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Mavacamten demonstrated significant reduction in need for septal reduction therapy in symptomatic obstructive HCM patients in phase III VALOR trial- BMS

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Published:3rd Apr 2022

Bristol Myers Squibb announced results from the Phase III 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 as a late-breaking clinical trial at the American College of Cardiology’s 71st 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.

Key findings at Week 16 included : i .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). ii. 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). iii. the proportion of patients who improved greater than 1 nyha class was significantly greater with mavacamten vs placebo (62.5% [35 56] vs 21.4% [12 56]; p><0.0001). iv. 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). v. 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).></0.0001).></0.0001).></0.0001).></0.0001).>

In the Phase III 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 greater than 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. 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. 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.

Condition: Hypertrophic Cardiomyopathy/Septal Reduction
Type: drug

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