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.”
Species: general tox
Rat (14-day, daily) and cynomolgus monkey (6-month, weekly); 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.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD); intravenous
“The Applicant has conducted all the pivotal reproductive toxicity studies (embryo-fetal development in rats and rabbits, fertility and early embryonic development, and pre- and postnatal development in rats) via intravenous route of administration QD, as opposed to the intranasal route to achieve adequate exposures during critical organogenesis period.”
Species: carcinogenicity
Not conducted (intermittent dosing; intranasal route impractical for long-term rodent studies)
“No carcinogenicity studies were conducted.”
Surrogate used in
No surrogate used; etripamil tested directly in rats and monkeys
“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.”
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.”
Genotox: Ames
Negative
“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).”
Genotox: in vitro mammalian
Chromosome aberration assay in human peripheral lymphocytes: negative
“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).”
Genotox: in vivo
Rat micronucleus (IV): negative
“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 model
Not conducted: intermittent dosing, no pharmacology/toxicology concern, intranasal long-term rodent dosing impractical
“Considering the intermittent clinical dosing and exposure profile, lack of obvious pharmacology- and toxicology-based concerns, and the technical challenges of conducting long-term studies in rodents with the intended nasal route of administration, the Division agreed that rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen”
Carcinogenicity timing
Not required (Division agreed rodent studies not warranted)
“Considering the intermittent clinical dosing and exposure profile, lack of obvious pharmacology- and toxicology-based concerns, and the technical challenges of conducting long-term studies in rodents with the intended nasal route of administration, the Division agreed that rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen”
hERG / QT
hERG IC50 0.12 µM, ~0.8x clinical free Cmax
“The IC50 for the inhibitory effect of etripamil [(-) MSP-2017] on hERG potassium current was 0.12 μM (n=3, 0.8× clinical free Cmax of 145.4nM).”
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.”
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
- Syncope Related to Hemodynamic Effects
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Australia: intranasal dose-escalation study in healthy adult males
“the IND for etripamil was opened on November 10, 2014, with a phase 1 first-in-human dose-escalation study (MSP-2017-1096) conducted in Australia with MSP-2017 administered intranasally at doses of 3.5, 7, 14, 30, 60, 105, and 140 mg in healthy adult male subjects (N=56).”
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month intranasal cynomolgus monkey study with 4-week recovery
“MSP-2017-1212/Etripamil: A 6-Month Intranasal Toxicity Study Followed by a 4-Week Recovery Period in Cynomolgus 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.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD); intravenous
“The Applicant has conducted all the pivotal reproductive toxicity studies (embryo-fetal development in rats and rabbits, fertility and early embryonic development, and pre- and postnatal development in rats) via intravenous route of administration QD, as opposed to the intranasal route to achieve adequate exposures during critical organogenesis period.”
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.”
PPND / ePPND: when
Rat PPND (intravenous) completed before the marketing application
“In the pre- and postnatal toxicity study in rats, intravenous administration of etripamil at doses of 0, 0.05, 0.15, and 0.374 mg/kg/day from GD 7 through lactation period (Postpartum Day 20) did not show any adverse effects on pre- and postnatal development”
Carcinogenicity
Species: carcinogenicity
Not conducted (intermittent dosing; intranasal route impractical for long-term rodent studies)
“No carcinogenicity studies were conducted.”
Carcinogenicity model
Not conducted: intermittent dosing, no pharmacology/toxicology concern, intranasal long-term rodent dosing impractical
“Considering the intermittent clinical dosing and exposure profile, lack of obvious pharmacology- and toxicology-based concerns, and the technical challenges of conducting long-term studies in rodents with the intended nasal route of administration, the Division agreed that rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen”
Carcinogenicity timing
Not required (Division agreed rodent studies not warranted)
“Considering the intermittent clinical dosing and exposure profile, lack of obvious pharmacology- and toxicology-based concerns, and the technical challenges of conducting long-term studies in rodents with the intended nasal route of administration, the Division agreed that rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen”
Safety marginopen answer page →
Safety margin at NOAEL
No systemic toxicity at ~1-2x AUC and 1-4x Cmax at the MRHD (rat, monkey); local nasal toxicity at all doses
“Etripamil was well tolerated in nonclinical studies following intranasal administration at exposures approximately 1- to 4- fold Cmax and 1- to 2- fold AUC at the MRHD.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Isolated rabbit hearts, spontaneously hypertensive rats and normotensive rabbits (BP, AV conduction, ECG)
“However, the Applicant demonstrated etripamil pharmacological effects in isolated rabbit hearts (ex vivo), and in spontaneously hypertensive rats (SHRs) and normotensive rabbits.”
Why that model
No dedicated animal model of PSVT; alternative arrhythmia models not used
“There are no dedicated animal models of PSVT. The Applicant did not directly assess the effect of etripamil in alternative arrhythmia animal models.”
Reviewer's view of the efficacy data
Pharmacology data considered supportive of the proposed calcium channel blocker mechanism of action
“Therefore, the provided pharmacological data are considered supportive for the proposed MOA of etripamil as a calcium channel blocker.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No rodent carcinogenicity studies for a chronically used intranasal drug
Why: Intermittent dosing, no pharmacology- or toxicology-based concern, technical challenges of long-term intranasal rodent dosing · Pharmacology or kinetics · Other reason
“Considering the intermittent clinical dosing and exposure profile, lack of obvious pharmacology- and toxicology-based concerns, and the technical challenges of conducting long-term studies in rodents with the intended nasal route of administration, the Division agreed that rodent carcinogenicity studies are not warranted for the proposed clinical indication and dosing regimen”
SpeciesAcceptedBeyond the letter
Chronic toxicity in one species (cynomolgus monkey); no chronic rodent study
Why: Technical challenge of long-term intranasal dosing in rodents, rapid biotransformation, intermittent clinical treatment · Pharmacology or kinetics · Other reason
“Considering the technical challenge of long-term administration via intranasal route in rodents, the rapid biotransformation of etripamil, and the intended intermittent clinical treatment (potentially 36 dosing occasions per year over a lifetime), a chronic toxicity study in one species (cynomolgus monkeys) was considered acceptable.”
DARTVerdict not stated
All pivotal reproductive toxicity studies dosed intravenously instead of by the clinical intranasal route
Why: Achieve adequate exposures during the critical organogenesis period · Pharmacology or kinetics
“The Applicant has conducted all the pivotal reproductive toxicity studies (embryo-fetal development in rats and rabbits, fertility and early embryonic development, and pre- and postnatal development in rats) via intravenous route of administration QD, as opposed to the intranasal route to achieve adequate exposures during critical organogenesis period.”
Safety marginVerdict not stated
Embryo-fetal studies: high doses limited by maternal toxicity, giving exposure multiples below 1 at the MRHD
Why: High doses limited by maternal toxicities (mortalities, clinical signs) in rats and rabbits
“Although no fetal toxicities were noted at any dose levels in both rat and rabbit embryo-fetal development studies, the high doses tested were limited due to maternal toxicities (mortalities, transient clinical signs) observed in both rats and rabbits. This resulted in low exposure multiples (<1) when compared to the exposure at the MRHD (see Table 53 below) given that the high doses were limited.”
Similar precedents
BrenzavvySmall molecules · bexagliflozin · SGLT2Monkey + rodent · 39 wkInpefaSmall molecules · sotagliflozin · SGLT1/SGLT2Rodent + dog or minipig · 39 wkBaxfendySmall molecules · baxdrostat · Aldosterone synthase (CYP11B2)Monkey + rodent · 39 wkFoundayoSmall molecules · orforglipron · GLP-1 receptor (non-peptide)Monkey + rodent · 39 wkJournavxSmall molecules · suzetrigine · NaV1.8Monkey + rodent · 13 wkNexletolSmall molecules · bempedoic acid · ATP citrate lyaseMonkey + rodent · 52 wk