Cobenfy
xanomeline and trospium
Species
MonkeyRat
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and monkey
“The binding affinity and functional activity of xanomeline at the mAChR receptors were generally similar between human and animal species (rat and monkey), therefore, supporting the use of the rat and monkey as the nonclinical species for pharmacology and toxicology evaluation.”
Why that species
Similar muscarinic receptor binding affinity and functional activity to human
“The binding affinity and functional activity of xanomeline at the mAChR receptors were generally similar between human and animal species (rat and monkey), therefore, supporting the use of the rat and monkey as the nonclinical species for pharmacology and toxicology evaluation.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In addition, the Applicant conducted toxicity studies with the combination via oral gavage, including repeat-dose toxicity studies in the rat for up to 90 days; embryofetal development toxicity studies in the rat and rabbit; and pre- and postnatal toxicity study with an additional follow-up pre- and postnatal study with xanomeline alone in the rat.”
Study lengthopen answer page →
Longest pivotal study
52 (1-year monkey, xanomeline)
“Table 92. Study: 1-Year Toxicology Study in the Monkey (GLP)”
Pivotal GLP studies
Xanomeline: rat and mouse dietary, monkey nasogastric, rat and monkey SC studies; combination: rat oral gavage up to 90 days
“The nonclinical studies for the NDA included toxicity studies conducted with xanomeline alone via dietary administration in the rat and mouse, nasogastric intubation in the monkey, and subcutaneous injection in the rat and monkey. In addition, the Applicant conducted toxicity studies with the xanomeline/trospium combination via oral gavage, including repeat-dose toxicity studies in the rat for up to 90 days”
Route in tox
Oral (diet, nasogastric, gavage) and subcutaneous
“The nonclinical studies for the NDA included toxicity studies conducted with xanomeline alone via dietary administration in the rat and mouse, nasogastric intubation in the monkey, and subcutaneous injection in the rat and monkey.”
Skipped studiesopen answer page →
Genotoxicity
Xanomeline negative in Ames, mouse lymphoma, rat hepatocyte UDS, CHO chromosome aberration and mouse micronucleus assays
“Xanomeline was not mutagenic or clastogenic in a battery of genetic toxicity tests. These tests included in vitro bacterial reverse mutation (Ames), mouse lymphoma TK, unscheduled DNA synthesis in rat hepatocytes, in vitro chromosome aberration in mammalian (CHO) cells and in vivo bone marrow micronucleus assay in mice.”
Carcinogenicity
Xanomeline 2-year dietary rat: no tumor increase up to 37 (males) and 46 (females) mg/kg/day, slightly above MRHD
“Xanomeline did not increase the incidence of tumors in rats treated for 2 years via the diet at doses up to 37 mg/kg/day in males and 46/mg/kg/day in females, respectively, which is slightly higher than the xanomeline dose at the MRHD of 125 mg/30 mg xanomeline/trospium, BID, based on body surface area (BSA).”
Reproductive & developmental
Embryofetal and developmental toxicity (decreased fetal/neonatal weight, stillbirths, neonatal deaths) at maternally toxic doses
“At these maternally toxic doses, embryofetal and developmental toxicities included decreased fetal and neonatal weight, stillborn pups, and/or neonatal deaths.”
Safety pharmacology
hERG IC50 70 nM but no QTc prolongation or arrhythmia in monkeys up to 12x clinical Cmax; increased heart rate and blood pressure
“Although xanomeline dose dependently inhibited the hERG channel (IC50=70nM), no abnormal cardiac rhythm or QTc prolongation was observed in qualitative ECG evaluation or post hoc analysis of the ECG tracing data in monkey studies at xanomeline concentrations up to 12 times the clinical Cmax.”
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 Cobenfy 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: Target organs: hepatobiliary, cardiovascular, CNS and GI (FDA integrated review, p. 72)
NOAEL / key findings
Target organs: hepatobiliary, cardiovascular, CNS and GI
“The target organs include the hepatobiliary, cardiovascular, CNS, and gastrointestinal (GI) systems.”
Risksopen answer page →
Immune & cytokine safety
Moderate skin sensitizer in mouse LLNA (EC3 125 µg/cm2)
“Xanomeline is a moderate skin sensitizer with an EC3 (3-fold stimulation index) potency of 125 µg/cm2”
Biodistribution & persistence
Low xanomeline exposure in rat fetal tissues (potential placental transfer); xanomeline and trospium in pup blood (potential milk transfer)
“Subcutaneous administration of xanomeline to pregnant rats resulted in low levels of exposure to xanomeline and its metabolites in fetal tissues, suggesting potential transplacental transfer of xanomeline and/or its metabolites. In pre- and postnatal developmental studies in the rat, after maternal oral administration, xanomeline and trospium were detected in neonatal pup blood on postnatal Day 4, suggesting potential lactational transfer of both drugs.”
Modality-specific risk
Hepatobiliary toxicity: biliary hyperplasia, biliary cysts/dilation and hepatocellular vacuolation/hypertrophy
“In nonclinical studies, oral administration of xanomeline alone or in combination with trospium caused dose- and duration-dependent hepatobiliary histopathology findings, including biliary (bile duct) hyperplasia, biliary cyst, biliary/biliary ductular dilation, and/or hepatocellular vacuolation/hypertrophy.”