”