Mavacamten Demonstrated Significant Reduction in Need for Septal Reduction Therapy in Symptomatic Obstructive HCM Patients in Phase 3 VALOR Trial

Mavacamten is a first-in-class, investigational cardiac myosin inhibitor being developed by Bristol Myers Squibb

Study met all primary and secondary endpoints and patients receiving mavacamten demonstrated improvement in key cardiac measures after 16 weeks of treatment

VALOR-HCM study presented as late-breaking clinical trial at the American College of Cardiology’s 71^st Annual Scientific Session

Bristol Myers Squibb (NYSE: BMY) today announced results from the Phase 3 VALOR-HCM study, which showed the addition of mavacamten, an investigational, first-in-class cardiac myosin inhibitor, significantly reduced the need for septal reduction therapy (SRT) in patients with severely symptomatic obstructive hypertrophic cardiomyopathy (obstructive HCM) who had been appropriate for SRT per the 2011 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines at baseline. Study participants were on maximally tolerated background regimens when they entered the trial and remained on them through the duration of the study. These data were presented today as a late-breaking clinical trial at the American College of Cardiology’s 71^st Annual Scientific Session.

At 16 weeks the primary and all secondary endpoints were met. Of patients treated with mavacamten, 82% had not proceeded with SRT and no longer met the criteria for SRT according to the 2011 ACC/AHA Guidelines compared to 23% of patients receiving placebo. Patients in the mavacamten arm also demonstrated reduction in left ventricular outflow tract (LVOT) gradients, improvement in New York Heart Association (NYHA) Classification, improvement in quality-of-life measures and improvement in cardiac biomarkers at a high degree of statistical significance compared to the placebo arm. No new safety signals were observed.

“VALOR-HCM builds upon findings of the Phase 3 EXPLORER-HCM trial and shows mavacamten to be an effective potential treatment option for those with severe symptomatic obstructive HCM who meet guideline criteria for SRT,” said Milind Desai, M.D., MBA, director of HCM center and director of clinical operations, Heart, Vascular & Thoracic Institute, Cleveland Clinic. “The data presented today are clinically meaningful and have demonstrated the potential to impact parameters leading to SRT eligibility.”

Key findings at Week 16 included:

• The composite percentage of patients who proceeded with SRT before or after Week 16 and those who remained eligible for SRT was significantly lower in those taking mavacamten than those receiving placebo (17.9% [10/56] vs 76.8% [43/56]; P<0.0001).
• Post-exercise LVOT peak gradient significantly decreased in patients treated with mavacamten vs placebo (mean values at Week 16 = 42.0 mmHg ± 30.0 mmHg vs 83.2 mmHg ± 36.4 mmHg due to reductions from baseline with mavacamten of -39.1 mmHg ± 36.5 mmHg vs -1.8 mmHg ± 28.8 mmHg with placebo).
• The proportion of patients who improved ≥1 NYHA Class was significantly greater with mavacamten vs placebo (62.5% [35/56] vs 21.4% [12/56]; P<0.0001).
• On the patient-reported 23-item Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-23 CSS), average scores of symptom frequency, symptom burden and physical limitation significantly improved in patients treated with mavacamten vs placebo (change from baseline: +10.4 ± 16.1 vs +1.9 ± 12.0; P<0.0001).
• Improvement in biomarkers of cardiac wall stress and myocardial injury with mavacamten treatment over placebo showed reduction in N-terminal pro brain natriuretic peptide (NT-proBNP) that was 67% greater and reduction in cardiac troponin I that was 47% greater (p<0.0001).
• Safety data show no subjects permanently discontinuing therapy due to left ventricular ejection fraction (LVEF) ≤30% and no subjects experiencing serious adverse events of congestive heart failure, syncope or sudden cardiac death. Two subjects transiently experienced LVEF <50% and resumed treatment on a lower dose after a short interruption.

“These results validate the promising potential of mavacamten as an important treatment option for symptomatic oHCM patients,” said Marie-Laure Papi, vice president and mavacamten development lead, Bristol Myers Squibb.

In the Phase 3 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 mavacamten (n=56) or placebo (n=56) for 16 weeks. Study participants remained consistent on their maximally tolerated baseline standard of care regimens, which included ß-blockers, calcium channel blockers and/or disopyramide administered as monotherapy or in combination. Echocardiograms were conducted to evaluate LVOT gradient and LVEF at baseline and during drug titration to guide dosing and assess safety at Weeks 4, 8 and 12. Change from baseline in SRT eligibility, post-exercise LVOT peak gradient, NYHA Class, KCCQ-23 CSS and biomarkers (NT-proBNP and cardiac troponin I) were analyzed at Week 16.

Eligibility for SRT was determined based on NYHA Class III or Class IV and LVOT gradient ≥ 50 mmHg at rest or with exertion from Valsalva or exercise, or NYHA Class II with exertional symptoms of syncope or near syncope and elevated gradients. NYHA Classification ranges from I to IV, with Class I showing no symptoms and Class IV exhibiting symptoms at rest.¹ The KCCQ-23 CCS is the average score of patient-reported clinical symptoms, including the frequency and burden of lower extremity swelling, fatigue and dyspnea as well as physical limitations, including, but not limited to, dressing, showering, walking and yardwork.² Scores are based on a scale of 0 (worst) to 100 (best), with a change of 5 points considered clinically important and ≥10 to 20 points considered a moderate-to-large improvement.^3,4

About the Phase 3 VALOR-HCM Trial

VALOR-HCM (NCT04349072) is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study of patients with symptomatic obstructive HCM (NYHA Class III-IV or NYHA Class II with exertional syncope or near syncope) who meet guideline criteria for septal reduction therapy (SRT) and have been referred for an invasive procedure. The study enrolled 112 patients randomized on a 1:1 basis to receive mavacamten or placebo. VALOR-HCM includes three treatment periods over 128 weeks: a 16-week placebo-controlled period, a 16-week active treatment period where all patients will receive mavacamten and a 96-week long-term extension period where all patients will continue to receive mavacamten.

The primary endpoint of VALOR-HCM is a composite of the number of patients who decide to proceed with SRT prior to or at Week 16 and the number of patients who remain SRT-guideline eligible (LVOT gradient of ≥50mmHg and NYHA Class III-IV or Class II with syncope) at Week 16 in the mavacamten group compared with the placebo group. Key secondary endpoints include impact on exercise gradient LVOT, NYHA Class and Kansas City Cardiomyopathy Questionnaire (KCCQ) and cardiac biomarkers (NT-proBNP and cardiac troponin I) at Week 16.

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 Mavacamten

Mavacamten is a first-in-class, oral, allosteric modulator of cardiac myosin being investigated for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (obstructive HCM) which is a progressive disease that thickens the heart walls and makes it harder for the heart to expand normally and fill with blood. It is a selective cardiac myosin inhibitor that targets the underlying pathophysiology of obstructive HCM.

Mavacamten has been shown to reduce cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation that results in hypercontractility, left ventricular hypertrophy and reduced compliance. Based on data from the EXPLORER-HCM study, the company has a PDUFA date in the U.S. of April 28, 2022.

In clinical and preclinical studies, mavacamten has consistently reduced biomarkers of cardiac wall stress, lessened excessive cardiac contractility, increased diastolic compliance and lessened left ventricular outflow tract (LVOT) gradients. Mavacamten is an investigational therapy and is not approved for use in any country.

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 will be consistent with the results to date, that mavacamten may not receive regulatory approval for the indication described in this release in the currently anticipated timeline or at all, any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such product candidate for such indication described in this release will be commercially successful. 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, 2021, 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

¹ Pahal P, Sharma S. Secondary Pulmonary Hypertension. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. [Figure, NYHA Classification - Heart failure. Contributed by the New York Health Association (NYHA)] Available from: https://www.ncbi.nlm.nih.gov/books/NBK526008/figure/article-28040.image.f1/

² Qualification of the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and its Component Scores A Patient-Reported Outcome Instrument for Use in Clinical Investigations in Heart Failure. [Updated 2020 April 9]. Food and Drug Administration [Internet]. Available from: https://www.fda.gov/media/136862/download

³ Spertus, J A, et al. Interpreting the Kansas City Cardiomyopathy Questionnaire in Clinical Trials and Clinical Care: JACC State-of-the-Art Review, Journal of the American College of Cardiology, Volume 76, Issue 20, 2020, Pages 2379-2390, ISSN 0735-1097, https://doi.org/10.1016/j.jacc.2020.09.542.

⁴ Spertus, J A, Jones P G. Development and Validation of a Short Version of the Kansas City Cardiomyopathy Questionnaire. Circulation: Cardiovascular Quality and Outcomes. 2015;8:469–476. https://doi.org/10.1161/CIRCOUTCOMES.115.001958.

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$BMY announces results from Phase 3 study of investigational myosin inhibitor in patients with symptomatic obstructive hypertrophic cardiomyopathy (#HCM) eligible for septal reduction therapy at #ACC22.