Kerendia
finerenone
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Even so, general toxicity studies using oral gavage exposure are available for mouse, rat and dog, where rat and dog are considered main general toxicology species and have been used for studies of up to 26- and 39-weeks duration respectively.”
Why that species
Pharmacologically relevant based on receptor binding and metabolite formation
“Both species are considered pharmacologically relevant based on appropriate binding data and formation of metabolites.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The oral route (oral gavage) has been used throughout the study programme, as this route is the intended clinical route.”
Species: general tox
Rat (up to 26 weeks) and dog (up to 39 weeks); mouse in shorter studies
“Even so, general toxicity studies using oral gavage exposure are available for mouse, rat and dog, where rat and dog are considered main general toxicology species and have been used for studies of up to 26- and 39-weeks duration respectively.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“a full battery of reproductive toxicology studies (including a fertility and early embryonic development study in rat, embryofetal developmental toxicity studies in rat and rabbit and a pre-and postnatal development study in rat)”
Species: carcinogenicity
Mouse and rat (2-year each)
“and two 2-year carcinogenicity studies in mouse and rat.”
Surrogate used in
No surrogate used; rat and dog pharmacologically relevant
“Both species are considered pharmacologically relevant based on appropriate binding data and formation of metabolites.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“Even so, general toxicity studies using oral gavage exposure are available for mouse, rat and dog, where rat and dog are considered main general toxicology species and have been used for studies of up to 26- and 39-weeks duration respectively.”
Pivotal GLP studies
26-week rat and 39-week dog oral gavage studies
“Even so, general toxicity studies using oral gavage exposure are available for mouse, rat and dog, where rat and dog are considered main general toxicology species and have been used for studies of up to 26- and 39-weeks duration respectively.”
Route in tox
Oral gavage
“The oral route (oral gavage) has been used throughout the study programme, as this route is the intended clinical route.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo mouse micronucleus assays
“Finerenone was also negative in the in vitro chromosomal aberration assay in mammalian cells and in the in vivo mouse micronucleus test.”
Carcinogenicity
2-year mouse and rat: no significant increase in neoplasms
“Two-year carcinogenicity studies conducted in mice and rats showed no significant increase in neoplasms in males or females in either study; the CDER Exec CAC concurred with this conclusion.”
Reproductive & developmental
Rat EFD: reduced fetal weight and retarded ossification at maternally toxic 10 mg/kg/day (19x unbound AUC)
“In the embryo-fetal toxicity study in rats, finerenone resulted in reduced placental weights and signs of fetal toxicity, including reduced fetal weights and retarded ossification at the maternal toxic dose of 10 mg/kg/day, corresponding to an AUC unbound of 19 times that in humans.”
Safety pharmacology
No adverse CNS, respiratory, hemodynamic/ECG or hERG effects
“Finerenone showed no adverse effects on CNS parameters and respiratory functions (rat), on hemodynamic/ECG parameters (dog), and on cardiac repolarization in vitro (hERG K+ current).”
Genotox: Ames
Negative in five S. typhimurium strains up to 5.0 mg/plate, with and without S9
“finerenone did not induce gene mutations by base-pair changes or frame-shifts in the genome of five S. typhimurium strains when tested up to a maximum recommended dose of 5.0 mg/plate in the absence and presence of S9 mix.”
Genotox: in vitro mammalian
In vitro chromosomal aberration assay in mammalian cells: negative
“Finerenone was also negative in the in vitro chromosomal aberration assay in mammalian cells and in the in vivo mouse micronucleus test.”
Genotox: in vivo
Mouse micronucleus: negative
“Finerenone was also negative in the in vitro chromosomal aberration assay in mammalian cells and in the in vivo mouse micronucleus test.”
Carcinogenicity model
2-year mouse and 2-year rat; no significant increase in neoplasms (Exec CAC concurred)
“Two-year carcinogenicity studies conducted in mice and rats showed no significant increase in neoplasms in males or females in either study; the CDER Exec CAC concurred with this conclusion.”
Carcinogenicity timing
2-year mouse and 2-year rat studies completed before the marketing application
“a full battery of reproductive toxicology studies (including a fertility and early embryonic development study in rat, embryofetal developmental toxicity studies in rat and rabbit and a pre-and postnatal development study in rat), and two 2-year carcinogenicity studies in mouse and rat.”
hERG / QT
hERG IC50 86 µmol/L, ~200x total and 2400x unbound clinical Cmax
“The hERG IC50 was 86 µmol/L (33 mg/L), which is approximately 200 times the total clinical Cmax (161 µg/L), and 2400 times the free fraction (Cmax, unbound 13.4 µg/L; fu 8.3%).”
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 Kerendia 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: Exaggerated pharmacology: adrenals (rat, dog) and reduced prostate size (dog) (FDA integrated review, p. 58)
NOAEL / key findings
Exaggerated pharmacology: adrenals (rat, dog) and reduced prostate size (dog)
“Target organs of exaggerated pharmacology after chronic treatment were the adrenals in both the rat and dog and also the prostate in the dog (decrease in prostate size and weight not accompanied by histopathological changes).”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
No specific affinity for melanin-bearing tissues (eye, skin) in pigmented rats
“Similar results were obtained in pigmented Long Evans rats and there was no indication of any specific affinity of substance-associated radioactivity to melanin bearing tissues such as eye wall or skin.”
Modality-specific risk
Disproportionate human metabolite M-1 (qualified in 9-month dog study)
“In the dog 9-month study, the disproportionate human metabolite M-1 was qualified.”
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
- Hyperkalemia
- Worsening of Renal Function in Patients with Heart Failure
Metabolic & endocrineNephrotoxicityCardiovascular
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 Kerendia 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: Exaggerated pharmacology: adrenals (rat, dog) and reduced prostate size (dog) (FDA integrated review, p. 58)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog study with no recovery group
“The finding was only identified in the 39-week study, was considered adverse by the study pathologist and had limited margins to clinical exposure at NOAEL and LOAEL. Further, as no recovery group was used in the study, the potential for recovery is not known.”
Pivotal GLP studies
26-week rat and 39-week dog oral gavage studies
“Even so, general toxicity studies using oral gavage exposure are available for mouse, rat and dog, where rat and dog are considered main general toxicology species and have been used for studies of up to 26- and 39-weeks duration respectively.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“a full battery of reproductive toxicology studies (including a fertility and early embryonic development study in rat, embryofetal developmental toxicity studies in rat and rabbit and a pre-and postnatal development study in rat)”
Reproductive & developmental
Rat EFD: reduced fetal weight and retarded ossification at maternally toxic 10 mg/kg/day (19x unbound AUC)
“In the embryo-fetal toxicity study in rats, finerenone resulted in reduced placental weights and signs of fetal toxicity, including reduced fetal weights and retarded ossification at the maternal toxic dose of 10 mg/kg/day, corresponding to an AUC unbound of 19 times that in humans.”
PPND / ePPND: when
PPND in rat completed and included in the marketing application
“a full battery of reproductive toxicology studies (including a fertility and early embryonic development study in rat, embryofetal developmental toxicity studies in rat and rabbit and a pre-and postnatal development study in rat), and two 2-year carcinogenicity studies in mouse and rat.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (2-year each)
“and two 2-year carcinogenicity studies in mouse and rat.”
Carcinogenicity model
2-year mouse and 2-year rat; no significant increase in neoplasms (Exec CAC concurred)
“Two-year carcinogenicity studies conducted in mice and rats showed no significant increase in neoplasms in males or females in either study; the CDER Exec CAC concurred with this conclusion.”
Carcinogenicity timing
2-year mouse and 2-year rat studies completed before the marketing application
“a full battery of reproductive toxicology studies (including a fertility and early embryonic development study in rat, embryofetal developmental toxicity studies in rat and rabbit and a pre-and postnatal development study in rat), and two 2-year carcinogenicity studies in mouse and rat.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog chronic study male NOAEL 0.5 mg/kg: 3x human total AUC (2x unbound)
“Males Females 0.5 5 2110 59500 116 3267 3X (2X) 86X (57X)”
NOAEL / key findings
Exaggerated pharmacology: adrenals (rat, dog) and reduced prostate size (dog)
“Target organs of exaggerated pharmacology after chronic treatment were the adrenals in both the rat and dog and also the prostate in the dog (decrease in prostate size and weight not accompanied by histopathological changes).”
Efficacy evidenceopen answer page →
Efficacy evidence
Animal models of heart failure and chronic kidney disease: heart and kidney protection
“In vitro and in vivo studies indicate that BAY 94-8862 is a potent and selective mineralocorticoid receptor (MR) antagonist with protective effects on the heart and/or kidney in animal models of heart failure and chronic kidney disease.”
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: protective effects shown, but high, clinically non-relevant doses limit interpretation and comparison with other MR antagonists
“Nevertheless, the used clinically non-relevant doses should be taken into consideration when interpreting the details of the results and when comparing with other compounds already in clinical use.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No finerenone MR binding data in mouse or rabbit (carcinogenicity and EFD species); relevance argued by receptor homology
Why: Aldosterone MR affinity in mouse and rabbit preparations and receptor sequence homology; indirect evidence of binding · Weight of evidence
“No data was presented however a thorough justification was presented including affinity to MR with aldosterone in rabbit and mouse preparations and presentations on sequence homologies of the receptors.”
“Although only indirect evidence of the binding of finerenone to MR, it is considered that rabbit and mouse are pharmacologically relevant as suitable species in the assessment of finerenone.”
Similar precedents
VafseoSmall molecules · vadadustat · HIF prolyl hydroxylaseRodent + dog or minipig · 39 wkJesduvroqSmall molecules · daprodustat · HIF prolyl hydroxylaseMonkey + rodent · 39 wkLupkynisSmall molecules · voclosporin · CalcineurinMonkey + rodent · 39 wkAdqueySmall molecules · difamilast · PDE4 (topical)Rodent + dog or minipig · 39 wkAgamreeSmall molecules · vamorolone · Glucocorticoid receptor (dissociative)Rodent + dog or minipig · 39 wkAnzupgoSmall molecules · delgocitinib · Pan-JAK (topical)Rodent + dog or minipig · 39 wk