Iqirvo
elafibranor
Species
MonkeyRatMouse
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (mouse up to 3 months)
“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and monkey studies of up to 12 months)”
Why that species
Dogs over-sensitive to PPAR toxicity; rats and monkeys recommended for PPAR agonists
“The reports indeed state that dogs are more sensitive to PPAR toxic effects than other species, and that it is recommended to conduct the general toxicity testing for this type of substances in rats and monkeys.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 52-week oral toxicity study in monkeys, elafibranor at 50 mg/kg/day caused body weight reduction by 22% in males”
Study lengthopen answer page →
Longest pivotal study
52 (12-month monkey)
“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and monkey studies of up to 12 months)”
Pivotal GLP studies
26-week rat and 52-week cynomolgus monkey oral studies
“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and monkey studies of up to 12 months)”
Route in tox
Oral
“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and monkey studies of up to 12 months)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, rat micronucleus and rat comet assays; positive in mouse lymphoma cells
“Elafibranor was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vivo rat micronucleus assay, and the in vivo comet assay in rats. Elafibranor was positive for mutagenicity in L5178Y tk+/- mouse lymphoma cells.”
Carcinogenicity
Liver tumors in mice and rats, attributed to rodent-specific PPARα effects; human relevance uncertain
“The liver tumors in mice and rats may be attributed to the expected rodent-specific PPARα-related liver toxicity and its related consequences. Therefore, the relevance to humans is uncertain.”
Reproductive & developmental
Rat pre/postnatal study: stillbirths, reduced pup survival and body weight at exposures at or below human
“Treatment of pregnant rats with elafibranor during organogenesis through lactation resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body, which occurred at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose”
Safety pharmacology
Dog telemetry: no effect at 30 mg/kg; dose-dependent tachycardia at 100–1000 mg/kg
“A single dose oral administration of elafibranor at 30 mg/kg had no effect on heart rate, arterial blood pressure, or electrocardiogram (Leads I, II, III, aVL, aVR and aVF) in the in vivo telemetry study in conscious dogs. At the doses of 100, 300, and 1000 mg/kg, elafibranor induced delayed (in terms of duration) and dose-dependent tachycardia.”
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 Iqirvo 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 small molecules 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: Monkey 52-week: minimal liver hypertrophy, degeneration/necrosis and single-cell necrosis at ≥10 mg/kg/day (0.5× human AUC) (FDA integrated review, p. 88)
NOAEL / key findings
Monkey 52-week: minimal liver hypertrophy, degeneration/necrosis and single-cell necrosis at ≥10 mg/kg/day (0.5× human AUC)
“Microscopic changes in liver included hepatocytic hypertrophy (minimal), hepatocellular degeneration/necrosis (minimal), single cell necrosis/apoptosis (minimal to slight), and granulocytic foci (minimal) at ≥ 10 mg/kg/day (0.5 times the recommended dose based on combined AUC for elafibranor and GFT1007).”
Risksopen answer page →
Immune & cytokine safety
Thymic atrophy in dogs from 30 mg/kg/day (females) and 100 mg/kg/day (males)
“Thymic atrophy was observed in female dogs starting from 30 mg/kg/day and in male dogs from 100 mg/kg/day.”
Biodistribution & persistence
Rat: highest in GI tract and liver, no tissue accumulation, cleared by 168 h
“No accumulation of radioactivity was observed in tissues or organs. The highest concentrations were measured in the digestive tract and liver, and no radioactivity was detected in any organ at 168 hours after administration.”
Modality-specific risk
Offspring toxicity in rat pre/postnatal study at low exposure multiples
“The findings in the pre- and postnatal development study in rats as described above appear to be clinically relevant, based on the low multiples (0.6 to 4.9) of the human AUC that produced adverse effects in the offspring, which included stillbirths, mortality, and reduced bodyweight.”