Axatilimab

Axatilimab is a monoclonal antibody that binds to colony stimulating factor-1 receptors (CSF-1R) expressed on monocytes and macrophages. Blocking CSF-1R with axatilimab reduces the levels of these circulating proinflammatory and profibrotic monocytes and monocyte-derived macrophages, as demonstrated by a reduction of nonclassical monocyte counts in nonclinical studies with axatilimab, and inhibits the activity of pathogenic macrophages in tissues.

CSF-1 and Interleukin (IL)-34

Axatilimab caused a dose-dependent increase from 0.15 mg/kg to 6 mg/kg (0.5 to 20 times the approved recommended dosage) in CSF-1 and interleukin (IL)-34 concentrations and a dose-dependent reduction in the levels of nonclassical monocytes in peripheral blood.

Axatilimab pharmacokinetics are presented as geometric mean (coefficient of variation [%CV]) in adult patients with cGVHD following axatilimab 0.3 mg/kg (maximum 35 mg) every 2 weeks, unless otherwise specified. Axatilimab AUC increased in a greater than dose-proportional manner following single-dose administration of axatilimab over a dose range of 0.15 mg/kg to 3 mg/kg (0.5 to 10 times the approved recommended dosage) in healthy subjects.

There was no axatilimab systemic accumulation following the approved recommended dosage.

Distribution

Axatilimab volume of distribution is 6.06 L (16.3% CV).

Elimination

Axatilimab total clearance is 0.07 L/h (38.8% CV). The median (5th to 95th percentile) time to 97% reduction from C_max after the end of infusion is 4.0 (2.3 to 7.2) days following axatilimab 0.3 mg/kg (maximum 35 mg).

The total clearance of axatilimab is composed of linear and non-linear components such that axatilimab clearance decreased from 2.32 mL/h/kg to 0.21 mL/h/kg and mean terminal half-life increased from 10.7 hours to 108 hours following single-dose administrations of axatilimab over a dose range of 0.15 mg/kg to 3 mg/kg (0.5 to 10 times the approved recommended dosage).

Metabolism

Axatilimab is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations

No clinically meaningful differences in the exposure of axatilimab were observed in adult and pediatric patients based on age (12 to 81 years), sex, body weight (40 to 151 kg), race (White, Black, or Asian), mild to moderate renal impairment (estimated creatinine clearance 30-89 mL/min by the Cockcroft-Gault equation), or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to ≤1.5 times ULN and any AST) following the approved recommended dosage of 0.3 mg/kg (maximum 35 mg) every 2 weeks.

The effect of severe renal impairment (estimated creatinine clearance 15-29 mL/min, Cockcroft-Gault equation) and moderate to severe hepatic impairment (total bilirubin >1.5 times ULN and any AST) on axatilimab pharmacokinetics is unknown.

Pediatric Patients

Axatilimab exposures in pediatric patients weighing 40 kg and above are comparable to those in adults following the approved recommended dosage of 0.3 mg/kg (maximum 35 mg) every 2 weeks.

In a 6-month chronic toxicity study in sexually immature cynomolgus monkeys, axatilimab was administered once weekly at doses of 10, 30, or 100 mg/kg/week via intravenous injection. The primary findings included periorbital swelling, widespread accumulation of basophilic material, and effects on bone at doses ≥10 mg/kg/week. Alterations in bone included decreases in bone markers, thickening of the growth plate and metaphysis and/or degeneration of the growth plate in the femur. In a 3-month toxicity study in sexually mature monkeys, intravenous administration of axatilimab at doses of 10, 30, or 100 mg/kg/week resulted in decreases in bone biomarkers at doses ≥30 mg/kg/week.