Isturisa
osilodrostat
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
“In repeated-dose toxicity studies osilodrostat was tested in mice for up to 13 weeks at 10 to 200 mg/kg/day, in rats for up to 26 weeks at 0.2 to 50 mg/kg/day and in dogs for up to 39 weeks at 0.1 to 10 mg/kg/day.”
Why that species
Pharmacokinetic and metabolic profiles qualitatively similar to humans
“Pharmacokinetic and metabolic profiles were qualitatively similar between humans and nonclinical species used for evaluating the potential toxicity or osilodrostat thereby supporting the translatability of the findings from these studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“39-Week Oral Gavage Chronic Toxicity and Toxicokinetic Study with LCI699 in Dogs with a 4-Week Recovery Period”
Species: general tox
Rat (26-week) and dog (39-week); mouse up to 13 weeks
“The NOAELs observed in the 26- and 39-week repeated-dose toxicity studies in the rat and the dog were 2.0 and 10 mg/kg/day, respectively, based on the frequency and severity of findings in the liver and female reproductive”
Species: DART
Rat (fertility, EFD) and rabbit (EFD)
“Effects on fertility were evaluated in the rat and embryofetal development was assessed in the rat and rabbit.”
Species: carcinogenicity
Wistar Han rat and CD1 mouse
“Carcinogenicity studies were conducted in Wistar Han rats and CD1 mice.”
Surrogate used in
No surrogate used; osilodrostat tested directly in mice, rats and dogs
“The toxicity of osilodrostat was assessed in a series of repeat-dose toxicity studies that were conducted in mice, rats, and dogs, including chronic (rat and dog) and carcinogenicity (mouse and rat) studies.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“39-Week Oral Gavage Chronic Toxicity and Toxicokinetic Study with LCI699 in Dogs with a 4-Week Recovery Period”
Pivotal GLP studies
26-week rat and 39-week dog repeat-dose studies
“The NOAELs observed in the 26- and 39-week repeated-dose toxicity studies in the rat and the dog were 2.0 and 10 mg/kg/day, respectively, based on the frequency and severity of findings in the liver and female reproductive”
Route in tox
Oral gavage
“26-Week Oral Gavage Chronic Toxicity and Toxicokinetic Study with LCI699 in Rats with a 13-Week Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Ames and micronucleus negative; structural aberrations in in vitro chromosome aberration assay
“Although the Ames and micronucleus assays were negative for the induction of genetic toxicity, there was an increase in structural abnormalities in the chromosome aberration assay.”
Carcinogenicity
Rodent liver tumors, likely via rodent-specific CAR activation; not relevant to humans
“Although the Sponsor did not definitively identify the MOA for tumor development in rodents, the overall weight of evidence indicates that the rodent liver neoplasms were most likely mediated by rodent-specific CAR activation which is not relevant in humans.”
Reproductive & developmental
Rat and rabbit EFD: increased fetal resorptions and altered morphology (rabbit at 7-fold MRHD)
“Embryofetal development studies revealed increased fetal resorptions and altered morphological development in rats and rabbits at exposures greater than 100-fold and 7-fold, respectively, the exposure at the MRHD.”
Safety pharmacology
hERG inhibition at >50-fold MRHD; QRS/QT/QTc prolongation in dogs (IV only) and NHPs
“Observations included inhibition of the hERG current at > 50-fold the MRHD, prolongation of the QRS, QT, and QTc levels in dogs at 11-fold following intravenous though not oral dosing, and in NHPs at >15-fold the MRHD.”
Genotox: Ames
Negative in five Salmonella strains up to 5000 µg/plate, ±S9
“Osilodrostat did not induce mutations when adequately tested in five histidine-requiring strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537 and TA102) at concentrations up to 5000 μg/plate in the absence and in the presence of a rat liver metabolic activation system (S9).”
Genotox: in vitro mammalian
Positive: structural chromosome aberrations in human peripheral blood lymphocytes, ±S9
“Osilodrostat induced structural chromosome aberrations when adequately tested in cultured human peripheral blood lymphocytes in both the absence and presence of a rat liver metabolic activation system (S9).”
Genotox: in vivo
Negative: rat bone marrow micronucleus and rat Comet assay (hepatocytes, leukocytes)
“Osilodrostat did not show any evidence of chromosomal aberrations in vivo in the rat bone marrow micronucleus test when adequately tested up to a single oral dose of 300 mg/kg. Osilodrostat did not induce any DNA damage when adequately tested in the Comet assay in hepatocytes or leukocytes of rats dosed twice orally up to 150 mg/kg.”
Carcinogenicity model
104-week mouse and 104-week rat (1, 3, 30 mg/kg/day)
“Long-term carcinogenicity studies have been performed in mice and rats with dosing at 1, 3 and 30 mg/kg/day for up to 103/104 weeks and 104 weeks, respectively.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies completed under the IND, before the marketing application
“Sponsor submitted safety report regarding observations from rat and mouse carcinogenicity studies”
hERG / QT
hERG IC50 54 µM, 42-fold above human total Cmax (1.3 µM) at 30 mg
“LCI699 concentration-dependently inhibited hERG channels at >10 µM and the IC50 was calculated to be 54 µM (12.3 µg/mL) which is 42-fold higher than the steady state Cmax for total drug (1.3 µM) predicted for 30 mg doses in humans.”
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 Isturisa 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: Targets: adrenal gland, liver and female reproductive tissues; mostly reversible (FDA pharmacology/toxicology review, p. 12)
NOAEL / key findings
Targets: adrenal gland, liver and female reproductive tissues; mostly reversible
“The primary target organs were the adrenal gland, liver, and female reproductive tissues. Adverse effects increased in severity with dosage and study duration, with most demonstrating recovery upon treatment cessation.”
Risksopen answer page →
Immune & cytokine safety
Strong skin sensitizer (Category 1A) in murine local lymph node assay
“LCI699 was determined to be a strong sensitizing agent (Category 1A) indicating there is the potential for an allergic response following skin contact.”
Biodistribution & persistence
Wide distribution, highest in adrenal, brain, kidney, liver, pancreas, spleen; melanin binding
“Osilodrostat is distributed into most tissues with the highest levels in the adrenal gland, brain, kidney, liver, pancreas, and spleen. LCI699 was found to bind melanin,”
Modality-specific risk
QT prolongation and arrhythmia (Torsades de Pointes in NHPs)
“In addition, Torsades de Pointes and ventricular tachycardia were seen in NHPs at 100-fold the exposure at the MRHD.”
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
- Hypocortisolism
- QTc Prolongation
- Elevations in Adrenal Hormone Precursors and Androgens
CardiovascularNephrotoxicityMetabolic & endocrine
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 Isturisa 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: Targets: adrenal gland, liver and female reproductive tissues; mostly reversible (FDA pharmacology/toxicology review, p. 12)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog oral study with 4-week recovery
“39-Week Oral Gavage Chronic Toxicity and Toxicokinetic Study with LCI699 in Dogs with a 4-Week Recovery Period”
Pivotal GLP studies
26-week rat and 39-week dog repeat-dose studies
“The NOAELs observed in the 26- and 39-week repeated-dose toxicity studies in the rat and the dog were 2.0 and 10 mg/kg/day, respectively, based on the frequency and severity of findings in the liver and female reproductive”
DART package
Species: DART
Rat (fertility, EFD) and rabbit (EFD)
“Effects on fertility were evaluated in the rat and embryofetal development was assessed in the rat and rabbit.”
Reproductive & developmental
Rat and rabbit EFD: increased fetal resorptions and altered morphology (rabbit at 7-fold MRHD)
“Embryofetal development studies revealed increased fetal resorptions and altered morphological development in rats and rabbits at exposures greater than 100-fold and 7-fold, respectively, the exposure at the MRHD.”
PPND / ePPND: when
Rat PPND completed before the marketing application
“An Oral (Gavage) Pre and Postnatal Developmental Toxicity Study in the Rat”
Carcinogenicity
Species: carcinogenicity
Wistar Han rat and CD1 mouse
“Carcinogenicity studies were conducted in Wistar Han rats and CD1 mice.”
Carcinogenicity model
104-week mouse and 104-week rat (1, 3, 30 mg/kg/day)
“Long-term carcinogenicity studies have been performed in mice and rats with dosing at 1, 3 and 30 mg/kg/day for up to 103/104 weeks and 104 weeks, respectively.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies completed under the IND, before the marketing application
“Sponsor submitted safety report regarding observations from rat and mouse carcinogenicity studies”
Safety marginopen answer page →
Safety margin at NOAEL
Rat 26-week and dog 39-week NOAELs ~14-16x clinical AUC (~4x Cmax)
“The margins to clinical exposure are approximately 4 and 14-16 based on Cmax and AUC0-24, respectively.”
NOAEL / key findings
Targets: adrenal gland, liver and female reproductive tissues; mostly reversible
“The primary target organs were the adrenal gland, liver, and female reproductive tissues. Adverse effects increased in severity with dosage and study duration, with most demonstrating recovery upon treatment cessation.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro human CYP11B1 inhibition; cortisol synthesis inhibition in ACTH-stimulated normal monkeys
“Using a different experimental design including higher doses (up to 10000 ug/kg), Weldon et al showed that osilodrostat inhibited ACTH stimulated cortisol synthesis in monkeys with an EC50 of 1500 nM being approximately 300-fold higher than EC50 for aldosterone synthesis.”
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
FDA: pharmacology showed desired cortisol lowering, with off-target aldosterone and possible estrogen lowering
“The pharmacology studies demonstrated that osilodrostat has the desired cortisol lowering activity although aldosterone levels are also lowered and, at higher drug levels, may also lower estrogens secondary to aromatase inhibition.”
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteCriticised but acceptedBeyond the letter
No toxicokinetics of major human metabolite M34.5 in pivotal rat studies; exposure only extrapolated from single-dose ADME data
Why: Extrapolated exposure margin with uncertainty factor suggests M34.5 likely qualified · Pharmacology or kinetics
“No TK assessments of M34.5 have been performed in any of the pivotal safety studies (including carcinogenicity and reproductive toxicity studies) conducted in the rat.”
“As the human exposure of M34.5 after repeat dosing of osilodrostat is only estimated in an uncertain simulation model, the addition of an uncertainty factor of 10 was used, resulting in exposure margin of 1.3 in the high osilodrostat dose (30 mg/kg/day) used in the 2-year rat cancer study. Thus, based on these extrapolations M34.5 has likely been toxicologically qualified.”
SpeciesAcceptedBeyond the letter
Toxicity from cortisol inhibition could not be studied: in rats and monkeys osilodrostat mainly inhibits aldosterone synthase
Why: Adverse effects of hypocortisolism are clinically well known · Human data · No relevant species
“Since no inhibition on PCC (plasma corticosterone concentration) in rats and monkeys not infused with ACTH is seen, toxicity associated with cortisol inhibition cannot be studied.”
“However, the adverse effects of hypocortisolism are clinically well known (e.g. nausea, vomiting, fatigue, abdominal pain, dizziness).”
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