PRINCETON, N.J.--(BUSINESS WIRE)--Bristol Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application (sNDA) to add positive data from the Phase 3 VALOR-HCM study to the U.S. Prescribing Information for CAMZYOS^® (mavacamten, 2.5 mg, 5 mg, 10 mg, 15 mg capsules). Data added to the label showed that treatment with CAMZYOS significantly reduced the composite endpoint of guideline-based eligibility for septal reduction therapy (SRT) at Week 16 or the decision to proceed with SRT prior to or at Week 16. This approval follows last year’s FDA approval of CAMZYOS, based on results from the Phase 3 EXPLORER-HCM trial, for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive HCM to improve functional capacity and symptoms.

$BMY announces FDA approves the supplemental New Drug Application (sNDA) to add positive data from the Phase 3 VALOR-HCM study to the U.S. Prescribing Information for its treatment for symptomatic NYHA class II-III obstructive #HCM.

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“At Bristol Myers Squibb, we are committed to delivering innovative medicines to help improve the lives of patients living with serious diseases,” said Catherine Owen, Senior Vice President and General Manager, U.S. Commercial, Bristol Myers Squibb. “CAMZYOS is the first and only FDA-approved cardiac myosin inhibitor that specifically targets the underlying source of the disease and is redefining the treatment landscape for symptomatic NYHA class II–III obstructive HCM. Results from the Phase 3 VALOR-HCM study reinforce the data from the Phase 3 EXPLORER-HCM trial and further strengthen the clinical profile of CAMZYOS. We are proud to offer this important therapy to patients.”

The full U.S. Prescribing Information for CAMZYOS includes a Boxed WARNING for the 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 moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors, and 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 including Boxed WARNING below.

Hypertrophic cardiomyopathy is the most commonly inherited heart disease, impacting between an estimated one in 200* and one in 500^† people in the U.S. Obstructive HCM, which is the most common type of HCM and represents about two-thirds of all cases, is largely caused by dysfunction in the sarcomere which leads to a thickened heart muscle that obstructs or reduces blood flow from the heart to the rest of the body.¹ Patients who are experiencing severe symptoms and have a dynamic LVOT gradient at rest or with provocation ≥ 50 mmHg, despite receiving the maximally tolerated medical therapy, may be eligible for SRT to reduce the thickness of the septal wall and alleviate obstruction.²

“SRT is an invasive surgical or catheter-based procedure and is typically available at comprehensive HCM treatment centers. In order to provide broader access to treatment for those patients whose obstructive HCM becomes so advanced that guidelines recommend SRT, more treatment options are needed,” said Anjali T. Owens, M.D., Medical Director of the Center for Inherited Cardiac Disease, Associate Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania, and VALOR-HCM trial investigator and executive committee member. “The VALOR-HCM study supports CAMZYOS as an oral treatment for obstructive HCM patients who are recommended for SRT.”

In the VALOR-HCM study, patients with symptomatic obstructive HCM (NYHA class III-IV or class II with exertional syncope or near syncope) who met the 2011 ACC/AHA Guideline criteria and were referred for SRT were randomized 1:1 to CAMZYOS (n=56) or placebo (n=56) for 16 weeks. At baseline, approximately 7% of the randomized patients were NYHA class II and 93% were NYHA class III+. The mean LVEF was 68%, and the mean post-exercise left ventricular outflow tract (LVOT) gradient was 84 mmHg. The baseline mean Kansas City Cardiomyopathy Questionaire-23 (KCCQ-23) Clinical Summary Score (CSS) was 68.

Results showed that CAMZYOS significantly reduced the primary composite endpoint of patient eligibility for SRT or the decision to proceed with SRT, with 82% of patients no longer eligible for the surgical procedure and deciding not to proceed with SRT after 16 weeks of treatment. Ten patients (18%) treated with CAMZYOS vs 43 patients (77%) in the placebo group decided to proceed with SRT prior to or at Week 16 or were SRT-eligible at Week 16; treatment difference (95% CI), 59% (44%, 74%); P<0.0001. Two patients (3.6%) in both the CAMZYOS and placebo groups decided to proceed with SRT prior to or at Week 16; 8 patients (14%) in the CAMZYOS group and 41 patients (74%) in the placebo group were SRT-eligible at Week 16.

Results also showed CAMZYOS met secondary endpoints (change from baseline to Week 16) vs the placebo group of:

• Mean post-exercise LVOT gradient (-39 mmHg for the CAMZYOS group vs -2 mmHg for the placebo group; difference [95% CI] of -38 mmHg [-49, -28], P<0.0001)
• Proportion with NYHA class improvement of at least 1 class (63% for the CAMZYOS group vs 21% for the placebo group; difference [95% CI] of 41% [25, 58], P<0.0001)
• KCCQ-23 CSS**, mean (+10 points for the CAMZYOS group vs +2 points for the placebo group; difference [95% CI] of 9 points [5, 14], P<0.0001)
  • Mean change in baseline in KCCQ-23 Total Symptom Score (TSS) (+10 vs +2)
  • Mean change in baseline in KCCQ-23 Physical Limitations (PL) (+10 vs +2)

**The Kansas City Cardiomyopathy Questionaire-23 Clinical Summary Score (KCCQ‑23 CSS) is derived from the Total Symptom Score (TSS) and the Physical Limitations (PL) score of the KCCQ‑23. The CSS ranges from 0 to 100 with higher scores representing less severe symptoms and/or physical limitations.

There were no new adverse reactions identified in VALOR-HCM. 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%). 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. Additionally, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF to <50% (median 48%: range 35-49%) while on treatment. In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS.

Bristol Myers Squibb offers various programs and resources to address the needs of patients and caregivers, and provide support that allows for access to therapies, including CAMZYOS. For additional information, visit CAMZYOS.com or call 855-CAMZYOS (855-226-9967) 8 am to 11 pm ET, Monday through Friday.

About VALOR-HCM

VALOR-HCM (NCT04349072) was a randomized, double-blind, placebo-controlled, multicenter Phase 3 study of patients with symptomatic, obstructive HCM (NYHA class II-IV) who met guideline criteria for septal reduction therapy (SRT; LVOT gradient of ≥ 50 mmHg and NYHA class III-IV, or class II with exertional syncope or near syncope) and had been referred or under active consideration (within the past 12 months) for an invasive procedure. Patients were required to have LVOT peak gradient ≥50 mmHg at rest or with provocation, and LVEF ≥60%. The study enrolled 112 patients (mean age of 60 years; 51% men; 93% ≥ NYHA class III) randomized on a 1:1 basis to receive mavacamten or placebo. At baseline, ninety-five percent of patients were on background therapies of a beta blocker, calcium channel blocker, disopyramide or a combination. The primary endpoint was a composite of the proportion of patients who decided to proceed with SRT prior to or at Week 16 or who remained SRT-guideline eligible (LVOT gradient of ≥50 mmHg and NYHA class III-IV, or class II with exertion induced syncope or near syncope) at Week 16. Key secondary endpoints included the change from baseline on post-exercise LVOT gradient, NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score and cardiac biomarkers (NT-proBNP and Cardiac Troponin I) at Week 16.

About CAMZYOS (mavacamten)

CAMZYOS (mavacamten) is the first and only cardiac myosin inhibitor approved in the U.S., 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 an allosteric and reversible inhibitor selective for cardiac myosin. CAMZYOS modulates the number of myosin heads that can enter “on actin” (power-generating) states, thus reducing the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM. CAMZYOS shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state. In HCM patients, myosin inhibition with CAMZYOS reduces dynamic left ventricular outflow tract (LVOT) obstruction and improves cardiac filling pressures.

About CAMZYOS 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 CAMZYOS 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 by telephone at 1-833-628-7367.

IMPORTANT SAFETY INFORMATION

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.

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.

Please see US Full Prescribing Information, including Boxed WARNING and Medication Guide.

About Bristol Myers Squibb

Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date, whether CAMZYOS^® (mavacamten) for the indication described in this release will be commercially successful, that any marketing approvals, if granted, may have significant limitations on their use, and that continued approval of such product candidate for such indication described in this release may be contingent upon verification and description of clinical benefit in confirmatory trials. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2022, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

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References

* The 2015 Semsarian publication identified that the prevalence of HCM gene carriers could be as high as 1 in 200.

† The 1995 CARDIA study—a multicenter, US-population–based echocardiography study of 4111 subjects (aged 23–35)—identified the prevalence of HCM as 1 in 500 people in the general population.

1. 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):e558-e631.
2. Desai, M., Owens, A., Geske, J., Rihal, C. S., Nishimura, R. A., & Ommen, S. R. (2022). Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy. Journal of the American College of Cardiology, 80(2), 95-108. doi: 10.1016/j.jacc.2022.04.048.
3. CAMZYOS [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2023.

Dr. Owens is a consultant and on advisory boards for Bristol Myers Squibb.

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