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”
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.”
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.”