NIKTIMVO Solution for injection Ref.[115487] Active ingredients: Axatilimab

Axatilimab-csfr is a monoclonal antibody that binds to colony stimulating factor-1 receptors (CSF-1R) expressed on monocytes and macrophages. Blocking CSF-1R with axatilimab-csfr 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-csfr, and inhibits the activity of pathogenic macrophages in tissues.

CSF-1 and Interleukin (IL)-34

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

Distribution

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

Elimination

Axatilimab-csfr 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-csfr 0.3 mg/kg (maximum 35 mg).

The total clearance of axatilimab-csfr is composed of linear and non-linear components such that axatilimab-csfr 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-csfr over a dose range of 0.15 mg/kg to 3 mg/kg (0.5 to 10 times the approved recommended dosage).

Metabolism

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

Specific Populations

No clinically meaningful differences in the exposure of axatilimab-csfr 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-csfr pharmacokinetics is unknown.

Pediatric Patients

Axatilimab-csfr 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.

No studies have been performed to assess the potential of axatilimab-csfr for carcinogenicity or genotoxicity.

Dedicated fertility studies have not been conducted with axatilimab-csfr. Administration of axatilimab-csfr to sexually mature cynomolgus monkeys in a 3-month toxicology study had no effect on menstrual cyclicity in females, sperm parameters (morphology, motility, or number) in males, and produced no histopathologic findings in female and male reproductive organs, indicating that axatilimab-csfr did not adversely affect reproductive function. Targeted deletion of CSF-1R or CSF-1 in rodent models resulted in impairment of fertility.

In a 6-month chronic toxicity study in sexually immature cynomolgus monkeys, axatilimab-csfr 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-csfr at doses of 10, 30, or 100 mg/kg/week resulted in decreases in bone biomarkers at doses ≥30 mg/kg/week.

The efficacy of NIKTIMVO was evaluated in AGAVE-201 (NCT04710576), a randomized, open-label, multicenter study in adult and pediatric patients with recurrent or refractory cGVHD who had received at least 2 lines of systemic therapy and required additional treatment. Patients with platelet count ≥50 × 10⁹/L, absolute neutrophil count ≥1 × 10⁹/L, ALT and AST ≤2.5 × ULN (≤5 × ULN if liver cGVHD was present), total bilirubin ≤1.5 × ULN, and creatinine clearance ≥30 mL/minute were eligible. Patients with uncontrolled infections were not eligible.

Treatment consisted of NIKTIMVO 0.3 mg/kg administered intravenously every 2 weeks until disease progression, lack of efficacy by 9 months, or unacceptable toxicity. Continued treatment with GVHD prophylaxis and standard care systemic cGVHD therapies were permitted as long as the patient had been on a stable dose for at least 2 weeks prior to study. Initiation of new systemic cGVHD therapy while on study was not permitted.

Demographics and baseline characteristics of the 79 patients treated with NIKTIMVO 0.3 mg/kg every 2 weeks in AGAVE-201 are summarized in Table 4.

Table 4. Demographics and Baseline Characteristics of Patients With cGVHD:

^* Prednisone equivalents/kilogram/day.

The efficacy of NIKTIMVO was based on overall response rate (ORR) through Cycle 7 Day 1, where overall response included complete response or partial response according to the 2014 NIH Consensus Development Project on Response Criteria. The ORR results from AGAVE 201 for the 0.3 mg/kg every 2 weeks dosage regimen are presented in Table 5. The median time to first response was 1.5 months (range, 0.9 to 5.1 months). The median duration of response, calculated from first response to progression, death, or new systemic therapies for cGVHD, was 1.9 months (95% CI: 1.6, 3.5). In patients who achieved response, no death or new systemic therapy initiation occurred in 60% (95% CI: 43, 74) of patients for at least 12 months since response.

Table 5. Efficacy Results From AGAVE-201:

CI = confidence interval

ORR results were supported by exploratory analyses of patient-reported symptom bother which showed at least a 7-point decrease in the modified Lee Symptom Scale score through Cycle 7 Day 1 in 56% (95% CI: 44, 67) of patients.