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”
Species: general tox
Rat (up to 26 weeks) and dog (up to 39 weeks)
“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.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“GLP-compliant reproductive toxicology studies including a fertility and early embryonic development study in rats, embryofetal development studies in rats and rabbits, and a pre- and post-natal development study in rats were conducted with aficamten.”
Species: carcinogenicity
Tg rasH2 mouse (26-week) and Sprague Dawley rat (2-year)
“The carcinogenic potential of aficamten was assessed in a 26-week study in transgenic rasH2 mice and a 2-year study in Sprague Dawley rats.”
Surrogate used in
No surrogate used
“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.”
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.”
Genotox: Ames
Negative
“Aficamten was not genotoxic in the in vitro bacterial (Ames) mutagenicity assay or the combined in vivo micronucleus assay and comet assay in rat.”
Genotox: in vitro mammalian
In vitro micronucleus assays (major metabolites only): negative
“GLP-compliant Ames assays and in vitro micronucleus assays were conducted for the two major metabolites of aficamten, with a follow-up combined in vivo micronucleus assay and comet assay conducted for metabolite M1a. Collectively, the metabolites were also negative for genotoxicity and clastogenicity.”
Genotox: in vivo
Combined rat micronucleus and comet assay: negative
“Aficamten was not genotoxic in the in vitro bacterial (Ames) mutagenicity assay or the combined in vivo micronucleus assay and comet assay in rat.”
Carcinogenicity model
26-week Tg rasH2 mouse and 2-year rat; no carcinogenicity up to 4-fold MRHD (free AUC) in rat
“There was no evidence of carcinogenicity with oral administration of aficamten at dose levels up to 2.0 mg/kg/day in the mouse or 3 mg/kg/day in the rat (corresponding to 4-fold the MRHD based on free AUC).”
Carcinogenicity timing
26-week rasH2 mouse and 2-year rat completed before the marketing application
“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”
hERG / QT
hERG IC50 not determined (insoluble above 10 µM); 3% and 3.7% inhibition at 3 and 10 µM
“The in vitro IC50 for aficamten against hERG was not determined due to insolubility of the drug above 10µM (3,400 ng/mL). At 3μM and 10μM aficamten, hERG was inhibited by 3% and 3.7% respectively (Nonclin-0003).”
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.”
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
- MYQORZO REMS Program
- Cytochrome P450 Interactions Leading to Heart Failure or Loss of Effectiveness
Cardiovascular
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week Beagle dog (oral gavage) with 2-month recovery
“Study Number/Title: Nonclin-0056/CK-3773274: A 39-Week Oral Gavage Toxicity Study in the Beagle Dog Followed by a 2-Month Recovery Period”
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.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“GLP-compliant reproductive toxicology studies including a fertility and early embryonic development study in rats, embryofetal development studies in rats and rabbits, and a pre- and post-natal development study in rats were conducted with aficamten.”
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.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“Pre- and post-natal development effects of aficamten were evaluated in rats.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (26-week) and Sprague Dawley rat (2-year)
“The carcinogenic potential of aficamten was assessed in a 26-week study in transgenic rasH2 mice and a 2-year study in Sprague Dawley rats.”
Carcinogenicity model
26-week Tg rasH2 mouse and 2-year rat; no carcinogenicity up to 4-fold MRHD (free AUC) in rat
“There was no evidence of carcinogenicity with oral administration of aficamten at dose levels up to 2.0 mg/kg/day in the mouse or 3 mg/kg/day in the rat (corresponding to 4-fold the MRHD based on free AUC).”
Carcinogenicity timing
26-week rasH2 mouse and 2-year rat completed before the marketing application
“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”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: no adverse effects at clinical free AUC exposure; no adverse findings in dogs only at exposures below clinical total AUC
“No adverse effects for either species were observed with chronic dosing at clinical exposure based on free AUC and up to 3-fold based on free Cmax. No adverse findings occurred in dogs at exposures less than clinical total AUC and total Cmax.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Transgenic MYH7 R403Q HCM mouse and A31P MYBPC3 cat model of hereditary obstructive HCM
“Prospect of clinical benefit was shown using heterozygous transgenic MYH7 R403Q mice with HCM, and a cat model of hereditary oHCM (A31P MYBPC3 mutation), using aficamten doses comparable to those used in toxicology studies.”
Why that model
Cardiac myosin motor highly conserved between species, making animal species pharmacologically relevant
“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.”
Reviewer's view of the efficacy data
FDA: the cat model reliably reflects human oHCM including LVOT obstruction; the transgenic mouse shows LV thickening without obstruction
“Notably, the transgenic mouse develops LV thickening without LVOT obstruction, while the cat model reliably reflects human oHCM symptoms including LVOT obstruction.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginCriticised but acceptedBeyond the letter
Chronic rat and dog exposure margins below ICH M3(R2) expectations because exaggerated pharmacology limited dosing
Why: Dose-limiting exaggerated pharmacology; HCM patients would likely tolerate reduced cardiac contractility better than animals · Pharmacology or kinetics
“In both species, chronic RDT studies generally may not have explored the full range of aficamten mediated effects in naïve animals due to lack of exposure due to dose limiting aficamten-related (exaggerated) pharmacology. As a result, exposure margins in the chronic RDT studies in rat and dog are below what is expected in ICH M3(R2).”
“Hypercontractility is one of the pathological hallmarks of hypertrophic cardiomyopathy, and the indicated patient population would likely tolerate a reduction in cardiac contractility to a greater extent than animals or humans with 'normal' cardiac contractility.”
CarcinogenicityCriticised but acceptedBeyond the letter
High mortality in the 104-week rat carcinogenicity study forced early termination of dose groups
Why: Transgenic mouse data and totality of evidence indicate low carcinogenic potential · Weight of evidence
“The high mortality in the 104-week carcinogenicity necessitated early termination of dose groups.”
“The transgenic mouse data did not suggest carcinogenic risk and the available data does not suggest involvement of aficamten in pro-oncogenic pathways. Overall, the totality of evidence is sufficient to suggest that aficamten has a low carcinogenic potential.”
DARTQuestioned
Rabbit EFD study limited to maternally toxic exposures below the MRHD; considered insufficient
Why: Maternal toxicity limited exposures to below the MRHD
“When aficamten was administered orally in an embryo-foetal toxicity study in the rabbit, increases in the number of late resorptions were observed at maternally toxic exposures below the MRHD. As such this study is considered insufficient.”
Impurity or metaboliteAcceptedBeyond the letter
No dedicated carcinogenicity study for major metabolite M1a, covered at only 0.5-fold exposure in the 2-year rat study
Why: M1a non-genotoxic, no concerning signals in rodent studies; minimal carcinogenic risk by weight of evidence · Weight of evidence
“The 2-year rat study, which reached 0.5-fold exposure, similarly demonstrated no concerning signals. Furthermore, M1a was determined to be non-genotoxic based on a comprehensive battery of assays and weight-of-evidence evaluation. Collectively, these data indicate minimal carcinogenic risk for this metabolite, therefore, we conclude that a dedicated carcinogenicity study is not warranted.”
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