Niktimvo
axatilimab
Sources:FDA multi-discipline review ↗
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“The in vivo toxicology of axatilimab was assessed in the cynomolgus monkey, the only toxicology species in which axatilimab binds to CSF-1R and blocks CSF-1-mediated signaling of the receptor.”
Why that species
Only toxicology species in which axatilimab binds CSF-1R and blocks CSF-1 signaling
“The in vivo toxicology of axatilimab was assessed in the cynomolgus monkey, the only toxicology species in which axatilimab binds to CSF-1R and blocks CSF-1-mediated signaling of the receptor.”
Surrogate molecule
Yes: murine anti-CSF-1R surrogate antibody, used for an investigative mouse acetaminophen hepatotoxicity study
“In addition, an investigative mouse study was conducted, using a surrogate murine anti-CSF-1R antibody, to assess whether administration of an anti-CSF-1R antibody would influence the toxicity induced by a known hepatotoxin”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“a GLP-compliant 13-week repeat-dose toxicity study with a 26-week recovery period in sexually mature cynomolgus monkeys, and a GLP-compliant, 26-week, repeat-dose toxicity study with an 8-week recovery in the cynomolgus monkey.”
Pivotal GLP studies
GLP 13-week (sexually mature, 26-week recovery) and 26-week (8-week recovery) cynomolgus monkey studies
“a GLP-compliant 13-week repeat-dose toxicity study with a 26-week recovery period in sexually mature cynomolgus monkeys, and a GLP-compliant, 26-week, repeat-dose toxicity study with an 8-week recovery in the cynomolgus monkey.”
Route in tox
IV (bolus)
“These studies evaluated only the IV route of administration, which is the clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; antibodies not expected to interact with DNA
“No formal genotoxicity studies for axatilimab have been conducted. Since monoclonal antibodies are not expected to interact directly with DNA”
Carcinogenicity
Not conducted; rodent studies not relevant as axatilimab is not pharmacologically active in rodents
“Because axatilimab is not active pharmacologically in rodents, conventional carcinogenicity studies in mice or rats are not relevant for axatilimab.”
Reproductive & developmental
No dedicated studies; weight-of-evidence (CSF-1/CSF-1R deficiency phenotypes) indicates potential reproductive and embryo-fetal risk
“The mechanism of action of axatilimab, the embryo-lethal and phenotypic effects of CSF-1 and CSF-1R deficiency and the role of CSF-1 and CSF-1R in the reproductive system collectively indicate the potential risk for axatilimab on reproductive and embryo-fetal development.”
Safety pharmacology
Incorporated into repeat-dose monkey studies; labored respiration at 30 and 100 mg/kg; no cardiovascular or CNS changes
“In the 26-week toxicology study, labored respiration (audible breathing) was noted in animals in the 30 mg/kg and 100 mg/kg dosing groups. There were no test article-related changes observed in the cardiovascular and central nervous (CNS) systems.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Niktimvo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Adverse findings at all doses: basophilic material accumulation in numerous organs and femoral growth plate thickening/degeneration (FDA multi-discipline review, p. 43)
NOAEL / key findings
Adverse findings at all doses: basophilic material accumulation in numerous organs and femoral growth plate thickening/degeneration
“Axatilimab-related microscopic findings included dose-dependent accumulation of basophilic material within numerous organs/tissues and alterations in femoral bone thickening of the growth plate and metaphysis and degeneration of the growth plate at all dose levels.”
Risksopen answer page →
Immune & cytokine safety
ADA inversely related to dose (6/12, 3/12, 1/12 animals in 13-week study), reducing exposure and PD effect
“In the 13-week toxicology study, the incidence of ADA induction was inversely related to the dose: 6/12 animals at 10 mg/kg, 3/12 animals at 30 mg/kg, and 1/12 animals at 100 mg/kg.”
Biodistribution & persistence
TCR conserved between human and monkey, consistent with CSF-1R expression including Kupffer cells and microglia
“In a GLP tissue cross-reactivity study, the observed antibody binding was well conserved between humans and cynomolgus monkey and concordant with the expected expression of CSF-1R in tissues, including liver Kupffer cells and microglia.”
Modality-specific risk
Hepatic enzyme elevation with CSF-1R inhibition, seen in monkeys and in patients
“Hepatic enzyme elevation was observed in cynomolgus monkeys and in patients with solid tumors treated with axatilimab-csfr and other CSF-1R inhibitors.”