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VALOR-HCM Study Design

VALOR-HCM: A Cutting Edge Trial for SRT-Eligible Adults With Symptomatic Obstructive HCM1,2

A second phase 3 randomized, double-blind, placebo-controlled trial that evaluated the efficacy and safety of CAMZYOS®2

2-week screening phase1,2

Select inclusion criteria1,2
  • Age ≥18 years
  • Diagnosis of obstructive HCM
  • NYHA class II with exertional syncope or near syncope or NYHA class III–IV
  • LVEF ≥60%
  • Guideline eligible for SRT, referred within 12 months, and actively considering the procedure*
  • LVOT peak gradient ≥50 mmHg at rest or with provocation
Select exclusion criteria3
  • Known infiltrative or storage disorder that mimics obstructive HCM
  • Planned invasive procedure during the first 32 weeks of the study
  • Any dose adjustment of background medication for obstructive HCM <14 days prior to screening or an anticipated change in regimen during the first 16 weeks of the study
  • Previously treated with invasive SRT or cardiotoxic agents
CAMZYOS(n=56)
Randomized 1:1 (N=112)1
Placebo(n=56)

16-week
treatment phase1-3

CAMZYOS and placebo were administered orally, once a day. Dosage was monitored and adjusted (as needed) at weeks 8 and 12 to optimize patient response (decrease in LVOT gradient with Valsalva maneuver) and maintain LVEF ≥50%

95% of patients were on background therapy of either BB, nondihydropyridine CCB, disopyramide, or combination therapy1,2CAMZYOS (n=53) | Placebo (n=53)
  • *SRT guideline eligibility was based on the 2011 ACC/AHA HCM guideline criteria.2,4
  • Includes Fabry disease, amyloidosis, or Noonan syndrome with left ventricular hypertrophy.3

ACC=American College of Cardiology; AHA=American Heart Association; BB=beta blocker; CCB=calcium channel blocker; HCM=hypertrophic cardiomyopathy; LVEF=left ventricular ejection fraction; LVOT=left ventricular outflow tract; NYHA=New York Heart Association; SRT=septal reduction therapy.

Primary composite endpoint1,2

The primary endpoint* was a composite of patients who:

Remained guideline eligible for SRT at week 16
OR
Decided to proceed with SRT prior to or at week 16

SRT eligibility criteria

NYHA class Il with exertion-induced syncope or near syncope

OR

NYHA class III or IV

AND

A dynamic LVOT gradient at rest or with provocation of ≥50 mmHg

Hierarchical secondary endpoints1‡:(from baseline to week 16)
  • Change in post-exercise LVOT peak gradient
  • Proportion of patients with ≥1 NYHA class improvement
  • Change in KCCQ-23–CSS
  • Change in serum concentration of NT-proBNP
  • Change in serum concentration of cardiac troponin I
Select prespecified exploratory endpoints2:(not powered for statistical significance)
  • Change in resting LVOT peak gradient
  • Change in Valsalva LVOT peak gradient

After 16 weeks, all patients, including those who received placebo, were offered the opportunity to transition into the active-controlled phase of VALOR-HCM and receive CAMZYOS. The vast majority (95%) of all patients, including 93% of those in the placebo group, chose to continue in this active phase of the trial rather than proceed with SRT.2

  • *Patients who discontinued treatment or whose response status could not be assessed at the end of the 16-week dosing period were classified as SRT eligible.2
  • SRT guideline eligibility was based on the 2011 ACC/AHA HCM guideline criteria.2,4
  • All assessments for secondary endpoints were performed and tested sequentially at a 2-sided alpha level of 0.05 hierarchical order (sequence as indicated above) upon achieving significance in the primary composite endpoint (with a 2-sided alpha level of 0.05 required to proceed).2

KCCQ-23–CSS=Kansas City Cardiomyopathy Questionnaire (23-item version) Clinical Summary Score; LVOT=left ventricular outflow tract; NT-proBNP=N-terminal pro B-type natriuretic peptide; NYHA=New York Heart Association.

Current ACC/AHA guidelines recommend SRT for patients who remain symptomatic despite maximally tolerated medical therapy.2 Clinical success rates from SRT procedures are high, estimated to be >90% to 95%.5

Prior to the VALOR-HCM study, there was no FDA-approved medical alternative to invasive SRT for drug-refractory symptomatic obstructive HCM patients.6 Development of additional therapies for symptomatic obstructive HCM represented a major unmet medical need.6

Risk of postoperative death associated with invasive procedures5:

  • 5-10% from alcohol septal ablation and myectomy at low-volume HCM centers
  • ~1% at comprehensive, primary HCM centers

Additional challenges for patients may include5:

  • Reintervention, due to recurring obstruction in an estimated 15-30% of alcohol septal ablations and myectomies
  • Conduction block requiring a permanent pacemaker
  • ICD intervention

Study Rationale

VALOR-HCM was designed to test if the addition of CAMZYOS to maximally tolerated medical therapy would allow severely symptomatic obstructive HCM patients to improve sufficiently enough that they no longer met guideline criteria for SRT at week 16 or choose not to undergo SRT prior to or at week 16.3

ICD=implantable cardioverter defibrillator.

Select patient baseline characteristics in VALOR-HCM1,2

Select patient baseline characteristics

Values in the table are mean (SD) or n (%) CAMZYOS (n=56) Placebo (n=56)
Age, years 59.8 ± 14.2 60.0 ± 10.5
Sex
Male 29 (51.8) 28 (50.0)
Female 27 (48.2) 28 (50.0)
Race*
White 48 (85.7) 52 (92.9)
Black 3 (5.4) 0 (0)
Asian
2 (3.6) 0 (0)
Unspecified or other 3 (5.4) 4 (7.1)
Duration of obstructive HCM disease, years 7.5 ± 9.4 6.7 ± 7.4
Medical history
Family history of HCM 17 (30.4) 15 (26.8)
Atrial fibrillation
11 (19.6)
8 (14.3)
Syncope or presyncope 29 (51.8) 30 (53.6)
Internal cardioverter defibrillator 9 (16.1) 10 (17.9)
NYHA functional class
Class II with exertional syncope 4 (7.1) 52 (92.9)
Class III or higher

The majority of patients were
NYHA class III or higher (93%)1

4 (7.1) 52 (92.9)

The majority of patients were NYHA class III or higher (93%)1

Type of SRT recommended
Alcohol septal ablation 8 (14.3) 7 (12.5)
Myectomy 48 (85.7) 49 (87.5)
Background HCM therapy
BB monotherapy 26 (46.4) 25 (44.6)
Nondihydropyridine CCB monotherapy 7 (12.5) 10 (17.9)
Disopyramide monotherapy 0 (0.0) 2 (3.6)
BB and CCB 6 (10.7) 10 (17.9)
BB and disopyramide 11 (19.6) 3 (5.4)
CCB and disopyramide 1 (1.8) 2 (3.6)
BB, CCB, and disopyramide 2 (3.6) 1 (1.8)
None, medication intolerance
36% of patients (n=20) taking
CAMZYOS and 29% of patients
(n=16) in the placebo group were
on combination therapy2
3 (5.4) 3 (5.4)
36% of patients (n=20) taking CAMZYOS and 29% of patients (n=16) in the placebo group were on combination therapy2
Echocardiographic parameters
LVOT gradient, mmHg    
Resting 51.2 ± 31.4 46.3 ± 30.5
Valsalva 75.3 ± 30.8 76.2 ± 29.9
Post-exercise 82.5 ± 34.7 85.2 ± 37.0
LVEF, % 67.9 ± 3.7 68.3 ± 3.2
Left atrial volume index, mL/m2 41.3 ± 16.5 40.9 ± 15.2
  • *Race was self-reported.2

BB=beta blocker; CCB=calcium channel blocker; HCM=hypertrophic cardiomyopathy; LVEF=left ventricular ejection fraction; LVOT=left ventricular outflow tract; NYHA=New York Heart Association; SD=standard deviation; SRT=septal reduction therapy.

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References:

  1. CAMZYOS [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2023.
  2. Desai MY, Owens A, Geske JB, et al. Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy. J Am Coll Cardiol. 2022;80(2):95-108.
  3. Desai MY, Owens A, Geske JB, et al. Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy. J Am Coll Cardiol. 2022;80(2):95-108 [supplementary appendix]
  4. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;58(25):e212-e260.
  5. Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020;142(25):e533-e631
  6. Desai MY, Wolski K, Owens A, et al. Study design and rationale of VALOR-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy who are eligible for septal reduction therapy. Am Heart J. 2021;239:80-89.
3500-US-2300530 07/23