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Industry Clinic

Data from BMS at AHA Bolster Evidence for BMS' oHCM Treatment Option

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MedpageToday

For U.S. Healthcare Professionals Only

For decades, treatment options for patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM), a heart disease characterized by the abnormal thickening of the septal wall of the left ventricle,1 have primarily focused on managing symptoms.2 Following pharmacologic therapy, invasive procedures were the only option for the most severely affected patients due to limited data and randomized evidence, leaving a significant medical need.2,3 Bristol Myers Squibb (BMS), recognizing the urgent need for a treatment option with a differentiated mechanism of action for patients with oHCM, advanced the clinical development of CAMZYOS® (mavacamten), which was approved by the U.S. Food and Drug Administration (FDA) in April 2022 for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III oHCM.4

CAMZYOS is a cardiac myosin inhibitor that is allosteric and reversible and helps modulate the number of myosin heads in the off state, reducing the number of myosin-actin cross-bridges that form.4 Decreasing the number of excess myosin-actin cross-bridges can reduce dynamic left ventricular outflow tract (LVOT) obstruction, improve cardiac filling pressures, improve energy consumption, and reduce cardiac contractility.4-6 CAMZYOS is the first and only approved cardiac myosin inhibitor that targets oHCM at the source and works to treat the underlying disease.4,5

CAMZYOS is now included in the AHA/ACC/Multisociety HCM guideline as a recommended treatment option for when symptoms persist after first-line therapy* and is a standard of care for symptomatic oHCM.2 More than 10,000 adult patients with NYHA class II-III oHCM in the U.S. have received a prescription for the medicine since it was approved by the FDA in 2022.7 BMS continues to evaluate CAMZYOS and recently presented impactful new data at the American Heart Association (AHA) Scientific Sessions 2024 that further supports the efficacy and safety profile of CAMZYOS in the management of patients with symptomatic NYHA class II-III oHCM.

*Beta blockers and nondihydropyridine calcium channel blockers are first-line therapies.

IMPORTANT SAFETY INFORMATION

INDICATION

CAMZYOS® (mavacamten) 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.

WARNING: RISK OF HEART FAILURE

CAMZYOS 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.

Please see additional Important Safety Information below and including Boxed WARNING.

First and Only FDA-Approved Cardiac Myosin Inhibitor

CAMZYOS is redefining the treatment landscape for symptomatic NYHA class II-III oHCM as the first and only FDA-approved cardiac myosin inhibitor that specifically targets the underlying source of the disease. An overview of the two pivotal Phase 3 trials – EXPLORER-HCM and VALOR-HCM – that support the use of CAMZYOS in adult patients with NYHA class II-III oHCM is available at .

The efficacy and safety of CAMZYOS were evaluated in EXPLORER-HCM, a Phase 3, randomized (1:1), double-blind, placebo-controlled trial that enrolled 251 adults with symptomatic NYHA class II-III oHCM, with LVOT peak gradient greater than or equal to 50 mmHg and left ventricular ejection fraction (LVEF) greater than or equal to 55%.4,5 At baseline, approximately 73% of the randomized patients were NYHA class II, and 27% were NYHA class III; 92% of patients were on background therapy with either a beta blocker (BB) or calcium channel blocker (CCB) as monotherapy.4,5

Mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups.4,5 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.4,5 At week 38, following an 8-week interruption of the trial drug, the mean LVEF was similar to baseline for both treatment groups.4,5 Additionally, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF less than 50% (median 48%; range 35-49%) while on treatment.4,5 In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS.4,5 Adverse reactions occurring in more than 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%).4,5

The long-term efficacy and safety profile of CAMZYOS is further supported by the findings of the EXPLORER-LTE trial, a cohort of MAVA-LTE, a five-year extension study designed to evaluate long-term safety, efficacy, and clinically guided dosing for CAMZYOS.8,9

New CAMZYOS Data Presented at AHA 2024

At AHA 2024, new real-world and long-term-extension data were unveiled, supporting the growing body of evidence for CAMZYOS. In a featured science presentation, researchers highlighted data from the almost 2.5 year (128 weeks) long-term safety and efficacy analysis, with simultaneous publication, of the VALOR-HCM trial, where patients transitioned from a 16-week Phase 3 double-blind, placebo-controlled, randomized study.10 This study analyzed CAMZYOS' impact on patient eligibility or the decision to proceed with septal reduction therapy (SRT) among SRT-eligible, adult patients with severely symptomatic oHCM (NYHA class II-III+, with LVEF of at least 60%, LVOT peak gradient of at least 50 mmHg), despite maximally-tolerated medical therapy.10

New real-world evidence was also presented, including long-term data from MARVEL-HCM, one of the largest observational studies (n=172) investigating the effectiveness and safety of CAMZYOS to date.11 Researchers evaluated clinical outcomes in adults with NYHA class II-III oHCM treated with CAMZYOS for up to 72 weeks at multiple health centers across the U.S., reporting on changes in NYHA class, LVOT gradients at rest and with Valsalva, and LVEF from baseline.11 At baseline, the cohort was characterized by 56% female participants, a mean age of 64 years, 47% in NYHA class III, a mean resting LVOT gradient of 47 mmHg, a mean Valsalva LVOT gradient of 89 mmHg, and 23% identifying as non-White.11 Additionally, insights were shared from COLLIGO-HCM, a real-world study with the aim of describing the real-world effectiveness and safety of CAMZYOS.12 The study examined echocardiogram measurements (resting and Valsalva LVOT gradients, and LVEF) and NYHA class and examined the effectiveness and safety of CAMZYOS for up to 60 weeks in an adult patient population (n=93) that was racially diverse and experienced a high disease burden (NYHA class II, 23%; class III, 77%).12

Collectively, these findings presented at the meeting further support the role of CAMZYOS as a standard of care in the treatment of adults with NYHA class II-III oHCM, impacting clinical measurements of the disease and patient symptoms.2

As part of BMS' long-standing dedication to patients with cardiovascular disease and its commitment to helping patients with oHCM, the company continues to strengthen the safety profile and efficacy of CAMZYOS, including in additional real-world studies.7

Physicians can learn more about CAMZYOS at . Please see Important Safety Information for CAMZYOS below and click for the U.S. Full Prescribing Information, including Boxed WARNING.

IMPORTANT SAFETY INFORMATION (Continued)

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 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. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS. However, CAMZYOS may reduce the effectiveness of certain other combined hormonal contraceptives (CHC). If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS.

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, CYP2C9, or CYP2C19 substrates may reduce plasma concentration of these drugs. Closely monitor when CAMZYOS is used with concomitant CYP3A4, CYP2C9, or CYP2C19 substrates unless otherwise recommended in the Prescribing Information.

Certain Combined Hormonal Contraceptives (CHC): Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of certain progestins, which may lead to contraceptive failure. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS, but if other CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and 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 .

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. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS. However, CAMZYOS may reduce the effectiveness of certain other combined hormonal contraceptives (CHC). If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS.

INDICATION

CAMZYOS® (mavacamten) 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. , including Boxed WARNING.

# # #

© 2024 MyoKardia, Inc., a Bristol Myers Squibb company. CAMZYOS® is a trademark of MyoKardia, Inc.

3500-US-2400662 12/24

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References:

  1. University of Maryland Medical Center. Hypertrophic cardiomyopathy types, symptoms, and causes. .
  2. Ommen S, Ho C, Asif I, et al; 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2024. .
  3. 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):3533-e577.
  4. CAMZYOS [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2024.
  5. 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.
  6. Anderson RL, Trivedi DV, Sarkar SS, et al. Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers. Proc Natl Acad Sci USA. 2018 Aug 28;115(35):E8143-E8152. .
  7. Data on file. Total unique patients started on CAMZYOS. Valid as of June 2024. Princeton, NJ: Bristol-Myers Squibb Company; 2024.
  8. Garcia-Pavia P, Oreziak A, Masri A, et al. Long-term effects of mavacamten treatment in obstructive hypertrophic cardiomyopathy (HCM): Updated cumulative analysis of the EXPLORER cohort of the MAVA-long-term extension (LTE) study up to 120 weeks. Presented at ESC 2023. Oral presentation 835382.
  9. Data on file. BMS-REF-MAVA-0039. Princeton, NJ: Bristol-Myers Squibb Company; 2023.
  10. Desai M, Wolski K, Owens A, et al. Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction: Week 128 Results from VALOR-HCM. Circulation. 2024 Nov 18. .
  11. Abraham T, Alsidaw S, Martinez MW, et al. Real-world Long-term Effectiveness of Mavacamten in Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy: A Multicenter Observational Study (MARVEL-HCM). 2024. Abstract presented at: American Heart Association Scientific Sessions; November 16-18, 2024; Chicago, IL.
  12. MacNamara JP, Adler A, Maor E, et al. Long-term effectiveness and safety of mavacamten in a real-world, multi-center, global study: Preliminary results of COLLIGO-HCM from a diverse cohort in the United States (COLLIGO-HCM). 2024. Abstract presented at: American Heart Association Scientific Sessions; November 16-18, 2024; Chicago, IL.

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