Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Axatilimab in Healthy Japanese Male Participants: Results from a Phase 1, Randomized, Double-Blind, Dose-Escalation Study.

Background: Axatilimab, an anti-colony-stimulating factor 1 receptor (CSF-1R) antibody, blocks colony-stimulating factor 1 (CSF-1) and interleukin-34 (IL-34) binding to CSF-1R on macrophages and monocytes. Axatilimab has demonstrated efficacy and safety in chronic graft-versus-host disease, and its safety, pharmacokinetics (PK), and pharmacodynamics (PD) were characterized in healthy Western participants.

Objective: The objective of this study was to evaluate the safety, PK, and PD of axatilimab among healthy Japanese men.

Methods: In this double-blind, randomized, dose-escalation study, eligible participants were healthy Japanese men aged 18-55 years, with a body weight of 50-100 kg, a body mass index of 18.0-30.0 kg/m², and no clinically significant findings on screening evaluation (clinical, laboratory, electrocardiogram, and physical exam). Participants were randomized to receive axatilimab or placebo in a 3:1 ratio in a blinded manner. Safety (30 d follow-up; primary endpoint), PK, and PD were evaluated at a clinic in Japan following single-dose infusions of axatilimab 0.3 mg/kg (n = 6), axatilimab 1.0 mg/kg (n = 9), or placebo (n = 5).

Results: Three participants receiving axatilimab experienced a nonserious treatment-emergent adverse event (nasopharyngitis [0.3-mg/kg dose], amylase level increased [1.0-mg/kg dose], and headache [1.0-mg/kg dose]), with no clinically meaningful trends in hematology, urinalysis, physiologic, and most clinical chemistry measures. PK exposure increased with the 1.0 mg/kg versus 0.3 mg/kg dose, with greater than dose-proportional increases in area under the curve. CSF-1 and IL-34 levels had dose-dependent increases following axatilimab infusion. A transient increase in nonclassical monocytes was observed for 8 h following axatilimab infusion and then decreased below baseline until day 8 (0.3 mg/kg) or day 15 (1.0 mg/kg). The inverse effect was observed with classical monocytes. Intermediate monocytes had similar transient increases as nonclassical monocytes.

Conclusions: A single dose of axatilimab 0.3 mg/kg and 1.0 mg/kg was generally well tolerated in healthy Japanese men. Safety, PK, and PD findings were consistent with those observed in healthy Western participants.

Trial registration: Japan Registry for Clinical Trials, jRCT2071220109; 27 February 2023.