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.”
Species: general tox
Rat (up to 26 weeks) and dog (up to 39 weeks)
“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.”
Species: DART
Rat and rabbit (EFD)
“Mavacamten was shown to be teratogenic in both rats and rabbits in embryo-fetal developmental studies.”
Species: carcinogenicity
Sprague-Dawley rat (104-week) and transgenic RasH2 mouse (6-month)
“Carcinogenicity of mavacamten was studied in the 104-week study with Sprague-Dawley rats and 6 months study with transgenic RasH2 mice.”
Surrogate used in
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.
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.”
Genotox: Ames
Negative up to 5000 µg/plate
“Mavacamten gave negative results in the Ames test up to the limit concentration of 5000 µg/plate and in the in vitro micronucleus assay in human lymphocytes, tested up to cytotoxic concentrations, both with and without metabolic activation.”
Genotox: in vitro mammalian
In vitro micronucleus in human lymphocytes: negative
“Mavacamten gave negative results in the Ames test up to the limit concentration of 5000 µg/plate and in the in vitro micronucleus assay in human lymphocytes, tested up to cytotoxic concentrations, both with and without metabolic activation.”
Genotox: in vivo
Rat bone marrow micronucleus (up to 8 mg/kg, MTD): negative
“An in vivo bone marrow micronucleus test in rats dosed up to 8 mg/kg (MTD) for 2 consecutive days was negative.”
Carcinogenicity model
6-month rasH2 transgenic 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.”
Carcinogenicity timing
26-week rasH2 mouse completed; 2-year rat ongoing at approval, to be completed post-approval
“The Division has agreed the 2-year rat carcinogenicity study can be completed post-approval and the study is currently ongoing.”
hERG / QT
Minimal hERG inhibition: 5% at 10 µM and 9.6% at 60 µM
“Minimal but statistically significant increased hERG inhibition of 5% and 9.6% in HEK293 cells was noted at 10µM and 60µM, respectively, compared to controls (1%).”
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.”
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
Boxed warning: Risk of heart failure
- Heart Failure
- CYP450 Drug Interactions Leading to Heart Failure or Loss of Effectiveness
- CAMZYOS REMS Program
- Embryo-Fetal Toxicity
CardiovascularEmbryo-fetal toxicity
US prescribing information, Boxed Warning and 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral dog study with 17-week recovery
“6.2.8. 39-Week oral toxicity study in dogs with a 17-week recovery”
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.”
DART package
Species: DART
Rat and rabbit (EFD)
“Mavacamten was shown to be teratogenic in both rats and rabbits in embryo-fetal developmental studies.”
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.”
PPND / ePPND: when
Rat PPND (segment III) completed before the marketing application
“In segment III pre- and post-natal development study in rats, MVA at doses up to 1.5 mg/kg/day did not cause F0 maternal systemic toxicity, F1 neonatal/developmental toxicity, F1 parental systemic toxicity, F1 reproductive toxicity, and F2 embryonic toxicity.”
Carcinogenicity
Species: carcinogenicity
Sprague-Dawley rat (104-week) and transgenic RasH2 mouse (6-month)
“Carcinogenicity of mavacamten was studied in the 104-week study with Sprague-Dawley rats and 6 months study with transgenic RasH2 mice.”
Carcinogenicity model
6-month rasH2 transgenic 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.”
Carcinogenicity timing
26-week rasH2 mouse completed; 2-year rat ongoing at approval, to be completed post-approval
“The Division has agreed the 2-year rat carcinogenicity study can be completed post-approval and the study is currently ongoing.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL exposures in all toxicology and reproductive studies below human exposure at the MRHD
“Plasma exposure in all toxicology studies and reproductive toxicology studies at the NOAEL is less than those in humans at the MRHD (Table 146).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Transgenic troponin T-mutant HCM mice dosed 6 months: improved diastolic function, preserved fractional shortening
“Transgenic mice with mutations in troponin T resulting in pathogenic HCM phenotypes which displayed marked diastolic dysfunction with minimal fibrosis, were administered 0.83 mg/kg/day for 6 months. Mavacamten improved diastolic function while preserving fractional shortening.”
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
EMA: improvement of HCM phenotype in transgenic mouse supports proof of concept
“Mavacamten was able to improve HCM phenotype in a transgenic mouse, thus further lending support to the proof of concept for mavacamten as a therapy in HCM.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
2-year rat carcinogenicity study still ongoing at approval; to be completed post-approval (rasH2 mouse study completed)
“The Division has agreed the 2-year rat carcinogenicity study can be completed post-approval and the study is currently ongoing.”
Safety marginCriticised but acceptedBeyond the letter
NOAEL exposures (Cmax and AUC) in all toxicity studies below human exposure at the MRHD
“In all toxicity studies (except carcinogenicity), plasma exposure (Cmax and AUC) at the no-observed adverse effect level is less than those in humans at the MRHD suggesting potential risk even at the therapeutic dose range.”
“Finally, there are no non-clinical findings that preclude from the approvability of MVA to patients with symptomatic HCM to reduce LVOT obstruction and ventricular filling pressures.”
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