Bristol Myers Squibb Receives European Commission Approval of CAMZYOS® (mavacamten), for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy (HCM)

CAMZYOS is the first and only cardiac myosin inhibitor approved in the European Union

Approval based on two positive Phase 3 trials, EXPLORER-HCM and VALOR-HCM, demonstrating significant benefit in patients treated with CAMZYOS versus placebo

PRINCETON, N.J.–(BUSINESS WIRE)–$BMY #BMS—Bristol Myers Squibb (NYSE: BMY) today announced that the European Commission (EC) has approved CAMZYOS^® (mavacamten, 2.5 mg, 5 mg, 10 mg, 15 mg capsules) for the treatment of symptomatic (New York Heart Association, NYHA, class II-III) obstructive hypertrophic cardiomyopathy (HCM) in adult patients. CAMZYOS is the first and only allosteric and reversible inhibitor selective for cardiac myosin approved in all European Union (EU) member states* and is the first cardiac myosin inhibitor that targets the underlying pathophysiology of HCM. The EC approval of CAMZYOS is based upon positive efficacy and safety results from two Phase 3 trials, EXPLORER-HCM and VALOR-HCM.

“This approval marks an important milestone for patients in Europe who will now have a therapeutic option in CAMZYOS, a first-in-class cardiac myosin inhibitor that treats the underlying pathophysiology of symptomatic obstructive HCM,” said Samit Hirawat, M.D., chief medical officer, Bristol Myers Squibb. “We’re proud to bring this innovative treatment to more patients around the world, while reinforcing our ongoing dedication to transforming patients’ lives through science on a global scale.”

Symptomatic obstructive HCM is an often-inherited heart disease that can be a chronic, debilitating, and progressive condition where patients may experience symptoms of shortness of breath, dizziness and fatigue as well as serious, life-altering complications, including heart failure, arrhythmias, stroke and in rare cases (~1%), sudden cardiac death.

“Obstructive HCM is a life-changing disease for many patients who suffer from symptoms that can significantly impact their quality of life. The positive results of both Phase 3 clinical trials showed that CAMZYOS demonstrated efficacy across all primary and secondary endpoints, including improvements in exercise capacity and symptom burden for these patients,” said Iacopo Olivotto, M.D., Professor of Cardiology at the University of Florence and Head of Cardiology at Meyer Children’s Hospital, Florence, Italy. “As the lead clinical investigator for EXPLORER-HCM, I am grateful to the patients who played a key role in this approval and look forward to having CAMZYOS available to patients in the EU who have long awaited a new treatment option for this chronic disease.”

Please see important safety information, including Boxed WARNING, from the U.S. prescribing information below.

Bristol Myers Squibb thanks the patients and investigators involved in both clinical trials.

*Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland, Wales).

Full European Summary of Product Characteristics for CAMZYOS is available from the EMA website at www.ema.europa.eu.

About EXPLORER-HCM

The EXPLORER-HCM Phase 3 trial (NCT03470545) was a double-blind, randomized, placebo-controlled, parallel group trial that enrolled a total of 251 adult patients with symptomatic (NYHA class II or III), obstructive hypertrophic cardiomyopathy. All participants had measurable left ventricular ejection fraction (LVEF) ≥55% and at least one peak LVOT gradient ≥50 mmHg (at rest or with provocation at diagnosis); in addition, Valsalva LVOT gradient ≥30 mmHg at baseline was required at screening. Ninety-two percent of patients were on background therapies of a beta blocker or calcium channel blocker. At baseline, approximately 73% of the randomized patients were NYHA class II and 27% were NYHA class III. The mean LVEF was 74%, and the mean Valsalva left ventricular outflow tract (LVOT) gradient was 73 mmHg. The baseline mean Kansas City Cardiomyopathy Questionaire-23 (KCCQ-23) Clinical Summary Score (CSS) was 71.

The primary endpoint was a composite functional endpoint, assessed at 30 weeks, and was defined as the proportion of patients who achieved either improvement of mixed venous oxygen tension (pVO₂) by ≥1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO₂ by ≥3.0 mL/kg/min plus no worsening in NYHA class. Key secondary endpoints include impact on exercise gradient LVOT, pVO₂, NYHA Class and Kansas City Cardiomyopathy Questionnaire (KCCQ)* and Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ)^† at Week 30.

The trial met all primary and secondary endpoints with statistical significance:

• At Week 30, 37% (n=45/123) of patients taking CAMZYOS achieved the composite primary endpoint, defined as the proportion of patients who achieved either improvement of mixed venous oxygen tension (pVO₂) by ≥1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO₂ by ≥3.0 mL/kg/min plus no worsening in NYHA class, versus 17% (n=22/128) treated with placebo. The difference was 19.4% (95% CI: 8.67, 30.13; p=0.0005).
• Additionally at Week 30, patients receiving CAMZYOS had greater improvement compared to placebo group across all secondary endpoints, including:
  • Change from baseline post-exercise LVOT peak gradient [-47 mmHg vs -10 mmHg; -35 difference (95% CI: -43, -28; p<0.0001)]
  • Change from baseline in pVO₂ [1.4 mL/kg/min vs -0.05 mL/kg/min; 1.4 difference (95% CI: 0.6, 2; p<0.0006)]
  • Number (%) of patients with improvement of NYHA class ≥1 [80 (65%) vs 40 (31%); difference of 34% (95% CI; 22%, 45%; p<0.0001)]
  • Change from baseline in KCCQ-23 CSS [14 vs 4; difference of 9 (95% CI: 5, 13); p<0.0001]
  • Change from baseline in HCMSQ SoB domain score [-2.8 vs -0.9; difference of -1.8 (95% CI: -2.4, -1.2); p<0.0001]

* The KCCQ-23 CSS is derived from the Total Symptoms Score (TSS) and the Physical Limitations (PL) score of the KCCQ-23. The CSS ranges from 0 to 100, with higher scores representing better health status.

^† The HCMSQ SoB domain score measures frequency and severity of shortness of breath. The domain score ranges from 0 to 18, with lower scores representing less shortness of breath.

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. 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, 95% 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 exercise gradient LVOT, NYHA Class and Kansas City Cardiomyopathy Questionnaire (KCCQ) and biomarkers at Week 16.

The trial met all primary and secondary endpoints with statistical significance:

• Results showed that CAMZYOS significantly reduced the primary composite endpoint of patient decision to proceed with SRT prior to or at Week 16 or patients who remain SRT eligible (LVOT gradient of ≥50 mmHg and NYHA class III-IV, or class II with exertional syncope or near syncope) at Week 16, with 82% of patients no longer eligible for the surgical procedure or deciding not to proceed with SRT after 16 weeks of treatment. Only 10 (17.9%) patients treated with CAMZYOS vs 43 (76.8%) patients 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), 58.9% (44.0%, 73.9%); p<0.0001.
• Results also showed CAMZYOS met secondary endpoints (change from baseline to Week 16) vs the placebo group of:
  • Change from baseline post-exercise LVOT peak gradient [-39.1 mmHg vs -1.8 mmHg; -37.2 mmHg difference (95% CI: -48.1, -26.2), p<0.0001]
  • Proportion with NYHA Class improvement of at least 1 class [62.5% vs 21.4%; 41.1% difference (95% CI: 24.5%, 57.7%), p<0.0001]
  • Change from baseline in KCCQ-23 CSS [10.4 vs 1.8; difference of 9.5 (95% CI: 4.9, 14), p<0.0001]
  • Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) [0.35 vs 1.13; difference of 0.33 (95% CI: 0.27, 0.42), p<0.0001]
  • Change from baseline in Cardiac Troponin I [0.5 vs 1.03; difference of 0.53 (95% CI: 0.41, 0.70), p<0.0001]

EXPLORER-HCM and VALOR-HCM Pooled Safety Data

The most commonly reported adverse reactions of the 179 patients treated with CAMZYOS in two Phase 3 studies were dizziness (17%), dyspnoea (12%), systolic dysfunction (5%) and syncope (5%). In these clinical studies, 5% (9/179) of patients in the CAMZYOS group experienced reversible reductions in LVEF <50% (median 45%: range: 35-49%) while on treatment. In 56% (5/9) of these patients, reductions were observed without other clinical manifestations. In all patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS and they completed the study on treatment. Dyspnoea was reported in 12.3% of patients treated with CAMZYOS compared to 8.7% of patients on placebo. In the EXPLORER-HCM study, most (67%) of the dyspnoea events were reported after CAMZYOS was discontinued, with median time to onset of 2 weeks (range: 0.1-4.9) after last dose.

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. It has also received regulatory approvals in Australia, Canada, Brazil, Switzerland, Macau, South Korea and Singapore. 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 LVOT obstruction and improves cardiac filling pressures.

About Obstructive Hypertrophic Cardiomyopathy

Obstructive hypertrophic cardiomyopathy (obstructive HCM) is a chronic, progressive disease in which excessive contraction of the heart muscle and reduced ability of the left ventricle to fill can make it difficult for blood to circulate to the rest of the body, leading to the development of debilitating symptoms and cardiac dysfunction. HCM can be hereditary and can develop at any age. Patients are typically diagnosed in their 40s or 50s, and as many as 50% of patients have a hereditary predisposition.

In obstructive HCM, which is the most common type of HCM, the left ventricular outflow tract (LVOT) where blood leaves the heart becomes obstructed by the enlarged heart muscle. As a result, obstructive HCM has also been associated with increased risks of atrial fibrillation, stroke, heart failure and, although rare, sudden cardiac death. The most frequent cause of obstructive HCM is mutations in the heart muscle proteins of the sarcomere. Obstructive HCM is estimated to affect 400,000-600,000 people worldwide, however many patients remain undiagnosed and/or asymptomatic.

About CAMZYOS REMS Program

CAMZYOS is only available in the U.S. through a restricted program called the CAMZYOS REMS Program because of the risk of heart failure due to systolic dysfunction. Further information is available at www.CAMZYOSREMS.com or by telephone at 1-833-628-7367.

U.S. 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.

U.S. 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.

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