CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`214998Orig1s000
`
`NON-CLINICAL REVIEW(S)
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration
`
`
`
`Memorandum
`
`
`
`Division of Pharmacology/Toxicology
`Office of Cardiology, Hematology, Endocrinology, & Nephrology
`Center for Drug Evaluation and Research
`
`NDA SECONDARY REVIEW
`
`
`
`
`
`
`
`Date: 5 October 2021
`NDA # 214998
`Applicant: MYOKARDIA INC
`Drug: Mavacamten (cardiac myosin inhibitor)
`Primary Reviewer: Gowra Jagadeesh, Ph.D
`Secondary Reviewer: Xuan Chi, Ph.D.
`
`
`MyoKardia INC is seeking market approval for mavacamten, proposed trade name CAMZYOS,
`as a treatment option for symptomatic obstructive hypertrophic cardiomyopathy (HCM) in
`adults. HCM is a genetically determined cardiac muscle disease most often caused by mutations
`in one of several sarcomere genes. The hallmark of HCM is left ventricular hypertrophy and
`hypercontractility accompanied by reduced left ventricular compliance. Mavacamten is a small
`molecule inhibitor of cardiac myosin. It reversibly inhibits the binding of cardiac myosin to
`actin, stabilizing this off-actin state and reducing the number of myosin motors engaging the
`actin filament. This results in reduced aggregate contractile force during cardiac systole and
`reduced residual cross-bridges during diastole, providing a mechanistic basis to reduce
`contractility, and improve diastolic relaxation as well as outflow tract obstruction in patients with
`HCM. Mavacamten would be a first-in-class cardiac myosin inhibitor, should it be approved. We
`agree with using “cardiac myosin inhibitor” as the Established Pharmacologic Class (EPC) for
`mavacamten, as this term is supported by the mechanism of action of the drug, and it is clinically
`meaningful and scientifically valid.
`
`Dr. Jagadeesh, the primary nonclinical reviewer, concludes that the pharmacology and
`toxicology data support approval of mavacamten. I concur with Dr. Jagadeesh’s assessment.
`
`The mechanism of action of mavacamten has been demonstrated by in vitro, ex vivo and in vivo
`pharmacology studies in multiple species, including healthy animals, animal models of HCM and
`purified recombinant proteins of human HCM mutations. 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. The
`pharmacologically active dose (PAD) obtained from a single oral dose study in telemetered
`healthy rat was 1 mg/kg/day, which reduced fractional shortening (FS) by approximately 20%. In
`the dog, 0.045 mg/kg mavacamten for 31 days produced approximately 11% reduction in FS.
`
`In the toxicology studies, mavacamten elicited expected pharmacological effects from inhibiting
`cardiac myosin, demonstrated by dose-dependent reduction in cardiac contractility culminating
`in cardiac failure or unintended deaths. Mortalities occurred at progressively lower doses with
`longer study durations. Additional findings in other organs were mostly secondary effects of
`
`
`
`Reference ID: 4867579
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`1
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`

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`heart failure. 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. It is
`uncertain whether pharmacological activity was present at these NOAEL doses, though a
`reduction in FS or ejection fraction of less than 10% may have been present in both species. At
`the highest doses, which are in fact similar to or lower than clinical exposures, unequivocal
`reductions were observed in cardiac contractility consistent with the intended pharmacologic
`effect of mavacamten, which was tolerated in dogs but lead to heart failure-related deaths in rats
`over a chronic period. Ejection fractions were reduced ~30% in both rats and dogs at this highest
`dose level. There is a narrow therapeutic window between the NOAEL and higher doses that
`substantially impacted cardiac contractility; in general, pharmacologically active doses largely
`overlap with doses that produce some toxicities. The dog seems to be the more sensitive species
`to the toxic effects of mavacamten, as the drug has higher bioavailability (87.1%) and longer
`half-life (161 h) in this species.
`
`Accumulation of the study drug was noted with repeated daily oral dosing, with accumulation
`ratios up to 2.8-fold in rats and 9-fold in dogs. The elimination half-life (t1/2) was long for dogs
`(161 h) and relatively short for rats (8 h), after a single oral administration. The slow rise in drug
`concentration due to accumulation appeared to allow dogs to tolerate the cardiac effects of
`mavacamten at a level that was less tolerated if experienced upon acute exposure. This suggests
`an active process of compensation might occur as concentrations of mavacamten increase toward
`a steady state.
`
`Mavacamten was found to be teratogenic in both rats and rabbits at clinically relevant exposures
`based on the maximum recommended human dose (MRHD, 15 mg/day). In all toxicity studies
`(except carcinogenicity studies), plasma exposure (Cmax and AUC) at the NOAEL is lower than
`that in humans at the MRHD (Table 1), suggesting potential risk at the therapeutic dose range.
`
`
`The following summarizes key issues that arose during review of the nonclinical program of
`mavacamten.
`
`Cardiac effects
`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. Cardiac toxicity resulting in heart
`failure and death was noted at maximum plasma concentrations of 725 ng/ml (at a dose of 1.2
`mg/kg/day in 26-week toxicity study, with an exposure margin of 0.8-fold relative to that in
`human at MRHD) in rats and 911 ng/ml in dogs (at a dose of 0.45 mg/kg/day in 13-week toxicity
`study, with an exposure margin of 0.8 to 1.1-fold relative to that in human at MRHD). The
`cardiac toxicities were exemplified by markedly decreased blood pressure, elevated plasma
`levels of NT-proBNP, greater absolute and relative heart weights, and echocardiogram findings
`of increased heart size and reduced systolic functions. Histopathology findings of note included
`myocardial degeneration, inflammation and/or hypertrophy, endocardial degeneration and
`necrosis, osseous metaplasia of cardiac muscles, atrial thrombus, and dilation. The toxicities
`observed in other organs (e.g., pulmonary edema, liver congestion with centrilobular necrosis,
`pancreatic edema, pre-renal azotemia) were secondary effects of cardiac failure. All these
`findings were reversible except for partial reversibility in the heart histopathology.
`
`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. However, sustained exposure of rats and dogs to mavacamten (at levels producing
`2
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`Reference ID: 4867579
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`

`

`moderate to marked functional cardiac depression for at least 7 days) were accompanied by
`modest (P <0.05) and reversible QTc prolongation, at lower exposure (0.3 to 0.4-fold) than in
`human at the MRHD (Table 1). This was speculated to be an electrophysiological adaptive
`response to sustained myosin inhibition in ventricles, which seems plausible.
`
`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. A plot between measured plasma concentrations and FS in rats
`show a non-linear but dose-dependent FS with no plateau in effect, posing a risk of fast
`deterioration of cardiac contractility as exposures
`increase.
`Interpretation of
`the
`exposure/response demonstrated in the nonclinical studies needs to consider the following key
`considerations when assessing human risk: firstly, mavacamten is slightly more potent in rats
`and dogs compared to humans (~2-fold based on IC50), suggesting a potential rightward shift in
`exposure/response in human subjects, and secondly, the indicated patient population has a
`hypercontractile myocardium and would likely tolerate a reduction in cardiac contractility to a
`greater extent than in animals or humans with ‘normal’ cardiac contractility. Thus, while the
`nonclinical studies clearly demonstrate that mavacamten is capable of disrupting myosin/actin
`interactions in a dose- and time-dependent manner that, in excess, can precipitate heart failure, a
`broader therapeutic window may be present in the intended patient population.
`
`Reproductive effect
`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. In rabbits, increased
`incidences of cleft palate, great vessel malformations (dilatation of pulmonary trunk and/or aortic
`arch), and fused sternebrae in fetuses were observed at the same doses that caused maternal
`toxicity. Based on these data, mavacamten has a high likelihood of being a teratogen when
`administered during gestation in humans. It is not known whether mavacamten is secreted into
`the milk. Mavacamten did not affect fertility of male or female rats or the fertility of F1 offspring
`of female rats dosed with mavacamten during gestation. Plasma exposures in all reproductive
`toxicology studies at the NOAEL is lower than those in humans at the MRHD (Table 1).
`
`
`
`
`Reference ID: 4867579
`
`3
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`

`

`Table 1. A summary of exposure margins basedonpivotal toxicology studies with mavacamten.
`Animal to human exposureratios is calculated based on MRHD of 15 mg/day
`(Adopted from the primary Pharmacology and Toxicology Review by Dr. Jagadeesh)
`
`Species,
`
`PK data-Tox study
`
`Multiple,
`
`
`
`
`
`study Parameter|CmaxSignificant findings AUC
`
`
`
`
`
`eeePeesagi|engin||YS
`etEF—20 [ee670 [|[|
`of insystolicfunctionPoNOEL|012K12X|0.08X09X
`week? peintervaleeee388 es6220 ae40X al37X
`3/39-
`
`Deaths from HF, extensive
`increase in heart size and a
`
`10700
`
`0.80X
`
`0.63 X
`
`0.22
`0.30X
`F 3800
`F 288
`
`Cardiac toxicity (severe M1040°|M 17200 1.10X 1.02X
`
`
`
`
`ventricular dilation) resulting F 782®|F 12300 0.81X 0.73X
`
`in heart failure. QTc interval
`prolongation*
`
`CarcinogenicityEYTO
`
`RasH2|M2 2230|Mrn 2.30x|1.78XNOAEL
`
`5gFertility
`
`developmentto implantation
`Embryo-fetal Development Toxicity
`
`Ral—[1S TeagenispotenBDHe|
`[0.75|Developmental___—_—‘[NOAEL|356[5690|0.40x|0.34X_
`[15[Matemal|NOAEL|108016500|1.12x|0.98X_
`
`
`Rabbi’ [12|Teratogenicpotenfial_—=—=—=——=«d|410016500|114X|O.98X_
`
`[0.6|Maternalanddevelopmental[NOAEL[516[7160|0.54x|O.42X_
`Pre- and Postnatal DevelopmentToxicity
`Fo Maternal, Fi:
`NOAEL
`1080
`developmental and
`reproductive, F2 embryonic
`
`0.98X
`
`1.12X
`
`Male and female combined mean Cmax and AUCO-24 values were used unless specified. M: male; F: female
`1: Based on EXPLORER-HCMstudy at a dose of 15 mg MYK-461 (mavacamten)/day for 10 days. Mean
`Cmax: 962 ng/ml, AUCo-24 16,891 h*ng/mL usedfor calculating exposure multiples (Sponsor communication).
`2: PK data measured on day 182
`3: PK data from 13-week study, measured on day 73 for males at 0.45 mg/kg/day and the rest on day 86.
`4: 39-week study: ECG evaluation showed prolongation (P <0.05) of QTcintervals in animals receiving = 0.18
`mg/kg/dayrelative to predose and control values. Echocardiogram evaluations indicated substantial increases
`in mean LV end-diastolic and a substantial reduction in mean LVejection fraction.
`5: Two males died/euthanized on days 70, 72
`6: One female euthanized on day 93
`7: TK measurements on day 182
`8: Exposure data in reproductive toxicity were based on gestation day 12
`9: At 1.5 mg/kg/day, increased post-implantation loss, altered fetal growth (such as lowerfetal body weight and
`reduced fetal ossification of bones (cervical and thoracic vertebrae and), visceral (heart) malformations and
`skeletal malformations were observed.
`10: Plasma concentrations of MYK-461 were not assessedin this study. Exposure multiples were based on the
`PK data in Embryo-fetal developmentstudyin rats.
`
`Reference ID: 4867579
`
`

`

`
`Pregnancy and Lactation
`Mavacamten was shown to cause visceral and skeletal malformations in both rats and rabbits and
`to increase post-implantation loss in rats, when administered during organogenesis at exposures
`close to the MRHD. In rats, the embryofetal toxicities were observed in the absence of maternal
`toxicities, while in the rabbits, they were concurrent with maternal toxicities.
`
`Due to the severity of these findings and their presence in two species at exposures close to that
`at MRHD, the primary reviewer and I both consider these findings informative of human risk
`and should be disclosed in the drug label, under Section 8.1 as part of the Risk Summary and
`Animal Data, as well as under Section 5.4 “Fetal Toxicity” as part of the Warmings and
`Precautions.
`
`The suggested language relevant to embryofetal toxicities in Section 5.4 and 8.1 of the drug label
`are included below:
`
`
`
`Reference ID: 4867579
`
`5
`
`(b) (4)
`
`

`

`Genotoxicity and Carcinogenicity
`A standard battery of genotoxicity studies (Ames assay, in vitro chromosome aberration assay in
`human lymphocytes, and in vivo rat micronucleus assay in bone marrow) were all negative. A
`26-week oral gavage carcinogenicity study was conducted in the RasH2 transgenic mouse to
`determine the carcinogenic potential of mavacamten and the results show that there were no
`drug-related neoplasms in either males or females in this study. This conclusion was concurred
`by CDER Executive Carcinogenicity Assessment Committee and is included in Section 13.1 of
`the drug label.
`
`The Division has agreed the 2-year rat carcinogenicity study can be completed post-approval and
`the study is currently ongoing.
`
`The suggested language under Section 13.1 of the drug label related to genotoxicity and
`carcinogenicity is included below:
`
`
`
`Reference ID: 4867579
`
`6
`
`(b) (4)
`
`(b) (4)
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`XUAN CHI
`10/05/2021 09:46:46 AM
`
`TODD M BOURCIER
`10/05/2021 09:56:53 AM
`I concur with Dr. Chi's conclusions and recommendations.
`
`Reference ID: 4867579
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`Applicant:
`Review Division:
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`Date of review
`Submission:
`
`214998
`0001, 0034
`January 28, 2021
`January 28, 2021
`Mavacamten (CAMZYOS®)
`Treatment of symptomatic obstructive
`hypertrophic cardiomyopathy
`MyoKardia Inc
`Pharmacology and Toxicology, OCHEN, OND
`G. Jagadeesh, Ph.D.
`Xuan Chi, Ph.D.
`Todd Bourcier, Ph.D.
`Alexis Childers
`
`September 22, 2021
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and necessary for approval of
`NDA 214998 are owned by MyoKardia Inc. or are data for which MyoKardia Inc., has obtained a written
`right of reference.
`Any information or data necessary for approval of NDA 214998 that MyoKardia does not own or have a
`written right to reference constitutes one of the following: (1) published literature, or (2) a prior FDA
`finding of safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data
`or information described or referenced below from reviews or publicly available summaries of a previously
`approved application is for descriptive purposes only and is not relied upon for approval of NDA 214998.
`
`Reference ID: 4860971
`
`1
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`

`

`NDA #214998
`
`
`
`
`Reviewer: G. Jagadeesh
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ............................................................................................ 13
`1.1
`INTRODUCTION (AND CLINICAL RATIONALE)............................................................. 13
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ....................................................... 14
`1.3
`RECOMMENDATIONS............................................................................................... 15
`1.3.1
`Approvability ................................................................................................. 15
`1.3.2
`Additional Non-Clinical Recommendations................................................. 15
`1.3.3
`Labeling ........................................................................................................ 15
`2 DRUG INFORMATION ............................................................................................... 16
`2.1
`DRUG ..................................................................................................................... 16
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS ............................................................ 16
`2.3
`DRUG FORMULATION .............................................................................................. 16
`2.4
`COMMENTS ON NOVEL EXCIPIENTS......................................................................... 16
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 16
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 17
`2.7
`REGULATORY BACKGROUND .................................................................................. 17
`3 STUDIES NOT REVIEWED ....................................................................................... 18
`
`4 PHARMACOLOGY ..................................................................................................... 19
`4.1
`PRIMARY PHARMACOLOGY ..................................................................................... 19
`4.1.1. In vitro studies ................................................................................................... 19
`4.1.1.1 Inhibition of myosin in various species and selectivity for cardiac versus
`skeletal forms of myosin by MYK-461........................................................................ 19
`4.1.1.2 Effects of MYK-461 In loaded and unloaded in-vitro motility assays .......... 24
`4.1.1.3 Effects of MYK-461 on the super-relaxed state of cardiac myosin ............. 26
`4.1.1.4 Effects of MYK-461 on the Pi release and ATPase rates of cardiac myosin
`...................................................................................................................................... 28
`4.1.2. Ex vivo studies .................................................................................................. 29
`4.1.2.1 Effects of MYK-461 on the Pi release and ATPase rates of cardiac myosin
`...................................................................................................................................... 29
`4.1.2.2 Effects of β-adrenergic receptor stimulation on MYK-461-induced functional
`depression of primary ventricular myocytes from healthy rats ................................. 32
`4.1.2.3 Effects of stretch and β-adrenergic receptor blockade on the cardiac effects
`of MYK-461 in isolated rat hearts ............................................................................... 34
`4.1.2.4 Biomechanical effects of MYK-461 in skinned ventricular muscle fibers
`from healthy animals ................................................................................................... 36
`4.1.2.5 Biomechanical effects of MYK-461 in skinned ventricular muscle fibers with
`pathogenic HCM mutations ........................................................................................ 39
`4.1.2.6 Functional effects of MYK-461 on human induced pluripotent stem cell
`derived cardiomyocytes .............................................................................................. 41
`4.1.3. In vivo studies ................................................................................................... 43
`4.1.3.1 Pharmacodynamic study of single oral dose of MYK-461 to mice.............. 43
`
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`NDA #214998
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`
`
`
`Reviewer: G. Jagadeesh
`
`4.1.3.2 Acute and chronic effects of myosin inhibition on mouse models of thin-
`filament pathogenic troponin mutations ..................................................................... 46
`4.1.3.3 Pharmacodynamic study of single oral dose of MYK-461 to rats ............... 48
`4.1.3.4 Effects of dobutamine and levosimendan on cardiac performance on
`depressed ventricular performance induced by MYK-461 in rats............................. 55
`4.1.3.5 Acute and chronic effects of MYK-461 on cardiac performance and
`hemodynamics in conscious dogs.............................................................................. 58
`4.1.3.6 Cardiovascular effects of a single oral dose of MYK-461 in dogs .............. 62
`4.2
`SECONDARY PHARMACOLOGY ................................................................................ 69
`4.3
`SAFETY PHARMACOLOGY ....................................................................................... 70
`4.3.1. Effect of MYK-461 on hERG channels expressed in HEK293 cells ............. 71
`4.3.2. Effect of single dose of MYK-461 on cardiovascular and respiration in
`telemetered dogs......................................................................................................... 73
`4.3.3. Effects of repeat doses of MYK-461 on cardiovascular performance and
`ECG in telemetered dogs............................................................................................ 77
`4.3.4. Effect of MYK-461 on CNS function in male rats ........................................... 80
`4.3.5. Effect of MYK-461 and its metabolite on cardiac ion channel currents
`expressed in HEK293 cells ......................................................................................... 81
`4.3.6. Effect of MYK-461 and its metabolite on action potential parameters in
`isolated rabbit Purkinje fibers ..................................................................................... 83
`4.3.7. In vitro and in silico electrophysiological evaluation of MYK-461 and its
`metabolite .................................................................................................................... 84
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS ................................................. 88
`5.1
`ABSORPTION .......................................................................................................... 88
`5.1.1
`Pharmacokinetics of MYK-461 following a single intravenous or oral
`administration across species .................................................................................... 88
`5.2. DISTRIBUTION ............................................................................................................ 91
`5.2.1
`In vitro plasma protein-binding and blood to plasma ratio ......................... 91
`4.2.2
`Tissue distribution studies in rats ................................................................ 92
`4.3. METABOLISM ............................................................................................................. 96
`4.3.1
`In vitro CYP450 enzyme inhibition of MYK-461 in human microsomes .... 96
`4.3.2
`In vitro CYP450 enzyme inhibition of MYK-461 in human microsomes .... 98
`4.3.3
`In vitro evaluation of MYK-461 as an inhibitor of CYP450 ....................... 100
`4.3.4
`In vitro evaluation of MYK-461 as an inductor of CYP450....................... 101
`4.4. EXCRETION.............................................................................................................. 103
`4.4.1
`Pharmacokinetics, distribution, metabolism, and excretion of [14C]MYK461
`following oral or intravenous administration to male rats ........................................ 103
`6 GENERAL TOXICOLOGY ....................................................................................... 106
`6.1
`SINGLE-DOSE TOXICITY ....................................................................................... 106
`5.1.1 Exploratory tolerability of MYK-461 following a series of single oral gavage
`doses in dogs ............................................................................................................ 106
`6.2
`REPEAT-DOSE TOXICITY ...................................................................................... 108
`6.2.1 One-Week exploratory oral toxicity study in wild-type RasH2 mice............. 108
`6.2.2 One-month oral range-finding toxicity study in wild-type RasH2 mice ........ 110
`6.2.3 6-Week oral toxicity study in rats followed by a 4-week recovery period .... 115
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`NDA #214998
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`
`
`
`Reviewer: G. Jagadeesh
`
`6.2.4 Three-month oral toxicity study in rats followed by a 4-week recovery period
`.................................................................................................................................... 124
`6.2.5 26-Week oral toxicity study in rats followed by a 3-month recovery period. 140
`6.2.6 Six-week oral toxicity study in dogs with a 4-week recovery period ............ 150
`6.2.7. 3-Month oral toxicity study in dogs with an 8- or 11-week recovery ........... 160
`6.2.8. 39-Week oral toxicity study in dogs with a 17-week recovery..................... 171
`7 GENETIC TOXICOLOGY ......................................................................................... 180
`7.1
`AMES ASSAY. IN VITRO BACTERIAL MUTATION TEST OF MYK-461 .......................... 180
`7.2
`AMES ASSAY. IN VITRO BACTERIAL MUTATION TEST OF MYK-460 (ENANTIOMER OF
`MYK-461) ...................................................................................................................... 183
`7.3. IN VITRO MICRONUCLEUS TEST OF MYK-461 IN HUMAN LYMPHOCYTES .................... 185
`7.4. IN VITRO MICRONUCLEUS TEST OF ENANTIOMER MYK-460 IN HUMAN LYMPHOCYTES 189
`7.5. IN VIVO CLASTOGENICITY (MICRONUCLEUS) ASSAY OF MYK-461 IN RATS................. 193
`8 CARCINOGENICITY ................................................................................................ 197
`8.1
`SIX-MONTH ORAL GAVAGE CARCINOGENICITY STUDY OF MYK-461 IN RASH2
`TRANSGENIC MOUSE ........................................................................................................ 197
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 209
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT TO IMPLANTATION OF MYK-461 IN
`RATS 209
`9.2
`EMBRYO-FETAL TOXICITY STUDY OF MYK-461 IN RATS ......................................... 215
`9.3
`EMBRYO-FETAL TOXICITY STUDY OF MYK-461 IN RABBITS .................................... 222
`9.4
`PRE- AND POSTNATAL DEVELOPMENT TOXICITY STUDY OF MYK-461 IN RATS ........ 231
`10
`SPECIAL STUDIES .............................................................................................. 239
`10.1 THREE-MONTH ORAL TOXICITY STUDY IN RATS FOR MYK-461 IMPURITY
`QUALIFICATION................................................................................................................. 239
`10.2 ELECTROPHYSIOLOGICAL EFFECTS OF ACUTE AND CHRONIC EXPOSURE TO MYK-461
`
`244
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 258
`
`REFERENCES ...................................................................................................... 273
`
`APPENDIX/ATTACHMENTS ............................................................................... 275
`
`12
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`13
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`Reference ID: 4860971
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`NDA #214998
`
`
`
`
`Reviewer: G. Jagadeesh
`
`Table of Tables
`
`
`Table 1. Ingredients, quality standards, pharmaceutical functions, unit compositions for
`mavacamten capsules ........................................................................................................ 17
`Table 2. Half-maximal inhibitory concentrations (IC50 mean, μM ± SD) of MYK-461 on
`the ........................................................................................................................................ 20
`Table 3. Half-maximal inhibitory concentrations (IC50 mean, μM ± SD) of MYK-461 on
`the ........................................................................................................................................ 22
`Table 4. Summary of actomyosin dose responses on recombinant human cardiac
`myosin (apparent IC50, mean, μM ± SD) .......................................................................... 22
`Table 5. Concentration dependent effects in the presence of MYK-461 (Average ± SD,
`n = 3-8 cells per concentration) in cardiac myocytes........................................................ 30
`Table 6. Isoproterenol countering the effect of MYK-461 (Mean ± SD) ......................... 31
`Table 7. Effects of MYK-461 on isometric tension development in skinned ventricular
`fibers from rat and pig at varying calcium concentrations ................................................ 37
`Table 8. Cardiac effects of MYK-461 (mavacamten) (single oral dose) in healthy mice
` ............................................................................................................................................. 45
`Table 9. Cardiac effects of acute myosin-inhibition with MYK-581 in WT and cTnI
`R193H transgenic mice ...................................................................................................... 47
`Table 10. Cardiac effects of chronic myosin-inhibition with MYK-461 in cTnT R92W
`transgenic mice ................................................................................................................... 47
`Table 11. Cardiac effects of chronic myosin-inhibition with MYK-461 in cTnT R92L
`transgenic mice ................................................................................................................... 48
`Table 12. Cardiac effects of MYK-461 (single oral dose) in conscious healthy rats...... 51
`Table 13. Acute hemodynamic effects of MYK-461 in conscious telemetered healthy
`rats ....................................................................................................................................... 53
`Table 14. Left-ventricular responses to MYK-461 (Mava, 4 mg/kg PO) in healthy rats 56
`Table 15. Acute effects of dobutamine (DOB) on the MYK-461-induced functional
`cardiac depression in healthy rats ..................................................................................... 56
`Table 16. Acute effects of levosimendan (LEVO) on the MYK-461-induced functional 56
`Table 17. Acute and chronic cardiovascular effects of MYK-461 in conscious healthy
`dogs ..................................................................................................................................... 61
`Table 18. Acute hemodynamic and cardiac effects of MYK-461 in conscious dogs at 3
`hr post dose (average of both studies) .............................................................................. 63
`Table 19. Acute hemodynamic and LV effects of MYK-461 and metoprolol in dogs...... 65
`Table 20. Acute electrocardiographic effects of MYK-461 in dogs .................................. 68
`Table 21. Pharmacokinetic parameters of MYK-461 and MYK-460 following a single
`oral dose of 10 mg/kg MYK-461 upon completion of the telemetry data collection (after
`day 30)................................................................................................................................. 76
`Table 22. Study design ....................................................................................................... 77
`Table 23. Chronic electrocardiographic and mechanical effects of MYK-461 in healthy
`dogs (14-day repeat-dose study) .................