Augtyro
repotrectinib
Species
MonkeyRat
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
Why that species
100% sequence homology of target binding sites with human and similar metabolism
“Rats (Sprague-Dawley) and monkeys (cynomolgus) are considered relevant toxicological species based on 100% sequence homology for the target binding sites and similar metabolism.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
13 (91-day rat and monkey)
“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
Pivotal GLP studies
28-day and 91-day oral GLP studies in rats and cynomolgus monkeys
“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”
Route in tox
Oral
“The oral route of administration is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; genotoxic via aneugenic mechanism in vitro (TK6 cells) and in vivo rat bone marrow micronucleus assay
“Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in an in vivo rat bone marrow micronucleus assay via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.”
Carcinogenicity
Not conducted; not warranted for the advanced cancer indication
“Carcinogenicity studies have not been conducted with repotrectinib and are not warranted for the proposed indication.”
Reproductive & developmental
Rat EFD: malrotated hindlimbs and lower fetal weights at ≥12 mg/kg; maternal skin lesions at ≥6 mg/kg
“In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses ≥12 mg/kg”
Safety pharmacology
No cardiovascular effects in monkeys or on hERG, Nav1.5 and Cav1.2 channels; no respiratory effects in rats or monkeys
“Repotrectinib had no toxicologically significant effects on cardiovascular function in vivo in monkeys or in vitro on hERG, hNaV1.5, or hCaV1.2 channels. Repotrectinib had no effect on respiratory function rats and monkeys.”
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 Augtyro 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 oncology small molecules (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Target organs: skin and CNS (rat), bone marrow (rat and monkey), GI tract (monkey); mostly reversible (EMA assessment report, p. 30)
NOAEL / key findings
Target organs: skin and CNS (rat), bone marrow (rat and monkey), GI tract (monkey); mostly reversible
“In the pivotal GLP-compliant RD-toxicity studies, the major target organs across species were the skin (rat), CNS (rat), bone marrow (rat and monkey), and GI (monkey). These findings were generally dose-dependent and were reversible or showed a trend towards reversibility.”
Risksopen answer page →
Immune & cytokine safety
Non-adverse decreased lymphocytes in blood and lymphoid organs in rats and monkeys
“In rats, non-adverse decreased lymphocytes in circulation and in multiple lymphoid organs were observed at ≥15 mg/kg (M) and at ≥5 mg/kg (F).”
Biodistribution & persistence
Wide distribution, highest in pigmented skin, uveal tract, liver and kidney; low CNS penetration
“The distribution of repotrectinib was widespread by 1 hour post-dose with the highest exposures in pigmented skin, uveal tract, liver, renal cortex, and kidneys with low distribution into non-circumventricular CNS tissue (protected by blood-brain barrier).”
Modality-specific risk
CNS toxicity (ataxia, tremors), possibly related to TRK inhibition
“CNS toxicity observed in animal studies with repotrectinib may be related to inhibition of TRK proteins.”