MyosinModulator(Mavacamten):

ANovelOralTreatmentforObstruc;veHCM

Mar;nMaron,MDDirector,HypertrophicCardiomyopathyCenter

TuBsMedicalCenter;ChaninT.MastHypertrophicCardiomyopathyCenter

MorristownMedicalCenter,NJ

Disclosure:ConsultantMyoKardia

DrugTherapyinHCM

1.  Beta-Blockers(Braunwald)………19642.Verapamil(Kaltenbach)…………..19793.Disopyramide(Pollick)…………….1982

NoNewDrugTherapyforHCMfor35Years

• AngiotensinIIInhibitors• AldosteroneInhibitors• LateNaChannelInhibitors• MetabolicModulator• MyosinModulator

RecentInves;ga;onalPharmacologicTrialsinHCM:

✖✖

✖✖

OralMyosinModulator(Mavacamten)“PrecisionMedicine”

•  DrugBindstothe“off-ac;n”stateofMyosin…interruptsMyofilaments•  DecreasepowerStrokeofcontrac;on

Mavacamten:DecreasesSystolicFunc;on(LowersEF)“Nega;veInotrope”

Poten;alTreatmentforObstruc;veHCM

MavacamtenIni;a;ve:

1.PhaseI(SafetyandTolerability)2.PIONEER-HCM(PhaseII)3.Explorer-HCM(PhaseIII)

MavacamtenIni;a;ve:

1.PhaseI(SafetyandTolerability)2.PIONEER-HCM(PhaseII)3.Explorer-HCM(PhaseIII)

PIONEER-HCM(OpenLabel)•  n=11

•  56yearsold(22-70years)

•  NYHAclassII(n=7);NYHAClassIII(n=4)

•  RestEF=70±7%

•  RestLVOTGradient=68±34mmHg

•  Mavacamten10or15mgfor12weeks(OffBBorCCB)

•  PrimaryEnd-point=GradientReduc;on

n=10(oneSAE)

55 40

70±7 55±13Ejec;onFrac;on

(%)

Baseline

68±34 14±28RestLVOT

Gradient(mmHg)

12Week

ConcordantChangeinRes;ngLVOTGradientandEF(n=10)

15%

HeitnerSetalHFSA2017

60 45

SignificantPropor;onofHCMPa;ents:

•  EF≤42%(OneSD)•  EF≤29%(TwoSD)

“PowerfulDrug”

7 2

3 1

Baseline

2

3

12Week

1

NYHAClass

0 75

22

1

3outof10(30%)NoImprovementinSymptoms

ChangeinNYHAFunc;onalClass(n=10)

HeitnerSetalHFSA2017

# of events # assessed related to study drug

# of patients

Headache 4 1 4

LVEF Reduction 3 3 3

Atrial Fibrillation 2 1 2

Dizziness 2 0 1

Dyspnea Exertional 2 1 2

Fatigue 2 0 2

Peripheral Edema 2 2 1

Rash 2 0 2

PIONEER-HCM:SafetyNon-SeriousAE

SeriousAE

OnePa;entRecurrentAF(2x)requiringDCCVandAn;arrhythmicTxPa;entElectedtoStopMavacamtenatWeek4

HeitnerSetalHFSA2017

ChangeinPeakVO2at12Weeks

0

5

10

15

20

25

30

20 24

PeakVO

2max(m

l/kg/m

in)

p=0.004

Baseline 12WeeksHeitnerSetalHFSA2017

MavacamtenIni;a;ve:

1.PhaseI(SafetyandTolerability)2.PIONEER-HCM(PhaseII)3.Explorer-HCM(PhaseIII)

Explorer-HCM

n=~200-250obstrucEveHCMptsPrimaryEnd-Point=peakVO2

0

10

20

30

40

50

60

70

80

BaselineGradient

GradientABerTx

DisopyramideΔEF=ê5-10%

MyectomyΔEF=None

MavacamtenΔEF=ê

ΔEF=<15% ΔEF=≥15%

Rela;onBetweenEjec;onFrac;on(Contrac;lity)andGradientReduc;oninHCM

LVOTGradien

t(mmHg

)

Benefit~95%

40

Benefit~60%

7574

5

YouCanObliterateGradientswithaDrug,ButatWhatCost?...

Dura;onofTimeonDrug(PhaseIII):~6-12months

AverageDura;onofTimeonDrug(Ifapproved):~>30years

Long-termEffectsofManipula;ngStructuralApparatusoftheHCMHeart?

45yrs

55yrs 65yrs 75yrs

~150,000HCMPa;entsinU.S.

~100,000Obstruc;veHCMPts.

~20,000HCMPtsonMavacamtenwithEF<42%

(Avg.ageof45years)

Poten;alImpactofMavacamtenonEFinUSHCMPopula;on(Ifapproved)

MavacamteninObstrucEveHCM

•  NoveloralmyosininhibitorshowingpromisingearlydatademonstraEngefficacyatloweringouTlowtractgradientsandpotenEallyimprovingfuncEonalcapacity

•  AwaiEngcompleEonoflargerrandomizedstudiestoinformshorttermefficacyandbothshortandlongertermsafety

INTERNATIONAL HCM SUMMIT

#HCMSummitVI

INTERNATIONAL HCM SUMMIT

Boston, MA October 2017

HYPERTROPHIC CARDIOMYOPATHY A Contemporary and Treatable Genetic Disease: Diagnosis, Heart Failure Management, and Prevention of Sudden Death