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”
Species: general tox
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.”
Species: DART
Not conducted; weight-of-evidence risk assessment submitted instead
“While no animal studies were conducted to assess the reproductive and developmental risks of axatilimab, a WoE-based risk assessment report was submitted.”
Species: carcinogenicity
Not conducted; 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.”
Surrogate used in
Yes: murine anti-CSF-1R surrogate (Ab535) in an investigative mouse acetaminophen hepatotoxicity study
“Ab535, the murine surrogate of axatilimab, did not potentiate the hepatotoxicity of acetaminophen in mice when evaluated in a 14-day hepatotoxicity study (CXR1316).”
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.”
Genotox: Ames
Not conducted (antibody 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”
Genotox: in vitro mammalian
Not conducted (antibody 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”
Genotox: in vivo
Not conducted (antibody 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 model
Not conducted; rodent studies not relevant (no pharmacological activity in rodents)
“Because axatilimab is not active pharmacologically in rodents, conventional carcinogenicity studies in mice or rats are not relevant for axatilimab.”
Carcinogenicity timing
Not required (rodent studies not relevant; FDA concurred)
“Because axatilimab is not active pharmacologically in rodents, conventional carcinogenicity studies in mice or rats are not relevant for axatilimab.”
hERG / QT
No cardiovascular or CNS changes in repeat-dose monkey studies
“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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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.”
Anti-drug antibodies: animals
13-week monkey study ADA inversely dose-related (6/12, 3/12, 1/12 at 10, 30, 100 mg/kg); ADA caused loss of 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. The presence of ADAs correlated with the loss of exposure and PD effect (i.e., increase in CSF-1).”
Anti-drug antibodies: patients
Treatment-emergent ADA in 33.7% (93/276) of cGVHD patients; neutralizing in 17.0%
“In clinical studies of axatilimab monotherapy, 93 of 276 assessable participants (33.7%) with cGVHD were treatment-emergent ADA-positive, and 47 participants (17.0%) were NAb-positive.”
Label warnings
- Infusion-Related Reactions
- Embryo-Fetal Toxicity
Hypersensitivity & infusion reactionsEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week GLP cynomolgus monkey study with 8-week recovery (also 13-week study with 26-week recovery)
“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.”
DART package
Species: DART
Not conducted; weight-of-evidence risk assessment submitted instead
“While no animal studies were conducted to assess the reproductive and developmental risks of axatilimab, a WoE-based risk assessment report was submitted.”
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.”
PPND / ePPND: when
No PPND or other DART animal studies; weight-of-evidence risk assessment submitted instead
“While no animal studies were conducted to assess the reproductive and developmental risks of axatilimab, a WoE-based risk assessment report was submitted.”
Carcinogenicity
Species: carcinogenicity
Not conducted; 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.”
Carcinogenicity model
Not conducted; rodent studies not relevant (no pharmacological activity in rodents)
“Because axatilimab is not active pharmacologically in rodents, conventional carcinogenicity studies in mice or rats are not relevant for axatilimab.”
Carcinogenicity timing
Not required (rodent studies not relevant; FDA concurred)
“Because axatilimab is not active pharmacologically in rodents, conventional carcinogenicity studies in mice or rats are not relevant for axatilimab.”
Safety marginopen answer page →
Safety margin at NOAEL
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro human and monkey monocytes, CSF-1R-expressing CHO cells and human cancer cells; PD endpoints in monkey single- and repeat-dose studies
“Primary PD studies and studies to characterize the antibody and its mechanism of action were conducted in vitro in human and cynomolgus monkey monocytes, CHO cells expressing the CSF-1R extracellular domain, and human cancer cells. Additionally, PD endpoints were incorporated into single-and repeat-dose studies in cynomolgus monkeys.”
Why that model
Monkey is the 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.”
Reviewer's view of the efficacy data
FDA generally agreed with the applicant's primary pharmacology assessment
“The Agency generally agrees with the Applicant’s assessment of the primary pharmacology studies as described above.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No reproductive or developmental toxicity studies; weight-of-evidence literature risk assessment (CSF-1/CSF-1R deficiency models) instead
Why: Weight-of-evidence risk assessment submitted in place of animal studies · Weight of evidence
“While no animal studies were conducted to assess the reproductive and developmental risks of axatilimab, a WoE-based risk assessment report was submitted.”
“To address the potential effects of axatilimab on embryo-fetal development, the Applicant submitted an assessment of the reproductive and developmental risk using a weight-of-evidence (WoE) approach.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies; rodent bioassays not relevant
Why: Axatilimab not pharmacologically active in rodents · No relevant species
“Because axatilimab is not active pharmacologically in rodents, conventional carcinogenicity studies in mice or rats are not relevant for axatilimab. The FDA’s Assessment: The FDA concurs.”
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