Abstract Body (Do not enter title and authors here): Background: In severely symptomatic obstructive hypertrophic cardiomyopathy (HCM) patients on maximally tolerated medical therapy, VALOR-HCM (NCT04349072) demonstrated a significant reduction in eligibility for septal reduction therapies (SRT) following mavacamten treatment. However, long-term safety & efficacy data on mavacamten is still needed.

Methods: A total of 112 symptomatic obstructive HCM patients (≥ 18 years old) who met HCM-guideline criteria & were eligible & considering SRT were randomized 1:1 to mavacamten or placebo for 16 weeks. After week 16, patients originally randomized to mavacamten continued the same dose they were receiving at Week 16. Patients originally randomized to placebo group started mavacamten 5 mg at Week 16. After week 32, dose adjustment was allowed every 12 weeks based on site-read echo if indicated (for left ventricular ejection fraction or LVEF ≥50% or elevated LV outflow tract or LVOT gradients). The efficacy endpoint was meeting guideline eligibility for SRT or decision to proceed with SRT prior to or at Week 128. Other endpoints included change from baseline to Week 128 in post-exercise LVOT gradient, New York Heart Association (NYHA) class, Kansas City Cardiomyopathy Questionnaire clinical summary score ((KCCQ-CSS), n-terminal pro brain natriuretic peptide (NT-proBNP), & cardiac troponin-I. We will report the dose-blinded safety & efficacy results through 128 weeks (end of treatment or EOT) in patients originally randomized to mavacamten (Day 1 to Week 128) & patients placebo patients who crossed over to mavacamten for 112 weeks exposure (Week 16 to Week 128).

Results: 108 patients qualified for Week 128 evaluation (original mavacamten group [n=56] and placebo to mavacamten group [n=52]). All patients were symptomatic (94% NYHA class III/IV) on maximally tolerated HCM therapy with majority on beta-blocker monotherapy (45%). Mean (±standard deviation) LVEF & peak resting, Valsalva, & post-exercise LVOT gradients were 68% ± 4, & 50 ± 31, 77 ± 30, & 84± 35 mmHg, respectively. Continued eligibility for SRT at Week 128, along with change from baseline analyses for the secondary endpoints will be presented. In addition, data on final mavacamten dosages, up or down-titration of background HCM therapies & safety data will be presented

Conclusions: In severely symptomatic drug-refractory obstructive HCM patients meeting SRT criteria, we will report on the safety & efficacy of mavacamten treatment at up to 128 weeks.