Ibtrozi
taletrectinib
Species
MonkeyRat
Longest study
12 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 taletrectinib administered orally once daily in 28-day and 12-week good laboratory practices (GLP)-compliant general toxicology studies using rats and cynomolgus monkeys.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Report 2021010: 85-Day Repeated-Dose Toxicity Study of Taletrectinib by Oral Gavage in Cynomolgus Monkeys with a 57-Day Treatment-Free Period”
Study lengthopen answer page →
Longest pivotal study
12 (85-day rat and monkey)
“GLP-compliant 28-day and pivotal 85-day toxicity and TK studies in rats and monkeys confirmed that taletrectinib produced target organ toxicity that would be anticipated for a typical TKI.”
Pivotal GLP studies
28-day and 12-week oral studies in rats and cynomolgus monkeys
“The Applicant evaluated the safety of taletrectinib administered orally once daily in 28-day and 12-week good laboratory practices (GLP)-compliant general toxicology studies using rats and cynomolgus monkeys.”
Route in tox
Oral (gavage), once daily
“The oral route of administration is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and additional mutagenicity tests and in the rat bone marrow/liver micronucleus assay
“Taletrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and additional mutagenicity tests. Taletrectinib was not clastogenic or aneugenic in the in vivo micronucleus study in rats in bone marrow and liver.”
Carcinogenicity
Not conducted; not warranted for the proposed indication
“Carcinogenicity studies have not been conducted with taletrectinib and are not warranted for the proposed indication.”
Reproductive & developmental
Rat and rabbit EFD: embryo-fetal mortality and structural abnormalities at or below human exposure
“In animal reproduction studies, oral administration of taletrectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities at exposures that were below or equal to the human exposure based on AUC at the recommended dose”
Safety pharmacology
hERG IC50 0.98 µM, hNav1.5 IC50 0.83 µM; no ECG or QTc effects in telemetered monkeys up to 100 mg/kg/day
“In vitro, taletrectinib inhibited hERG currents and hNav1.5 with IC50 values of 0.98 µM and 0.83 µM, respectively, indicating a potential effect on QT prolongation. However, in the telemetered monkey cardiovascular study, there were no effects on any electrocardiogram (ECG) parameters, including QTc at the highest non-severely toxic dose (HNSTD) of 100 mg/kg/day.”
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 Ibtrozi 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 in rats and monkeys: lung, lymph nodes, kidney, GI tract and pituitary (FDA multi-discipline review, p. 45)
NOAEL / key findings
Target organs in rats and monkeys: lung, lymph nodes, kidney, GI tract and pituitary
“Drug-related target organs in both species included lung, lymph nodes, kidney, GI tract, and pituitary.”
Risksopen answer page →
Immune & cytokine safety
Thymic atrophy and lymph node erythrophagocytosis and foamy macrophages in monkeys
“Additional findings were noted in the thymus (atrophy), lymph nodes (erythrophagocytosis, foamy macrophages), and kidneys (basophilic casts, dilation, hyperplasia, vacuolation).”
Biodistribution & persistence
Wide distribution in rats; melanin binding in eye and skin; choroid plexus accumulation, crosses the blood-brain barrier
“Taletrectinib was distributed throughout rat tissues. There was notable distribution of taletrectinib to melanin-containing tissues of the eyeball and skin. Taletrectinib also accumulated in the choroid plexus region of the brain indicating the drug can cross the blood brain barrier.”
Modality-specific risk
Embryofetal toxicity (labeled warning)
“Because taletrectinib can cause fetal harm, the review team recommends an embryofetal toxicity warning.”