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U.S. Full Prescribing Information, including Boxed WARNING

EXPLORER-HCM: A Groundbreaking Phase 3 Trial for
Symptomatic NYHA Class
II–III Obstructive HCM1,2

A randomized, double blind, placebo-controlled trial evaluated the efficacy and safety of CAMZYOS® vs placebo1-3

5-week
screening phase3

Select inclusion criteria4
  • ≥18 years old, body weight >45 kg at screening
  • NYHA class II or III
  • Diagnosis of obstructive HCM
  • Left ventricular ejection fraction (LVEF) ≥55%
  • LVOT ≥50 mmHg at rest or with provocation
  • Able to safely perform upright cardiopulmonary
    exercise testing (CPET)
Select exclusion criteria2,4
  • Known infiltrative or storage disorder that mimics
    obstructive HCM (Fabry disease, amyloidosis, or
    Noonan syndrome with left ventricular hypertrophy)
  • Underwent SRT within 6 months prior to screening or
    plans to have SRT during the study
  • Treatment (within 14 days prior to screening) or planned
    treatment with disopyramide, ranolazine, or a
    combination of beta blockers (BBs) and calcium channel
    blockers (CCBs); prior treatment with cardiotoxic agents
CAMZYOS(n=123)
Randomized 1:1 (N=251)2
Placebo(n=128)

30-week
treatment phase1,2

CAMZYOS and placebo were administered orally, once a day. Dosage was monitored and adjusted (as needed) at weeks 8 and 14 to optimize patient response (decrease in LVOT gradient with Valsalva maneuver), maintain LVEF ≥50%, and was further informed by plasma concentrations of CAMZYOS

8-week washout phase1,2

Study drug was discontinued and participants returned for key assessments at week 38

92% of patients were on background
therapy with BBs or CCBs2*CAMZYOS (n=119/123) | Placebo (n=112/128)
  • *Patients on BBs or CCBs were allowed to continue
    background therapy.2

See select baseline patient
characteristics below

The primary composite functional endpoint and hierarchical secondary endpoints
were designed to assess treatment parameters for symptomatic NYHA class II–III
obstructive HCM2

Primary composite functional endpoint measured change from baseline to week 30 in symptoms (NYHA) and functional
capacity (pVO2)1,2

≥1 NYHA class improvement AND ≥1.5 mL/kg/min improvement in pVO2
OR
No worsening in NYHA class AND ≥3.0 mL/kg/min improvement in pVO2
Primary composite functional
endpoint explained >
Hierarchical secondary endpoints1,2†:(Measured from baseline to week 30)
  • Change in post-exercise LVOT gradient
    ≤30 mmHg
  • Change in pVO2
  • Proportion of patients with ≥1 NYHA
    class improvement
  • Change in KCCQ-23–CSS
  • Change in HCMSQ-SoB
Select prespecified exploratory endpoints2,5:(Not powered for statistical significance)
  • Post-exercise LVOT peak gradient <50 mmHg
  • Post-exercise LVOT peak gradient <30 mmHg
  • Proportion of patients with reductions in serum concentrations
    of N-terminal pro B-type natriuretic peptide (NT-proBNP) and
    high-sensitivity cardiac troponin I (hs-cTnI)
  • †All assessments for secondary endpoints were
    performed and Type I error was controlled in
    hierarchical order (sequence as indicated above)
    upon achieving significance in the primary endpoint
    (with two-tailed P<0.05 required to proceed).2

HCMSQ-SoB=Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath subscore; KCCQ-23–CSS=Kansas City Cardiomyopathy Questionnaire
(23-item version) Clinical Summary Score; LVEF=left ventricle ejection fraction; LVOT=left ventricular outflow tract; NYHA=New York Heart Association; SRT=septal reduction therapy.

Select baseline patient characteristics in EXPLORER-HCM1,2

Select patient baseline characteristics

  CAMZYOS (n=123) Placebo (n=128)
Age, mean (SD), years 59 (12.2) 59 (11.8)
Women, n (%) 57 (46) 45 (35)
Race, n (%)
White
Black or African American
American Indian or Alaska Native
Asian
Unknown 		115 (94)
1 (1)

0

4 (3)
3 (2) 		114 (89)
5 (4)

1 (1)

2 (2)
6 (5)
Background HCM
treatment, n (%)
Beta blocker
Calcium channel blocker‡ 		94 (76)
25 (20) 		95 (74)
17 (13)
NYHA class, n (%)
Class II
Class III 		88 (72)
35 (28) 		95 (74)
33 (26)
pVO2 mean (SD), mL/kg/min
18.9 (4.9)
19.9 (4.9)
LVOT gradient at
baseline, mean
(SD), mmHg
Valsalva
Post-exercise§ 		72 (32)
86 (34) 		74 (32)
84 (36)
LVEF, mean (SD), (%) 74 (6) 74 (6)
Critical cardiac history
Atrial fibrillation, n (%)
Implantable
cardioverter-
defibrillator, n (%)
Prior invasive SRT, n (%) 		12 (10)
27 (22)


11 (9) 		23 (18)
29 (23)


8 (6)
  • ‡Nondihydropyridine calcium channel blockers.2
  • §Data missing for one patient in the CAMZYOS group and one patient in the placebo group.2

SD=standard deviation.

Study procedures used in EXPLORER-HCM to determine
the efficacy and safety of CAMZYOS

Open for study procedures >
Primary composite
functional endpoint

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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. Olivotto I, Oreziak A, Barriales-Villa R, et al; EXPLORER-HCM study investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet.
    2020;396(10253):759-769.
  3. Ho CY, Olivotto I, Jacoby D, et al. Study design and rationale of EXPLORER-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. Circ Heart Fail. 2020;13(6):e006853.
  4. Ho CY, Olivotto I, Jacoby D, et al. Study design and rationale of EXPLORER-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. Circ Heart Fail. 2020;13(6):e006853 [supplementary appendix].
  5. Olivotto I. Efficacy and safety of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy: results of the EXPLORER-HCM study. Presented at ESC Congress The Digital Experience; 2020.
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References:

  1. CAMZYOS [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2023.
  2. Olivotto I, Oreziak A, Barriales-Villa R, et al; EXPLORER-HCM study investigators. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet.
    2020;396(10253):759-769.
  3. Ho CY, Olivotto I, Jacoby D, et al. Study design and rationale of EXPLORER-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. Circ Heart Fail. 2020;13(6):e006853.
  4. Ho CY, Olivotto I, Jacoby D, et al. Study design and rationale of EXPLORER-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. Circ Heart Fail. 2020;13(6):e006853 [supplementary appendix].
  5. Olivotto I. Efficacy and safety of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy: results of the EXPLORER-HCM study. Presented at ESC Congress The Digital Experience; 2020.
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