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”
Species: general tox
Mouse (up to 3 months), rat (up to 6 months) and monkey (up to 12 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)”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicology studies of elafibranor included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Species: carcinogenicity
Sprague-Dawley rat (104-week) and mouse
“Carcinogenicity of elafibranor was tested in rats and mice. In the GLP-compliant 104-week study with Sprague-Dawley rats, elafibranor induced increased incidence of hepatocellular carcinomas/adenomas and pancreatic acinar cell adenomas in both sexes”
Surrogate used in
No surrogate used; elafibranor tested directly
“The nonclinical safety profile of elafibranor was evaluated in safety pharmacology 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)”
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.”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
Mouse lymphoma L5178Y: positive for mutagenicity; weak reproducible micronucleus induction
“Elafibranor was positive for mutagenicity in L5178Y tk+/- mouse lymphoma cells. In the in vitro micronucleus assay in L5178Y tk+/- mouse lymphoma cells, elafibranor induced a weak but reproducible genotoxic effect.”
Genotox: in vivo
Rat micronucleus and rat comet assay: negative
“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.”
Carcinogenicity model
Rat: 'tumour triade' (liver, pancreatic acinar, Leydig cell) and preputial gland carcinomas; mouse: hepatocellular tumours at all doses
“In the rat carcinogenicity study, elafibranor induced the “tumour triade” (hepatocellular carcinomas/adenomas and pancreatic acinar cell adenomas in both sexes and Leydig cell adenomas in males), as well as increased incidence of preputial gland carcinomas. In the mouse carcinogenicity study, increased incidence of hepatocellular carcinoma, adenoma and adenoblastoma at all dose levels was observed.”
Carcinogenicity timing
2-year mouse and 2-year rat studies completed before the marketing application
“In a 2-year study in Sprague-Dawley rats, elafibrinor produced hepatocellular adenoma in males and females at a dose of 30 mg/kg/day”
hERG / QT
20% hERG inhibition at >500-fold clinical Cmax; GFT1007 no effect
“In vitro human ether-a-go-go (hERG) studies with elafibranor did not reveal potential adverse effects on cardiac function, since elafibranor induced only a 20% inhibition of hERG tail current at a concentration >500-fold higher than the expected plasma Cmax at the therapeutic dose of 80 mg elafibranor.”
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.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
- Myalgia, Myopathy, and Rhabdomyolysis
- Fractures
- Adverse Effects on Fetal and Newborn Development
- Drug-Induced Liver Injury
- Hypersensitivity Reactions
- Biliary Obstruction
MusculoskeletalEmbryo-fetal toxicityHepatotoxicityHypersensitivity & infusion reactionsGastrointestinal
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week cynomolgus monkey oral study with 8-week recovery
“52-Week Toxicity Study by the Oral Route (Gavage) in Cynomolgus Monkeys Followed by an 8-Week Treatment-Free Period (GFT505_TOX3_009)”
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)”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicology studies of elafibranor included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
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”
PPND / ePPND: when
Rat PPND completed before the marketing application
“A pre- and postnatal development study was performed using oral administration of 10, 30, or 100 mg/kg/day elafibranor in female rats during organogenesis through lactation.”
Carcinogenicity
Species: carcinogenicity
Sprague-Dawley rat (104-week) and mouse
“Carcinogenicity of elafibranor was tested in rats and mice. In the GLP-compliant 104-week study with Sprague-Dawley rats, elafibranor induced increased incidence of hepatocellular carcinomas/adenomas and pancreatic acinar cell adenomas in both sexes”
Carcinogenicity model
Rat: 'tumour triade' (liver, pancreatic acinar, Leydig cell) and preputial gland carcinomas; mouse: hepatocellular tumours at all doses
“In the rat carcinogenicity study, elafibranor induced the “tumour triade” (hepatocellular carcinomas/adenomas and pancreatic acinar cell adenomas in both sexes and Leydig cell adenomas in males), as well as increased incidence of preputial gland carcinomas. In the mouse carcinogenicity study, increased incidence of hepatocellular carcinoma, adenoma and adenoblastoma at all dose levels was observed.”
Carcinogenicity timing
2-year mouse and 2-year rat studies completed before the marketing application
“In a 2-year study in Sprague-Dawley rats, elafibrinor produced hepatocellular adenoma in males and females at a dose of 30 mg/kg/day”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: most repeat-dose exposure margins for elafibranor <1 (CHMP); findings likely clinically relevant
“Based on the exposure margins recalculated by the CHMP, the observed findings in the preclinical studies are likely to be clinically relevant, as most of the exposure margins for the repeat-dose toxicity studies for elafibranor are <1”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
NASH in db/db mice on MCD diet and chemically induced (CCl4) liver fibrosis in rats; no PBC model
“Due to the absence of an animal model that adequately mimics the pathophysiology of human primary biliary cholangitis (PBC), the pharmacological effects of elafibranor have been studied in rodent models of NASH (characterized by liver inflammation and fibrosis, relevant to PBC) and chemically induced liver fibrosis.”
Why that model
No animal model adequately mimics human PBC; NASH and fibrosis models used instead
“Due to the absence of an animal model that adequately mimics the pathophysiology of human primary biliary cholangitis (PBC), the pharmacological effects of elafibranor have been studied in rodent models of NASH (characterized by liver inflammation and fibrosis, relevant to PBC) and chemically induced liver fibrosis.”
Reviewer's view of the efficacy data
EMA: effective on steatosis in NASH and CCl4 models, but may not translate to PBC benefit given distinct pathophysiology
“Nevertheless, although elafibranor is effective in reducing steatosis in the NASH and CCL4 animal models, it may not necessarily translate to a therapeutic benefit in PBC in human, as the underlying mechanisms and pathophysiology of PBC are distinct from those of steatosis-related liver diseases.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginQuestioned
Most repeat-dose exposure margins for elafibranor below one (CHMP recalculation); findings considered likely clinically relevant
“Based on the exposure margins recalculated by the CHMP, the observed findings in the preclinical studies are likely to be clinically relevant, as most of the exposure margins for the repeat-dose toxicity studies for elafibranor are <1”
GenotoxicityAcceptedBeyond the letter
Clastogenic in vitro; accepted as non-genotoxic based on negative in vivo micronucleus, Comet and UDS assays
Why: Negative in vivo micronucleus, Comet and UDS assays with adequate exposure demonstrated by TK · Weight of evidence
“With regard to genotoxicity, elafibranor was conclusively demonstrated to be clastogenic in vitro; however, it produced negative results in two in vivo micronucleus tests, as well as in vivo Comet assay and UDS test in liver.”
“Adequate exposure to elafibranor was demonstrated by means of TK measurements. Based on this, elafibranor is considered non-genotoxic in vivo.”
Impurity or metaboliteAcceptedBeyond the letter
Metabolite GFT3351 not major in rats, so in vivo genotoxicity not covered; only in vitro tests
Why: Negative results in two GLP-compliant in vitro genotoxicity tests · Weight of evidence
“It should be noted that GFT3351 is not formed as a major metabolite in rats, thus its genotoxicity in vivo is not considered to be covered by in vivo tests conducted with elafibranor in rats.”
“However, the lack of genotoxic response in two GLP-compliant in vitro tests does not suggest concern regarding potential genotoxic properties of GFT3351.”
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