Milind Y Desai MD MBA Haslam Family Endowed Chair in Cardiovascular Medicine - PowerPoint Presentation

Slide1

Milind Y Desai MD MBAHaslam Family Endowed Chair in Cardiovascular Medicine Professor of Medicine, CCLCMDirector, Hypertrophic Cardiomyopathy CenterHeart, Vascular & Thoracic Institute

Myosin Inhibition to Defer Surgical Myectomy or Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy

Results of the VALOR-HCM Trial

Disclosures: Dr. Desai is a consultant for Bristol Myers Squibb and Medtronic

The VALOR-HCM study was funded by

MyoKardia, Inc., a wholly owned subsidiary of Bristol Myers Squibb

On behalf of the VALOR-HCM investigators

Trial Leadership

Executive Steering Committee

Steven E. Nissen MD MACC (Chair)

Jeffrey

Geske

MD

Anjali Owens MD

Hartzell Schaff MD

Srihari Naidu MD

Nicholas Smedira MD MBAAmy Sehnert MD (non-voting) Jay Edelberg MD PhD (non-voting)Cleveland Clinic Center for Clinical ResearchChristina Sewell RNEllen Mc Erlean RN MSNPaul Cremer MD MSKathy Wolski MPHMyoKardia, Inc., a wholly owned subsidiary of Bristol Myers SquibbKathy Lampl MDWanying Li PhDLulu Sterling PhD

Milind Y. Desai MD MBAPrincipal Investigator

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by primary left ventricular (LV)

hypertrophy.

Prevalence: 1:200 to 1:500, Estimated 15-20 million

worldwide.

Two-thirds of patients have obstructive HCM (

oHCM

).

Symptoms are typically related to dynamic LV outflow tract (LVOT)

obstruction.

Ommen S, Mital S et al. J Am Coll Cardiol. 2020 Dec 22;76(25) Maron B, Desai M et al. J Am Coll Cardiol. 2022 Feb 1;79(4):372-389

Obstructive HCM

Current medical therapies not developed specifically for

HCM.

Septal reduction therapies (SRT), either surgical septal myectomy or alcohol ablation, are recommended for patients with intractable symptoms despite maximal medical therapy.

Although SRT improves long-term survival, symptoms and quality of life, optimal results require specialized care not widely available.

Accordingly, there is an unmet need for noninvasive alternatives to SRT for highly symptomatic

oHCM

patients.

Ommen S,

Mital

S et al. J Am Coll Cardiol. 2020 Dec 22;76(25):e159-e240Maron B, Desai M et al. J Am Coll Cardiol. 2022 Feb 1;79(4):390-414Desai M Smedira N et al. Circulation. 2013 Jul 16;128(3):209Desai M, Smedira N et al. JAMA Network Open (in press)

Mavacamten: Mechanism of Action

Reduces myosin-actin cross bridges

To attenuate hypercontractility and

improved compliance and energetics

Normal contractility

Effective relaxation

Mavacamten

, a targeted inhibitor of cardiac myosin,

decreases

the number

of myosin-actin cross-bridges and reduces excessive contractility characteristic of HCMIn oHCM, improves LVOT gradient, QOL and physical functioningOlivotto et al. Lancet. 2020 Sep 12;396(10253):759-769.Spertus J et al. Lancet. 2021 Jun 26;397(10293):2467-2475Hyper contractilityImpaired relaxationAltered myocardial energetics

Primary Objective

VALOR HCM sought to determine if addition of mavacamten

to maximally-tolerated medical therapy would allow severely symptomatic

oHCM

patients to improve sufficiently that they no longer

met guideline criteria for SRT or chose not to undergo SRT for 16 weeks

Gersh et al. HCM Guidelines. J Am Coll Cardiol. 2011 Dec 13;58(25):e212-60

VALOR-HCM Study Design (19 US HCM Centers)

.

.

Desai M et al. Am Heart J 2021 Sep;239:80-89

Starting dose

5 mg QD

10 mg, 5 mg,

2.5 mg15 mg, 10 mg,5 mg, 2.5 mgRandomizedn=112Mavacamten titrated using core-lab measured ECHO LVEF and LVOT gradient at rest and Valsalva provocationTitration at weeks 8 and 12EchoEchoEcho, Stress Echo and SRT EvaluationDouble-Blind Placebo-Controlled Treatment (16 weeks)BaselineScreening 2 weeksMavacamten (n=56)2.5, 5, 10, or 15 mg once a dayPlacebo (n=56)8 Weeks

4 Weeks

12 Weeks

Echo

Stress

SRT Evaluation

16 weeks

Echo

Key inclusion criteriaAge ≥18 yearsDocumented HCM with maximum septal wall thickness ≥15 mm or ≥13 mm with family history of HCM (determined by a core echo laboratory)

Severe symptoms despite maximally-tolerated medical therapyNYHA functional Class III/IV or Class II with exertional syncope or near

syncopeMaximal medical HCM therapy could include

disopyramide and/or combination beta blockers and calcium channel blockersDynamic

LVOT gradient at rest or with provocation (Valsalva maneuver or exercise) ≥50 mmHgDocumented LV ejection fraction ≥60%

Must have been referred within the past 12 months for SRT and actively considering scheduling the procedurePatients could elect to proceed to SRT at any time following randomization

Desai M et al. 2021 Sep;239:80-89

Primary and Secondary EndpointsPrimary endpoint: Composite of patient decision to proceed with SRT or continue to meet 2011 ACC/AHA

guideline eligibility for SRT after 16 weeks.Five secondary endpoints tested in a hierarchical fashion, comparing Week 16 to baseline:1) Change in post-exercise LVOT gradient

2) Number of patients with a ≥1 class of NYHA improvement

3) Change in KCCQ clinical summary score4) Change in NT-

proBNP5) Change in Troponin I

Gersh et al. HCM Guidelines. J Am Coll

Cardiol. 2011 Dec 13;58(25):e212-60

Mavacamten

(n=56)

Placebo (n=56)

Age

59.8 years

60.9 years

Female

sex

48.2%50.0%Family history of HCM30.4% 26.8%NYHA Class III or higher92.9% 92.9%Type of SRT recommended Myectomy Alcohol septal ablation48 (85.7%)8 (14.3%)49 (87.5%)7 (12.5%)Medical therapy Beta Blocker monotherapy n(%) Nondihydropyridine CCB monotherapy Combination therapy26 (46.43%)7 (12.50%)20 (35.7%)25 (44.64%)10 (17.86%)16 (28.5%)Resting LVOT Gradient51.2 mmHg

46.3

mmHg

Post-exercise Gradient

82.5 mmHg

85.2 mmHg

Results: Baseline Characteristics

22

(20%) were on

disopyramide

(mono or combination therapy)

Parameters

Mavacamten

(N=56)

Placebo

(N=56)

Treatment

Difference (95% CI)

p-value

Composite of:

Decision to proceed with SRT by Week 16 or guideline eligible at Week 16

n/N (%)10/56 (17.9)43/56 (76.8)58.93 (43.99,73.87) P <0.0001Proceeded with SRT by Week 16 n(%)2 (3.6)2 (3.6)SRT guideline eligible at Week 16 and did not proceed with SRT n(%)8 (14.3)39 (69.6)SRT status not evaluable(imputed as meeting criteria) n(%)0 (0.00)2 (3.6)Primary Endpoint ITT Population

Patients who Underwent SRT

or Remained Guideline Eligible for SRT

Patients Who Improved

by 0, ≥1, or ≥2 NYHA Class

Primary Endpoint and NYHA Class Improvement

Secondary Efficacy Endpoints:

Change in LVOT Gradient at Rest and ValsalvaResting LVOT

gradient (mm Hg)

Valsalva LVOT gradient (mm Hg)

All p < 0.001

Resting LVOT gradient difference

-33.4 mm Hg (95% CI, -42.3, -24.5)

51±19

46±30

46±29

14±9Valsalva LVOT gradient difference-47.6 mm Hg (95% CI, -58.2, -37.0)28±2178±3175±3176±30

Safety and Secondary Efficacy Endpoints:

LV Ejection Fraction and KCCQ Change Over Time

LV Ejection Fraction (%)

KCCQ-23 Clinical Summary Score

p < 0.001

KCCQ-23 CSS difference

9.4 (95% CI, 4.9, 14.0)

p = ns

LV ejection fraction difference

-4.0 % (95% CI, -5.5, -2.5)

68±468±468±365±780±1867±1966±2070±16

Secondary Efficacy Endpoints: NT-Pro BNP and Troponin I Changes Over Time

All p < 0.001

735.8 (95% CI 519.2, 1042.8)

629.2 (95% CI 462.8, 855.2)

537.6 (95% CI 393.4, 734.7)

251.0 (95% CI 181.4, 347.2)

735.8 (95% CI 519.2, 1042.8)

Troponin I geometric mean ratio difference

0.53 (95% CI, 0.41, 0.70)

17.09 (95% CI 12.18, 23.97)

13.75 (95% CI 10.34, 18.28)13.39 (95% CI 10.19, 17.60)8.51 (95% CI 6.12, 11.83)

Mavacamten

(n=56)

Placebo (n=55)

Ejection Fraction <50%

2 (3.6%)

0 (0%)

Atrial Fibrillation

2 (3.6%)

0 (0%)

Nonsustained VT0 (0%)5 (9.1%)Chest Pain2 (3.6%) 3 (5.5%)Fatigue 5 (8.9%) 2 (3.6%)Nausea 4 (7.1%) 1 (1.8%)Headache2 (3.6%)5 (9.1%)Rash 4 (7.1%)0 (0%)Selected Adverse Events in Safety PopulationNo subjects experienced SAEs of CHF, Syncope, or Sudden Cardiac DeathNo permanent treatment discontinuations due to LVEF ≤30%

LimitationsPrimary endpoint driven by reduction in guideline eligibility for SRT

Duration of randomization 16 weeksWhether myosin inhibition can allow patients to avoid SRT during long term administration remains uncertain Long-term safety has not been determined

Effect of mavacamten

on life threatening arrhythmias and sudden death, not assessed Current

study included predominantly white patients treated at high-volume HCM centers with established SRT programs

ConclusionsIn oHCM patients with intractable symptoms, referred for SRT, administration of the cardiac myosin inhibitor,

mavacamten, titrated using echocardiography:Significantly reduced eligibility for invasive SRT procedures at 16 weeks (P<0.0001)

Showed treatment benefits for all secondary endpoints, all P<0.0001:Reduction in post-exercise LVOT gradient,

≥1 class improvement in NYHA Class Improvement in KCCQ-clinical summary score

Reduction in NT ProBNP

Reduction in troponin INo new safety signals observed

First evidence of concomitant use with disopyramide (20%)

Additional data is needed to assess the durability of improvement in SRT eligibility over longer time periods

AcknowledgementsVALOR HCM Site InvestigatorsM. Desai (Cleveland Clinic), J. Geske (Mayo Clinic-Rochester), M. Sherrid (New York University Langone Medical Center), A.T. Owens (University of Pennsylvania-Heart and Vascular Center), S. Saberi

(University of Michigan Cardiovascular Center), A. Wang (Duke University School of Medicine), M. Fifer (Massachusetts General Hospital), D. Fermin (Spectrum Health), N. Lakdawala (Brigham and Women’s Hospital), A. Masri (Oregon Health & Science University), M. Zenker (Saint Thomas West Hospital), J Stendahl (Yale University School of Medicine), M. Wheeler (Stanford University Medical Center), R. Bach (Washington University School of Medicine), J.

Orford (Intermountain Medical Center), S. Naidu (Westchester Medical Center), F. Rader (Cedars-Sinai Medical Center), P. Bajona

(Allegheny General Hospital), M. Desai and C Asher (Cleveland Clinic Florida-Weston)

Independent Data Monitoring Committee

Jean Rouleau MD (Chairman) Montreal Heart, Gary S. Francis MD University of Minnesota, Kenneth Mahaffey MD Stanford University, A.A. Afifi Ph.D. (statistician) UCLA School of Public Health.Axio, a Cytel Company: David Kerr MS (SDAC Biostatistician)

AcknowledgmentsC5Research Imaging Core Lab:

W Jaber MD, S Harb MD, A Flinn RDCS, A Borowski RDCS, J Drinko RDCS, A Kanta RDCS, M Martin RDCS, M Park RDCS, J Odabashian

RDCS, C McDowell, M

Baksar

, E Balazs.C5Research Stats: Qiuqing Wang MPH (statistician), Craig Balog MS (statistical programming support).Medpace Contract Research Organization: Richard Lee MD (Medical Monitor), James Creager BS (Clinical Trial Manager), Sophia Jung BS (Data Manager)Additional acknowledgements: Dr. Milind Desai acknowledges the contribution of his colleagues in the HCM center, Barbara Bittel, RN BSN and Susan Ospina MSN, CNP in the conduct of the trial.Our sincere thanks to all the patients who participated in the trial