Jideytro
zidesamtinib
Species
RatDog
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 dog
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
Why that species
Metabolite profiles similar to human (including M9) and ability to achieve adequate systemic exposure
“The Wistar-Han rat and beagle dog were selected as appropriate species for toxicity based on having metabolite profiles similar to human (inclusive of the main des-ethyl metabolite in patients designated M9) and ability to achieve adequate systemic exposure.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
Pivotal GLP studies
28-day and 13-week oral twice-daily GLP studies in rats and dogs
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”
Route in tox
Oral (twice daily)
“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs. Oral administration is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Positive in in vivo rat micronucleus assays; negative in Ames and in vitro TK6 clastogenicity assay
“Zidesamtinib was genotoxic in the in vivo rat micronucleus assays. Zidesamtinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro assay in human lymphoblastoid TK6 cells.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”
Reproductive & developmental
Rat EFD: 100% post-implantation loss at ≥8 mg/kg/day (about 3.5x human AUC)
“There was 100% post-implantation loss at ≥8 mg/kg/day (approximately 3.5 times the human exposure based on AUC at the recommended dose).”
Safety pharmacology
hERG IC50 73.9 µM (~161-fold free Cmax); 11% QTc increase in telemetered dogs at 30 mg/kg
“zidesamtinib inhibited in vitro human ether-à-go-go related gene (hERG) potassium channel current with an IC50 of 73.9 µM, which is approximately 161-fold higher than the human free steady-state Cmax. Additional cardiovascular safety pharmacology assessment identified an 11% increase in QTc prolongation in telemetered conscious dogs following a single oral administration of zidesamtinib at 30 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 Jideytro 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: pancreas and liver (rat), CNS (dog), GI tract and lymphoid organs (both species) (FDA multi-discipline review, p. 37)
NOAEL / key findings
Target organs: pancreas and liver (rat), CNS (dog), GI tract and lymphoid organs (both species)
“The major target organs of zidesamtinib in the 13-week studies included the pancreas and liver (rats), CNS (dogs), and gastrointestinal (GI) tract and lymphoid organs (both species).”
Risksopen answer page →
Immune & cytokine safety
Dose-dependent lymphoid depletion (GALT, lymph nodes, spleen, thymus) in dogs, incompletely reversible at 4 mg/kg/day
“Dogs had dose-dependent decreased cellularity of lymphoid tissues, including gut-associated lymphoid tissue (GALT), lymph nodes, spleen, and thymus, which did not completely resolve in the 4 mg/kg/day group.”
Biodistribution & persistence
Rapid wide tissue distribution in rats (within 15 minutes), including male reproductive and melanin-pigmented tissues (uvea, skin)
“Following a single oral dose to rats, 14C-zidesamtinib distributed to nearly all tissues within 15 minutes. Radioactivity was detected in male reproductive tissues (seminal vesicle, prostate gland, epididymis, and testes) and melanin-pigmented tissues (uveal tract and skin).”
Modality-specific risk
Off-target TRK inhibition: CNS toxicity and embryo-fetal toxicity
“the totality of the nonclinical and clinical data demonstrates a functional off-target TRK inhibition by zidesamtinib, which can have safety implications for both CNS toxicity and embryo-fetal development (discussed below).”