Gemtesa
vibegron
Species
MonkeyRat
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 cynomolgus monkey
“General toxicity of chronic oral administration of vibegron was adequately evaluated in rats (3 & 6 months) and monkeys (3 & 9 months).”
Why that species
Metabolic profile in rat and monkey similar to human
“The choice of toxicology species rats and monkeys was based on that the metabolic profile of these species is similar to that of human.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Vibegron was tested up to 9 months in monkeys and 6 months in rats.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“Vibegron was tested up to 9 months in monkeys and 6 months in rats.”
Pivotal GLP studies
3- and 6-month rat and 3- and 9-month monkey oral studies
“General toxicity of chronic oral administration of vibegron was adequately evaluated in rats (3 & 6 months) and monkeys (3 & 9 months).”
Route in tox
Oral
“The oral route of administration was utilised in all toxicology studies to match the intended clinical administration route.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, human lymphocyte chromosome aberration and rat bone marrow micronucleus assays
“Vibegron was not mutagenic in in vitro microbial reverse mutation (Ames) assays, showed no genotoxic activity in an in vitro human peripheral blood lymphocyte chromosomal aberration assay, and did not increase the frequency of micronucleated polychromatic erythrocytes in an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
2-year mouse and rat: no treatment-related malignancies
“Two year carcinogenicity studies were also conducted in mice and rats, with no treatment-related malignancies observed in either species at adequate exposure margins”
Reproductive & developmental
Rat and rabbit EFD: no embryo-fetal toxicity up to 1867-fold (rat) and 285-fold (rabbit) clinical AUC
“No embryo-fetal developmental toxicity was observed in rats at doses up to 300 mg/kg/day (1867-fold the AUC at the clinical dose) or in rabbits at doses up to 100 mg/kg/day (285-fold the AUC at the clinical dose).”
Safety pharmacology
Rhesus monkey: increased heart rate, respiration rate and body temperature
“Cardiac safety pharmacology studies in the rhesus monkey indicated that vibegron significantly increased heart rate, respiration rate and body temperature.”
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 Gemtesa 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: Rat NOAEL 30 mg/kg/day (~21.3-fold AUC); monkey NOEL 25 mg/kg/day based on ECG findings (FDA pharmacology/toxicology review, p. 4)
NOAEL / key findings
Rat NOAEL 30 mg/kg/day (~21.3-fold AUC); monkey NOEL 25 mg/kg/day based on ECG findings
“In rats, the NOAEL was determined to be 30 mg/kg/day (~ 21.3-fold AUC at the clinical dose of 75 mg) and in monkeys, a NOEL (due to ECG findings) was determined to be 25 mg/kg/day (6.4-fold Cmax at the clinical dose of 75 mg, 2.1-fold AUC).”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Associated with eye melanin, not irreversibly bound
“suggesting that vibegron is associated with eye melanin but not irreversibly bound.”
Modality-specific risk
Cardiac conduction effects: transient QRS widening and configuration changes in 9-month monkey study
“Further evaluations of cardiac toxicity in the 9-month chronic study in monkeys confirmed these effects with transient ECG findings at the highest dose tested (75-fold the clinical AUC) that resolved after 24 hrs, along with marked increases in QRS duration and changes in QRS configuration.”