Long Term Follow Up Data from Phase 3 Study of CAMZYOS® (mavacamten) Underscores Established Efficacy and Safety Profile in Patients with Symptomatic Obstructive Hypertrophic[...]

PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced new long-term follow-up results from the EXPLORER-LTE cohort of the MAVA-Long-Term Extension (LTE) study evaluating CAMZYOS ^® (mavacamten) in adult patients with New York Heart Association (NYHA) class II-III symptomatic obstructive hypertrophic cardiomyopathy (oHCM).

The long-term follow-up efficacy and safety data, presented today at the European Society of Cardiology (ESC) Congress in London, reinforce the established efficacy and safety profile of CAMZYOS, a first-in-class cardiac myosin inhibitor. With inclusion in both the ESC and AHA/ACC clinical guidelines as a recommended option for when symptoms persist after first-line therapy, CAMZYOS is a standard of care for symptomatic oHCM.

Patients experienced consistent and sustained improvements in echocardiographic measures and biomarkers after up to 3.5 years (180 weeks) of continuous treatment, including resting left ventricular outflow tract (LVOT) gradient, Valsalva LVOT gradient, left atrial volume index and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels. They also experienced an improvement in symptoms and functional capacity as measured by NYHA class and patient-reported outcomes, including most patients achieving NYHA class I. The safety profile of CAMZYOS for up to 3.5 years remained consistent with the established safety profile, with no new safety signals identified.

"The consistent and sustained improvements in multiple cardiac measures over more than three years with CAMZYOS shows that this therapy meets an important treatment need for patients with symptomatic obstructive HCM," said Pablo García-Pavia, MD, PhD, head of the Inherited Cardiac Diseases and Heart Failure Unit at the Department of Cardiology of Hospital Universitario Puerta de Hierro and professor at the Spanish Cardiovascular Research Institute (CNIC) in Madrid, Spain. "These positive long-term data, together with the inclusion of CAMZYOS in ESC clinical guidelines for obstructive HCM, underscore the important role of this medicine in the long-term care of this lifelong condition that requires ongoing management."

At the data cutoff, 211 of 231 patients who enrolled in MAVA-LTE, of which EXPLORER-LTE is a cohort, were on CAMZYOS; 185 and 99 patients had reached Week 156 and 180, respectively. Key findings from the EXPLORER-LTE data analysis showed sustained improvements from baseline to Weeks 156 and 180 in echocardiographic measures and biomarkers. In echocardiographic markers, patients experienced a reduction of 55.3 mmHg in Valsalva LVOT gradient at both Week 156 and 180 and a reduction of 40.2 mmHg and 40.3 mmHg in mean resting LVOT gradient at Week 156 and 180, respectively. Improvements from baseline to Weeks 144 and 180 were sustained in mean left atrial volume index, with patients experiencing a reduction of 3.5 mL/m2 and 5.5 mL/m2, respectively. The mean left ventricular ejection fraction (LVEF) decreased by 11% from baseline to Week 180, and the mean (63.9%) remained within normal range. Evaluation of biomarker data showed that median NT-proBNP levels decreased by 504 ng/L at Week 156 and 562 ng/L by Week 180.

At Week 180, most patients (66.3%) were NYHA class I. Overall, 108 patients (46.8%) achieved a complete response - defined as achieving NYHA class I and a Valsalva LVOT gradient of ≤30 mmHg during the study and retained a complete response until the data cutoff. Patient-reported outcomes as measured by the HCM Symptom Questionnaire (HCMSQ) found improvement in shortness of breath score from baseline with treatment during the first 12 weeks and was sustained through Weeks 156 and 180.

"These results, representing the longest duration of follow up of the Phase 3 EXPLORER study to date, further reinforce the established safety and efficacy profile of CAMZYOS," said Roland Chen, MD , senior vice president and head of Immunology, Cardiovascular & Neuroscience (ICN) Development at Bristol Myers Squibb. "As the first and only approved cardiac myosin inhibitor for patients with symptomatic obstructive HCM and with thousands of patients around the world treated to date, CAMZYOS, which targets the source of symptomatic obstructive HCM, is redefining the treatment landscape for this patient population."

The EXPLORER-LTE analysis found no new safety signals observed with CAMZYOS treatment. A total of 20 patients (8.7%) experienced transient reductions in LVEF <50%, all recovered to LVEF ≥50% following treatment interruption and 14 patients reinitiated treatment with CAMZYOS.

About the EXPLORER-HCM and MAVA-LTE Trials

The double-blind, randomized, placebo-controlled, parallel group EXPLORER-HCM Phase 3 trial ( NCT03470545 ) enrolled 251 adult patients with symptomatic (NYHA class II or III) obstructive hypertrophic cardiomyopathy (oHCM). 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. Among study participants, 92% were on background therapies of a beta blocker or calcium channel blocker. 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 (pVO ₂ ) by ≥1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO ₂ by ≥3.0 mL/kg/min plus no worsening in NYHA class. Key secondary endpoints included impact on exercise gradient LVOT, pVO ₂ , NYHA class and Kansas City Cardiomyopathy Questionnaire (KCCQ) and Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) at Week 30.

EXPLORER-LTE is a cohort of the MAVA-LTE study ( NCT03723655 ), an ongoing, dose-blinded, 5-year study of CAMZYOS in patients with symptomatic oHCM who completed the EXPLORER-HCM trial. All participants in the EXPLORER-LTE cohort started on 5 mg of CAMZYOS daily, and dose adjustments were made at Weeks 4, 8 and 12 based on site-read echocardiography measures of Valsalva LVOT gradient and LVEF only. Dose adjustment was also possible at Week 24 following site-read echocardiography assessment of post-exercise LVOT gradient. Subsequent to Week 24, dose adjustment was possible if site-read Valsalva LVOT gradient was >30 mmHg and LVEF ≥50%.

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 (oHCM) to improve functional capacity and symptoms, and in the European Union, indicated for the treatment of symptomatic (NYHA, class II-III) oHCM in adult patients. It has also received regulatory approvals in countries and regions across five continents including Argentina, Australia, Brazil, Canada, China, Chile, Great Britain, Hong Kong, Israel, Macau, Singapore, South Korea, Switzerland, and the United Arab Emirates. 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.

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. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS. However, CAMZYOS may reduce the effectiveness of 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, 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 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 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. 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.

Please see U.S. 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 the results of future post-marketing studies will be consistent with the results of this study, that CAMZYOS (mavacamten) may not be commercially successful, any marketing approvals, if granted, may have significant limitations on their use, and that continued approval of CAMZYOS for such indications may be contingent upon verification and description of clinical benefit in additional confirmatory trials. No forward-looking statement can be guaranteed. 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, 2023, 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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