Livdelzi
seladelpar
Species
MonkeyRatMouseDog
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 (also mouse and dog)
“Repeat-dose po administration of seladelpar was evaluated at up to 13 weeks in CD-1 mice, up to 26 weeks in Sprague-Dawley rats, up to 4 weeks in dogs, and up to 52 weeks in cynomolgus monkeys.”
Why that species
Multiple species chosen because PPAR sensitivity differs between species
“The selection of multiple species for the non-clinical programme was justified by the sensitivity differences towards PPARs between species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“General toxicology studies with seladelpar (orally administered) were performed in mice, rats, dogs, and monkeys, with adverse effects noted in each species.”
Species: general tox
Rat (up to 6 months) and monkey (up to 12 months)
“The nonclinical safety profile of seladelpar has been extensively explored in (1) single- and repeated-dose toxicology studies in rats (up to 6 months) and monkeys (up to 12 months)”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicology studies using oral administration of seladelpar included a fertility study in male and female rats, EFD studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Species: carcinogenicity
Rat and mouse (2-year)
“(4) 2-year carcinogenicity studies in mice and rats”
Surrogate used in
No surrogate molecule; PPARα-knockout mice used to separate PPARδ from PPARα activation
“Seladelpar was shown to activate PPARα and PPARδ in C57Bl/6N wild-type mice and only PPARδ in the PPARα-knockout mice at the same exposure levels as in the 2-year carcinogenicity study.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week monkey)
“Repeat-dose po administration of seladelpar was evaluated at up to 13 weeks in CD-1 mice, up to 26 weeks in Sprague-Dawley rats, up to 4 weeks in dogs, and up to 52 weeks in cynomolgus monkeys.”
Pivotal GLP studies
Oral studies up to 26 weeks in rats and 52 weeks in cynomolgus monkeys (13-week mouse, 4-week dog)
“Repeat-dose po administration of seladelpar was evaluated at up to 13 weeks in CD-1 mice, up to 26 weeks in Sprague-Dawley rats, up to 4 weeks in dogs, and up to 52 weeks in cynomolgus monkeys.”
Route in tox
Oral
“General toxicology studies with seladelpar (orally administered) were performed in mice, rats, dogs, and monkeys, with adverse effects noted in each species.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and in vivo mouse micronucleus assays
“Genetic toxicology studies showed that seladelpar was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma assay, and the in vivo mouse micronucleus test.”
Carcinogenicity
2-year mouse: hepatocellular adenoma or carcinoma at 6x (males) and 140x (females) human AUC
“In a 2-year study in mice, oral administration of seladelpar produced hepatocellular adenoma or carcinoma at 6 times the human exposure (AUC at the recommended dose) in males and at 140 times the human exposure in females.”
Reproductive & developmental
No effects on male or female rat fertility (up to 271x and 115x human AUC)
“Seladelpar had no effects on fertility or reproductive function in male rats at up to 271 times the human exposure (AUC) at the recommended dose or in female rats at up to 115 times the human exposure.”
Safety pharmacology
No significant cardiovascular, respiratory or CNS concerns
“Overall, the safety pharmacology data indicates that there are no safety issues of significant concern for cardiovascular function, respiratory function, or the central nervous system.”
Genotox: Ames
Negative
“Seladelpar was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma assay, and the in vivo mouse micronucleus test.”
Genotox: in vitro mammalian
Negative in vitro mouse lymphoma assay
“Seladelpar was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma assay, and the in vivo mouse micronucleus test.”
Genotox: in vivo
Negative mouse micronucleus
“Seladelpar was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma assay, and the in vivo mouse micronucleus test.”
Carcinogenicity model
2-year mouse: hepatocellular adenoma/carcinoma at 6x (males) and 140x (females) human AUC; 2-year rat also conducted
“Carcinogenicity studies were performed in rats and mice. In a 2-year study in mice, oral administration of seladelpar produced hepatocellular adenoma or carcinoma at 6 times the human exposure (AUC at the recommended dose) in males and at 140 times the human exposure in females.”
Carcinogenicity timing
2-year mouse and 2-year rat completed before the marketing application
“The carcinogenicity of seladelpar was evaluated in 2-year studies in mice and rats”
hERG / QT
7.7% hERG inhibition at 3 µM; ~857-fold free human concentration
“The inhibition of hERG was assessed for seladelpar up 3 μM showing an inhibition of 7.7%. The margin based on the free drug concentration of 3.5 nM in human, is x857.”
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 Livdelzi 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: Main target organs: liver, skeletal and cardiac muscle, stomach and kidney (FDA integrated review, p. 93)
NOAEL / key findings
Main target organs: liver, skeletal and cardiac muscle, stomach and kidney
“The main target organs of toxicity were liver, skeletal and cardiac muscle, stomach, and kidney.”
Risksopen answer page →
Immune & cytokine safety
No immunotoxicity in repeat-dose studies; negative mouse local lymph node assay
“Seladelpar did not show potential for immunotoxicity in the repeat-dose toxicity studies and no sensitisation potential was recorded in the local lymph node assay in mouse.”
Biodistribution & persistence
Wide distribution in rats (QWBA), highest in liver, kidney and bladder
“Seladelpar was widely distributed in rats, as demonstrated by quantitative whole-body autoradiography (QWBA) data in both non-pigmented and pigmented rats with the highest radioactivity detected in the liver, kidney, and bladder.”
Modality-specific risk
Rodent liver effects and tumors; PPARα-dependent (rodent-specific) mode of action investigated
“The 14-day study in the PPARα null mice showed that wild-type mice are more sensitive to liver effects that PPARα null mice, suggesting that PPARα plays a role in the observed liver effects in mice.”
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
- Fractures
- Liver Test Abnormalities
- Biliary Obstruction
MusculoskeletalHepatotoxicityGastrointestinal
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 Livdelzi 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: Main target organs: liver, skeletal and cardiac muscle, stomach and kidney (FDA integrated review, p. 93)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week cynomolgus monkey (oral gavage) with 8-week recovery
“52-Week Oral Gavage Toxicity and Toxicokinetic Study With MBX-8025 in Cynomolgus Monkeys With an 8-Week Recovery Phase (Study #8308417)”
Pivotal GLP studies
Oral studies up to 26 weeks in rats and 52 weeks in cynomolgus monkeys (13-week mouse, 4-week dog)
“Repeat-dose po administration of seladelpar was evaluated at up to 13 weeks in CD-1 mice, up to 26 weeks in Sprague-Dawley rats, up to 4 weeks in dogs, and up to 52 weeks in cynomolgus monkeys.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicology studies using oral administration of seladelpar included a fertility study in male and female rats, EFD studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Reproductive & developmental
No effects on male or female rat fertility (up to 271x and 115x human AUC)
“Seladelpar had no effects on fertility or reproductive function in male rats at up to 271 times the human exposure (AUC) at the recommended dose or in female rats at up to 115 times the human exposure.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“Reproductive and developmental toxicology studies using oral administration of seladelpar included a fertility study in male and female rats, EFD studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Carcinogenicity
Species: carcinogenicity
Rat and mouse (2-year)
“(4) 2-year carcinogenicity studies in mice and rats”
Carcinogenicity model
2-year mouse: hepatocellular adenoma/carcinoma at 6x (males) and 140x (females) human AUC; 2-year rat also conducted
“Carcinogenicity studies were performed in rats and mice. In a 2-year study in mice, oral administration of seladelpar produced hepatocellular adenoma or carcinoma at 6 times the human exposure (AUC at the recommended dose) in males and at 140 times the human exposure in females.”
Carcinogenicity timing
2-year mouse and 2-year rat completed before the marketing application
“The carcinogenicity of seladelpar was evaluated in 2-year studies in mice and rats”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL AUC margins ~2x (male) / 11x (female) in 52-week monkey; ~5x / 13x in 26-week rat
“The AUC margins at NOAEL in the repeat-dose studies were around 5/13 (M/F) in the 26-week rat study and 2/11 (M/F) in the 52-week monkey study.”
NOAEL / key findings
Main target organs: liver, skeletal and cardiac muscle, stomach and kidney
“The main target organs of toxicity were liver, skeletal and cardiac muscle, stomach, and kidney.”
Efficacy evidenceopen answer page →
Efficacy evidence
Carbon tetrachloride (CCl4) liver fibrosis model in mice
“The effect of seladelpar in a carbon tetrachloride (CCl4) model of liver fibrosis in mice was investigated.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: in vivo data demonstrate PPARδ pharmacodynamics (reduced C4, hepatic bile acid synthesis and CYP7A1 mRNA)
“These results demonstrate PPARδ pharmacodynamic effect by in vivo reduction in C4 plasma levels, reduction in hepatic bile acid synthesis and decreased CYP7A1 mRNA in liver following seladelpar exposure.”
Flexibilityopen answer page →
Flexibility accepted
Safety pharmacologyCriticised but acceptedBeyond the letter
Cardiovascular/respiratory safety pharmacology in dogs without data showing dog relevance; female dog and guinea pig studies non-GLP
Why: Clinical data and no ECG or cardiovascular effects in the 52-week monkey study · Human data · Weight of evidence
“No in vitro affinity or potency studies have been presented in the primary pharmacology section to assess the relevance of dog for the cardiovascular and respiratory studies which is a deficiency.”
“However, in light of clinical data and that no cardiovascular effects including ECG anomalies has been detected in the 52-week repeat dose toxicity study on Cynomolgus monkey, this limitation is not pursued.”
OtherCriticised but acceptedBeyond the letter
Several bioanalysis/toxicokinetic deficiencies across studies; only data from the most critical studies considered reliable
Why: Bioanalysis/TK data from the most critical studies considered reliable · Weight of evidence
“Several deficiencies were identified with regards to bioanalysis. Despite these deficiencies, it is concluded that bioanalysis/TK data from the most critical studies can be considered reliable.”
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