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.