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.”
Species: general tox
Rat (3 and 6 months) and monkey (3 and 9 months)
“General toxicity of chronic oral administration of vibegron was adequately evaluated in rats (3 & 6 months) and monkeys (3 & 9 months).”
Species: DART
Rats and rabbits (fertility, embryofetal, pre- and postnatal development)
“Reproductive studies to examine fertility, embryofetal development, and pre- and postnatal development were also conducted in rats and rabbits.”
Species: carcinogenicity
Mouse and rat (2-year)
“Two year carcinogenicity studies were also conducted in mice and rats, with no treatment-related malignancies observed in either species at adequate exposure margins”
Surrogate used in
No surrogate used; vibegron tested directly
“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.”
Genotox: Ames
Negative (microbial reverse mutation)
“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.”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral blood lymphocytes: negative
“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.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“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 model
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”
Carcinogenicity timing
2-year mouse and rat studies completed before the marketing application
“Two year carcinogenicity studies were also conducted in mice and rats, with no treatment-related malignancies observed in either species at adequate exposure margins”
hERG / QT
No significant hERG inhibition at 31 μM (112-fold Cmax at MRHD); 21.4% inhibition at 101 μM (365-fold)
“In CHO-K1 Chinese Hamster Ovary cells, at a concentration of 31 μM (112-fold the MRHD of 75 mg using Cmax)(N=5), MK-4618 had no statistically significant effect on hERG channel tail current, but at the maximum testable concentration of 101 μM (365 fold)(N=4), it inhibited hERG current by 21.4%.”
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.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
- Urinary Retention
- Angioedema
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
Repeat-dose tox before first-in-human
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.
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month cynomolgus monkey oral study; recovery not stated
“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).”
DART package
Species: DART
Rats and rabbits (fertility, embryofetal, pre- and postnatal development)
“Reproductive studies to examine fertility, embryofetal development, and pre- and postnatal development were also conducted in rats and rabbits.”
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).”
PPND / ePPND: when
PPND in rat completed before the marketing application
“A pivotal PPND study has been performed in pregnant Crl:CD (SD) rats at doses up to 500 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (2-year)
“Two year carcinogenicity studies were also conducted in mice and rats, with no treatment-related malignancies observed in either species at adequate exposure margins”
Carcinogenicity model
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”
Carcinogenicity timing
2-year mouse and rat studies completed before the marketing application
“Two year carcinogenicity studies were also conducted in mice and rats, with no treatment-related malignancies observed in either species at adequate exposure margins”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL ~21.3x AUC; monkey NOEL (ECG findings) 2.1x AUC, 6.4x Cmax at 75 mg
“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).”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Acetic acid-induced bladder overactivity model (rat)
“The functional studies utilised a model for bladder overactivity where acetic acid is administered to induce a hyperactive state of the bladder.”
Why that model
Species chosen for β3-AR expression: dominant in human and monkey bladder; rats express β3 and β2; mice and rabbits only β2
“β3 AR is the dominant receptor in bladder smooth muscle in humans and monkeys. β3 and β2 receptor subtypes are expressed in rats. β2 receptors only are expressed in mice and rabbits.”
Reviewer's view of the efficacy data
FDA: adequately evaluated; selective β3-AR agonist shown to relax detrusor and increase bladder capacity
“Vibegron has been adequately evaluated in nonclinical studies for pharmacology, pharmacokinetics and toxicology. Studies showed that vibegron is a selective agonist for the β-3 AR over β-1 and β-2 AR and demonstrated its intended pharmacologic function of relaxing the detrusor smooth muscle of the urinary bladder during bladder filling to increase bladder capacity.”
Flexibilityopen answer page →
Flexibility accepted
No departure named in the public reviews.
Similar precedents
FilspariSmall molecules · sparsentan · Endothelin A / angiotensin II receptorsMonkey + rodent · 39 wkVanrafiaSmall molecules · atrasentan · Endothelin A receptorRodent + dog or minipig · 39 wkAugtyroSmall molecules · repotrectinib · ROS1/TRKMonkey + rodent · 13 wkCobenfySmall molecules · xanomeline and trospium · Muscarinic M1/M4 agonist; peripheral antagonistMonkey + rodent · 52 wkDayvigoSmall molecules · lemborexant · Orexin OX1/OX2 receptorsMonkey + rodent · 39 wkFotivdaSmall molecules · tivozanib · VEGFR1-3Monkey + rodent · 39 wk