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.”
Species: general tox
Xanomeline alone: rat and mouse (diet), monkey (nasogastric), rat and monkey (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.”
Species: DART
Combination: rat and rabbit (EFD), rat (pre/postnatal)
“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, embryofetal development studies in the rat and rabbit, and pre- and postnatal development studies in the rat.”
Species: carcinogenicity
Xanomeline: rat and mouse (dietary)
“Nonetheless, in the rat and mouse carcinogenicity studies, oral administration of xanomeline via the diet did not cause necrotic lesions or progress into neoplastic tumors in the liver at doses up to 1.5 and 3 times the MRHD (125 mg BID) of xanomeline.”
Surrogate used in
No surrogate used; rat and monkey receptor pharmacology similar 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.”
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.”
Genotox: Ames
Xanomeline: negative
“Xanomeline was not mutagenic in the in vitro bacterial reverse mutation (Ames assay) or mouse lymphoma assay. Xanomeline did not induce unscheduled DNA synthesis in rat hepatocytes and was not clastogenic in the in vitro chromosome aberration assay or in the in vivo mouse bone marrow micronucleus assay.”
Genotox: in vitro mammalian
Xanomeline: mouse lymphoma, CHO chromosome aberration and rat hepatocyte UDS negative
“Xanomeline was not mutagenic in the in vitro bacterial reverse mutation (Ames assay) or mouse lymphoma assay. Xanomeline did not induce unscheduled DNA synthesis in rat hepatocytes and was not clastogenic in the in vitro chromosome aberration assay or in the in vivo mouse bone marrow micronucleus assay.”
Genotox: in vivo
Xanomeline: mouse bone marrow micronucleus negative
“Xanomeline was not mutagenic in the in vitro bacterial reverse mutation (Ames assay) or mouse lymphoma assay. Xanomeline did not induce unscheduled DNA synthesis in rat hepatocytes and was not clastogenic in the in vitro chromosome aberration assay or in the in vivo mouse bone marrow micronucleus assay.”
Carcinogenicity model
Xanomeline rat and mouse dietary studies: no liver tumors at up to 1.5x and 3x the MRHD
“Nonetheless, in the rat and mouse carcinogenicity studies, oral administration of xanomeline via the diet did not cause necrotic lesions or progress into neoplastic tumors in the liver at doses up to 1.5 and 3 times the MRHD (125 mg BID) of xanomeline.”
Carcinogenicity timing
Xanomeline dietary rat and mouse carcinogenicity studies completed before the marketing application
“Nonetheless, in the rat and mouse carcinogenicity studies, oral administration of xanomeline via the diet did not cause necrotic lesions or progress into neoplastic tumors in the liver at doses up to 1.5 and 3 times the MRHD (125 mg BID) of xanomeline.”
hERG / QT
Xanomeline hERG IC50 70 nM, but no QTc prolongation or arrhythmia in monkeys up to 12x clinical Cmax
“Xanomeline did not cause QTc prolongation. 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.”
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
- Risk of Urinary Retention
- Risk of Use in Patients with Hepatic Impairment
- Risk of Use in Patients with Biliary Disease
- Decreased Gastrointestinal Motility
- Risk of Angioedema
- Risk of Use in Patients with Narrow-angle Glaucoma
- Increases in Heart Rate
- Anticholinergic Adverse Reactions in Patients with Renal Impairment
- Central Nervous System Effects
HepatotoxicityGastrointestinalCardiovascularNephrotoxicityNeurotoxicity
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
1-year GLP rhesus monkey study of xanomeline (nasogastric) with high-dose recovery group; recovery length not stated
“Table 92. Study: 1-Year Toxicology Study in the Monkey (GLP) Study Parameters Details Doses and RoA 0 (water control), 1(LD), 5 (MD), and 12.5 (HD) mg/kg/day; nasogastric intubation Species/strain Rhesus monkey (Macaca Mulatta) Number/sex/group Main study: n=4/sex/group Recover: n=2/sex for HD only”
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”
DART package
Species: DART
Combination: rat and rabbit (EFD), rat (pre/postnatal)
“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, embryofetal development studies in the rat and rabbit, and pre- and postnatal development studies in the rat.”
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.”
PPND / ePPND: when
Rat PPND with the combination plus follow-up rat PPND with xanomeline alone, reviewed under the IND before the marketing application
“pre- and postnatal toxicity study with an additional follow-up pre- and postnatal study with xanomeline alone in the rat. Most of the nonclinical studies, including all pivotal safety studies, were submitted, and reviewed under the IND.”
Carcinogenicity
Species: carcinogenicity
Xanomeline: rat and mouse (dietary)
“Nonetheless, in the rat and mouse carcinogenicity studies, oral administration of xanomeline via the diet did not cause necrotic lesions or progress into neoplastic tumors in the liver at doses up to 1.5 and 3 times the MRHD (125 mg BID) of xanomeline.”
Carcinogenicity model
Xanomeline rat and mouse dietary studies: no liver tumors at up to 1.5x and 3x the MRHD
“Nonetheless, in the rat and mouse carcinogenicity studies, oral administration of xanomeline via the diet did not cause necrotic lesions or progress into neoplastic tumors in the liver at doses up to 1.5 and 3 times the MRHD (125 mg BID) of xanomeline.”
Carcinogenicity timing
Xanomeline dietary rat and mouse carcinogenicity studies completed before the marketing application
“Nonetheless, in the rat and mouse carcinogenicity studies, oral administration of xanomeline via the diet did not cause necrotic lesions or progress into neoplastic tumors in the liver at doses up to 1.5 and 3 times the MRHD (125 mg BID) of xanomeline.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat EFD (combination) NOAEL ~3x the xanomeline dose at the MRHD (BSA)
“The NOAEL for maternal and embryofetal toxicity was 75 mg/50 mg/kg/day for the combination, which is approximately three and eight times the xanomeline and trospium dose, respectively, at the MRHD of 125 mg/30 mg xanomeline/trospium, BID, based on BSA.”
NOAEL / key findings
Target organs: hepatobiliary, cardiovascular, CNS and GI
“The target organs include the hepatobiliary, cardiovascular, CNS, and gastrointestinal (GI) systems.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rodent and monkey models of schizophrenia: conditioned avoidance, psychostimulant-induced hyperactivity, schedule-controlled behavior
“Xanomeline exhibited antipsychotic-like effects in several animal models of schizophrenia, including conditioned avoidance responding in rodents, psychostimulant-induced hyperactivity in rodents, and scheduled-controlled behavior in rodents and monkeys.”
Why that model
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.
Reviewer's view of the efficacy data
Antipsychotic effects likely mediated by central muscarinic receptors; therapeutic efficacy established clinically
“The antipsychotic effects of xanomeline were abolished by coadministration of scopolamine, a centrally and peripherally active mAChR antagonist, but not by N-methyl-scopolamine, a peripherally active mAChR antagonist, demonstrating that xanomeline’s antipsychotic effects are likely mediated by its activity at the central mAChRs. The therapeutic efficacy of KarXT for the treatment of schizophrenia was determined in the clinical studies.”
Flexibilityopen answer page →
Flexibility accepted
OtherVerdict not stated
No new nonclinical program for trospium; relies on prior FDA finding of safety for the approved trospium product
Why: Previous Agency finding of safety and effectiveness for trospium chloride · Other reason
“For trospium, the Applicant is relying on the Agency’s previous finding of safety and effectiveness of trospium chloride under NDA 021595 (Sanctura).”
First doseAccepted with a conditionBeyond the letter
Deaths in 14-day rat combination study left no NOAEL; no trospium-alone arm; clinical hold before dose escalation
Why: Hold lifted on commitment not to escalate beyond the starting dose until 40-day rat combination data were reviewed
“We informed the Applicant that based on animal deaths in their 14-day combination study with low and high doses there was now an unknown no observed adverse effect level (NOAEL) and safety margins could not be established to inform dosing.”
“On August 3, 2017, the Division removed the clinical hold acknowledging the Applicant’s commitment to refrain from escalating the dose beyond the initial starting dose until data from the first dose cohort and full study report of the 40-day rat combination study was submitted and reviewed.”
CarcinogenicityCriticised but acceptedBeyond the letter
Rat carcinogenicity protocol not submitted for ECAC dose concurrence; high dose exceeded the MTD
Why: No tumor increase at lower doses, slightly above the MRHD on a body surface area basis
“The Applicant did not submit the study protocol for ECAC concurrence on dose selection. The high dose exceeded the MTD and caused excessive decreases in body weight (↓up to 45%), weight gain (↓up to 70%), and food consumption (↓up to 19%), precluding an adequate assessment for carcinogenic effect at this dose.”
“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).”
Safety marginCriticised but acceptedBeyond the letter
Toxicokinetic data unreliable (cross-contamination, high variability); safety margins based on body surface area, not exposure
Why: Rat PK bridging study showed adequate exposure to xanomeline and major human metabolites · Pharmacology or kinetics
“Therefore, the TK data are unreliable to use quantitatively, and they are evaluated only from a qualitative perspective. The safety margin calculations listed in the drug label are based on body surface area and not on exposure data.”
“Data from the PK bridging study demonstrated that all three routes of administration in rats provided adequate exposure levels of xanomeline and the important human metabolites relative to the clinical exposure (Table 87).”
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