Myqorzo
aficamten
Species
RatDog
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 dog
“Repeat oral dose toxicology studies up to 26 weeks in rats and 39 weeks in dogs were conducted to support the chronic oral administration of aficamten intended for clinical use.”
Why that species
Both pharmacologically relevant: cardiac myosin motor highly conserved; supported by in vitro and in vivo pharmacology
“Both species are considered pharmacologically relevant given the high conservation of the cardiac myosin motor between species and based on in vitro and single-dose in vivo pharmacology studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Study Number/Title: Nonclin-0054/A 26-Week Study of CK-3773274 by Oral Gavage in Rats With a 2-Month Recovery Period”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Repeat oral dose toxicology studies up to 26 weeks in rats and 39 weeks in dogs were conducted to support the chronic oral administration of aficamten intended for clinical use.”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“Repeat oral dose toxicology studies up to 26 weeks in rats and 39 weeks in dogs were conducted to support the chronic oral administration of aficamten intended for clinical use.”
Route in tox
Oral (gavage)
“Study Number/Title: Nonclin-0054/A 26-Week Study of CK-3773274 by Oral Gavage in Rats With a 2-Month Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, combined in vivo micronucleus and comet assays
“Aficamten was not mutagenic or clastogenic in a standard battery of genotoxicity studies including the Ames assay and a combined in vivo micronucleus assay and comet assay.”
Carcinogenicity
26-week rasH2 mouse and 2-year rat: no drug-related tumors (rat up to 4x MRHD unbound AUC)
“There were no aficamten-related tumor findings in a 26-week carcinogenicity study in transgenic rasH2 mice at doses up to 2.0 mg/kg/day or in a 2-year carcinogenicity study in Sprague Dawley rats at doses up to 3 mg/kg/day (corresponding to 4-times the exposure at the MRHD based on AUCunbound).”
Reproductive & developmental
Rat EFD: increased external malformations (kinked tail) at exposures above the MRHD
“A rat embryofetal development (EFD) study demonstrated an increase in external malformations (kinked tail) at aficamten exposures higher than clinical exposures at the MRHD.”
Safety pharmacology
No hERG inhibition at clinical concentrations; ECG changes reflect cardiac compensation to pharmacology
“Effects observed on electrocardiogram readings after repeated aficamten dosing are typical of cardiac compensation due to the intended pharmacologic action of aficamten. Aficamten and its metabolites did not have inhibitory effects on the hERG channel at clinically relevant concentrations.”
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 Myqorzo 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: Heart primary target in rats and dogs; dose- and duration-dependent cardiac toxicity up to heart failure from exaggerated pharmacology (FDA integrated review, p. 111)
NOAEL / key findings
Heart primary target in rats and dogs; dose- and duration-dependent cardiac toxicity up to heart failure from exaggerated pharmacology
“The heart was identified as the primary organ of toxicity in both species with repeated aficamten administrations. Cardiac toxicities culminating in heart failure resulting from exaggerated pharmacology of the drug were observed in both rats and dogs in a dose- and duration-dependent fashion.”
Risksopen answer page →
Immune & cytokine safety
Guinea pig dermal sensitisation study (modified Buehler) negative: no erythema after topical application
“A sensitization Study of CK-3773274 by Dermal Administration in Guinea Pigs – Modified Buehler Design Negative, aficamten did not induce erythema after 48 hours of topical application.”
Biodistribution & persistence
Reversible melanin binding: higher levels in pigmented skin, prolonged retention in eye uveal tract
“Pigmented skin showed higher concentrations of radioactivity than nonpigmented skin, which, together with the prolonged presence of radioactivity in eye uveal tract, indicated (reversible) melanin binding.”
Modality-specific risk
Exaggerated pharmacology: cardiac toxicity (dilated cardiomyopathy, heart failure) in healthy animals near clinical exposure
“Cardiac effects were, unsurprisingly, observed in repeat-dose toxicology studies conducted in rats and dogs at or near exposure levels anticipated for clinical use, which were interpreted as direct results of the intended pharmacology in healthy animals.”