Cardamyst
etripamil
Species
MonkeyRat
Longest study
26 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 cynomolgus monkey
“General toxicity studies were conducted with intranasal administration of etripamil for durations of up to 14 days in rats (once daily [QD]) and 6 months (once weekly) in monkeys.”
Why that species
Rapid metabolism to the primary inactive metabolite MSP-2030 similar in rats, monkeys and humans
“Rats (rodent) and monkeys (nonrodent) were selected as appropriate animal species for toxicity testing because etripamil is rapidly metabolized to a primary inactive metabolite (MSP-2030) similarly in rats, monkeys, and humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“No mortality, body weight changes, clinical chemistry, organ weights, macroscopic, or systemic microscopic findings were associated with the administration of etripamil up to 5.7 mg/kg/week.”
Study lengthopen answer page →
Longest pivotal study
26 (6-month monkey)
“General toxicity studies were conducted with intranasal administration of etripamil for durations of up to 14 days in rats (once daily [QD]) and 6 months (once weekly) in monkeys.”
Pivotal GLP studies
14-day daily rat and 6-month once-weekly monkey intranasal studies
“General toxicity studies were conducted with intranasal administration of etripamil for durations of up to 14 days in rats (once daily [QD]) and 6 months (once weekly) in monkeys.”
Route in tox
Intranasal
“General toxicity studies were conducted with intranasal administration of etripamil for durations of up to 14 days in rats (once daily [QD]) and 6 months (once weekly) in monkeys.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and in vivo rat micronucleus (IV) assays
“Etripamil was not genotoxic in a bacterial reverse mutation assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, and an in vivo micronucleus study in rats (IV administration).”
Carcinogenicity
Not conducted (intermittent dosing; long-term intranasal rodent studies technically challenging)
“Given the intermittent clinical dosing, lack of obvious pharmacology-based concerns, and the technical challenges for conducting long-term studies in rodents with the intended intranasal route of administration, rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen.”
Reproductive & developmental
IV rat EFD: no adverse embryofetal effects up to 0.375 mg/kg/day (~3x Cmax, 0.4x AUC at MRHD)
“In pregnant rats, intravenous administration of etripamil throughout the period of organogenesis did not result in any adverse effects on embryofetal development at doses up to 0.375 mg/kg/day, approximately 3x the C max and 0.4x the AUC at the MRHD.”
Safety pharmacology
No neurologic, respiratory or cardiovascular liabilities; PR prolongation in monkeys consistent with pharmacology
“Safety pharmacology studies did not identify any neurologic, respiratory, or cardiovascular liabilities that would impact clinical development. Prolongation of the PR-interval observed in the cardiovascular assessment in monkeys was consistent with the expected pharmacological effect of etripamil.”
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 Cardamyst 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: No significant systemic toxicity up to highest doses in 6-month monkey and 14-day rat; local nasal toxicity at all doses (FDA integrated review, p. 80)
NOAEL / key findings
No significant systemic toxicity up to highest doses in 6-month monkey and 14-day rat; local nasal toxicity at all doses
“In the 6-month monkey and 14-day rat studies, there were no significant systemic toxicities observed up to the highest doses tested. However, local nasal toxicity at the site of administration was noted at all doses in both species.”
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
Low exposure in CNS tissues (cerebrum, cerebellum, medulla, spinal cord)
“Central nervous system tissues (cerebrum, cerebellum, medulla, and spinal cord) had low exposure to radioactivity (<100 ng equiv/g).”
Modality-specific risk
Local nasal toxicity at the administration site, considered a reactive or adaptive response
“The nasal toxicity was limited to the site of administration and is considered a reactive or adaptive response to repeated intranasal administration of etripamil.”