Camzyos
mavacamten
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
“A consistent finding in all repeat-dose toxicity studies (up to 26 weeks in rats and up to 39 weeks in dogs) was dose-dependent reduction in cardiac contractility.”
Why that species
Pharmacological activity: mavacamten is active (slightly more potent) in the toxicology species
“Mavacamten is slightly more potent in the species used for general toxicological assessment, and comparable potencies were exhibited by the recombinant wild type human beta cardiac myosin and five HCM mutants.”
Surrogate molecule
No surrogate; the clinical compound was tested
“A consistent finding in all repeat-dose toxicity studies (up to 26 weeks in rats and up to 39 weeks in dogs) was dose-dependent reduction in cardiac contractility.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“A consistent finding in all repeat-dose toxicity studies (up to 26 weeks in rats and up to 39 weeks in dogs) was dose-dependent reduction in cardiac contractility.”
Pivotal GLP studies
26-week rat and 39-week dog repeat-dose studies
“A consistent finding in all repeat-dose toxicity studies (up to 26 weeks in rats and up to 39 weeks in dogs) was dose-dependent reduction in cardiac contractility.”
Route in tox
Oral
“39-Week oral toxicity study in dogs with a 17-week recovery”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, human lymphocyte clastogenicity and rat micronucleus assays
“Mavacamten was not genotoxic in a bacterial reverse mutation test (Ames test), a human in vitro lymphocyte clastogenicity assay, or a rat in vivo micronucleus assay.”
Carcinogenicity
6-month rasH2 mouse and 2-year rat: no evidence of carcinogenicity
“There was no evidence of carcinogenicity seen in a 6-month rasH2 transgenic mouse study at mavacamten doses of up to 2.0 mg/kg/day in males and 3.0 mg/kg/day in females, or in a 2-year rat study at mavacamten doses up to 0.6 mg/kg/day.”
Reproductive & developmental
Teratogenic in rat and rabbit EFD; in rats post-implantation loss, situs inversus and skeletal malformations
“Mavacamten was shown to be teratogenic in both rats and rabbits in embryo-fetal developmental studies. In rats, mavacamten increased post-implantation loss, lowered mean fetal body weight, slightly reduced fetal skeletal ossification, induced heart malformations (total situs inversus), and increased the incidence of skeletal malformations relative to control.”
Safety pharmacology
No hERG or action-potential effects in vitro; low proarrhythmic risk
“In vitro and in silico electrophysiological data indicate low torsadogenic/proarrhythmogenic risk with mavacamten, as shown by the lack of an effect on hERG channel or any action potential parameters.”
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 Camzyos 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: NOAEL 0.3 mg/kg/day (rat) and 0.06 mg/kg/day (dog), based on cardiac echo, ECG and histology endpoints (FDA pharmacology/toxicology review, p. 3)
NOAEL / key findings
NOAEL 0.3 mg/kg/day (rat) and 0.06 mg/kg/day (dog), based on cardiac echo, ECG and histology endpoints
“A no-observed-adverse-effect-level (NOAEL) was determined to be 0.3 mg/kg/day and 0.06 mg/kg/day, respectively for the rat and dog, based on echocardiographic, electrocardiographic, or histological endpoints in the heart in the chronic toxicity studies.”
Risksopen answer page →
Immune & cytokine safety
Thymus decreased in size from decreased cellularity in rats and dogs
“Other target organs of toxicity in both rats and dogs were liver (centrilobular necrosis, congestion and vacuolation), lungs (increased alveolar macrophages and inflammation) and thymus (decrease in size as a result of decreased cellularity).”
Biodistribution & persistence
Low CNS levels; selective association with melanin-containing eye tissues in rat QWBA
“Low radioactivity concentrations were documented in central nervous system tissues (cerebellum, cerebrum, medulla, and spinal cord). Low levels of [14C]MYK-461-derived radioactivity were selectively associated with melanin-containing tissues of the eye”
Modality-specific risk
Exaggerated pharmacology: heart failure with narrow NOAEL-to-lethal-dose margin (4-fold rat, 2.5-fold dog)
“Both rat and dog studies show that mavacamten has a narrow separation (4-fold in rats and 2.5-fold in dogs) between the NOAEL and the dose that caused heart failure and mortality, indicative of a narrow therapeutic window.”