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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 for SRT-eligible patients 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 and 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) 4 (7.1)
Class III or higher

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

 52 (92.9) 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.

Primary composite
endpoint

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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
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Important Safety
Information
WARNING: RISK OF HEART FAILURE

CAMZYOSTM (mavacamten) reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction.

Echocardiogram assessments of LVEF are required prior to and during treatment with CAMZYOS. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Interrupt CAMZYOS if LVEF is <50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status.

Concomitant use of CAMZYOS with certain cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to systolic dysfunction; therefore, the use of CAMZYOS is contraindicated with the following:

  • Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors
  • Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers

Because of the risk of heart failure due to systolic dysfunction, CAMZYOS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CAMZYOS REMS PROGRAM.

CONTRAINDICATIONS

CAMZYOS is contraindicated with concomitant use of:

  • Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors
  • Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers
WARNINGS AND PRECAUTIONS

Heart Failure

CAMZYOS reduces systolic contraction and can cause heart failure or totally block ventricular function. Patients who experience a serious intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation or other uncontrolled tachyarrhythmia) are at greater risk of developing systolic dysfunction and heart failure.

Assess the patient’s clinical status and LVEF prior to and regularly during treatment and adjust the CAMZYOS dose accordingly. New or worsening arrhythmia, dyspnea, chest pain, fatigue, palpitations, leg edema, or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should also prompt an evaluation of cardiac function.

Asymptomatic LVEF reduction, intercurrent illnesses, and arrhythmias require additional dosing considerations.

Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited.

CYP 450 Drug Interactions Leading to Heart Failure or Loss of Effectiveness

CAMZYOS is primarily metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant use of CAMZYOS and drugs that interact with these enzymes may lead to life-threatening drug interactions such as heart failure or loss of effectiveness.

Advise patients of the potential for drug interactions, including with over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine). Advise patients to inform their healthcare provider of all concomitant products prior to and during CAMZYOS treatment.

CAMZYOS Risk Evaluation and Mitigation Strategy (REMS) Program

CAMZYOS is only available through a restricted program called the CAMZYOS REMS Program because of the risk of heart failure due to systolic dysfunction. Notable requirements of the CAMZYOS REMS Program include the following:

  • Prescribers must be certified by enrolling in the REMS Program.
  • Patients must enroll in the REMS Program and comply with ongoing monitoring requirements.
  • Pharmacies must be certified by enrolling in the REMS Program and must only dispense to patients who are authorized to receive CAMZYOS.
  • Wholesalers and distributors must only distribute to certified pharmacies.

Further information is available at www.CAMZYOSREMS.com or by telephone at 1-833-628-7367.

Embryo-Fetal Toxicity

CAMZYOS may cause fetal toxicity when administered to a pregnant female, based on animal studies. Confirm absence of pregnancy in females of reproductive potential prior to treatment and advise patients to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. CAMZYOS may reduce the effectiveness of combined hormonal contraceptives (CHCs). Advise patients using CHCs to use an alternative contraceptive method that is not affected by CYP 450 enzyme induction or to add nonhormonal contraception. Advise females of reproductive potential about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy.

ADVERSE REACTIONS

In the EXPLORER-HCM trial, adverse reactions occurring in >5% of patients and more commonly in the CAMZYOS group than in the placebo group were dizziness (27% vs 18%) and syncope (6% vs 2%). There were no new adverse reactions identified in VALOR-HCM.

Effects on Systolic Function

In the EXPLORER-HCM trial, mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups. Mean (SD) absolute change from baseline in LVEF was -4% (8) in the CAMZYOS group and 0% (7) in the placebo group over the 30-week treatment period. At Week 38, following an 8-week interruption of trial drug, mean LVEF was similar to baseline for both treatment groups. In the EXPLORER-HCM trial, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF <50% (median 48%: range 35-49%) while on treatment. In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS.

DRUG INTERACTIONS

Potential for Other Drugs to Affect Plasma Concentrations of CAMZYOS

CAMZYOS is primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and moderate to strong inhibitors or inducers of CYP3A4 may affect the exposures of CAMZYOS.

Impact of Other Drugs on CAMZYOS:

  • Moderate to Strong CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors: Concomitant use increases CAMZYOS exposure, which may increase the risk of heart failure due to systolic dysfunction. Concomitant use is contraindicated.
  • Moderate to Strong CYP2C19 Inducers or Moderate to Strong CYP3A4 Inducers: Concomitant use decreases CAMZYOS exposure, which may reduce CAMZYOS’ efficacy. The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers as the levels of induced enzyme normalizes. Concomitant use is contraindicated.
  • Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors: Concomitant use with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor increases CAMZYOS exposure, which may increase the risk of adverse drug reactions. Initiate CAMZYOS at the recommended starting dose of 5 mg orally once daily in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Reduce dose of CAMZYOS by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on CAMZYOS treatment and intend to initiate a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate CAMZYOS until 12 weeks after inhibitor initiation. Avoid initiation of concomitant weak CYP2C19 and moderate CYP3A4 inhibitors in patients who are on stable treatment with 2.5 mg of CAMZYOS because a lower dose is not available.

Potential for CAMZYOS to Affect Plasma Concentrations of Other Drugs

CAMZYOS is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C19, or CYP2C9 substrates may reduce plasma concentration of these drugs. Closely monitor when CAMZYOS is used in combination with CYP3A4, CYP2C19, or CYP2C9 substrates where decreases in the plasma concentration of these drugs may reduce their activity.

Hormonal Contraceptives: Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of ethinyl estradiol and progestin, which may lead to contraceptive failure or an increase in breakthrough bleeding. Advise patients to use a contraceptive method that is not affected by CYP 450 enzyme induction (e.g., intrauterine system) or add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS.

Drugs That Reduce Cardiac Contractility

Expect additive negative inotropic effects of CAMZYOS and other drugs that reduce cardiac contractility. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited.

If concomitant therapy with a negative inotrope is initiated, or if the dose of a negative inotrope is increased, monitor LVEF closely until stable doses and clinical response have been achieved.

SPECIFIC POPULATIONS

Pregnancy

CAMZYOS may cause fetal harm when administered to a pregnant female. Advise pregnant females about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy. There is a pregnancy safety study for CAMZYOS. If CAMZYOS is administered during pregnancy, or if a patient becomes pregnant while receiving CAMZYOS or within 4 months after the last dose of CAMZYOS, healthcare providers should report CAMZYOS exposure by contacting Bristol Myers Squibb at 1-800-721-5072 or www.bms.com.

Lactation

The presence of CAMZYOS in human or animal milk, the drug’s effects on the breastfed infant, or the effects on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAMZYOS and any potential adverse effects on the breastfed child from CAMZYOS or from the underlying maternal condition.

Females and Males of Reproductive Potential

Confirm absence of pregnancy in females of reproductive potential prior to initiation of CAMZYOS. Advise females of reproductive potential to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. Use of CAMZYOS may reduce the effectiveness of CHCs. Advise patients using CHCs to use an alternative contraceptive method or add nonhormonal contraception.

INDICATION

CAMZYOS is indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.

CAMZYOS is available in 2.5 mg, 5 mg, 10 mg, and 15 mg capsules.

Please see U.S. Full Prescribing Information, including Boxed WARNING.

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
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