SEQUOIA-HCM (NCT5186818) is a phase 3, international, double-blind, randomized, placebo-controlled trial in which patients with symptomatic oHCM received aficamten or placebo in addition to standard-of-care drug treatment. ^, The trial design and primary results have been described previously. ^, All patients provided written informed consent, and the study was conducted in accordance with the principles outlined in the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. An independent data and safety monitoring committee reviewed unblinded safety data during the conduct of the trial.

Eligible patients (aged 18 to 85 years) had a confirmed clinical diagnosis of oHCM with resting LVOT-G ≥30 mm Hg, Valsalva LVOT-G ≥50 mm Hg, left ventricular ejection fraction (LVEF) ≥60%, New York Heart Association (NYHA) functional class II–III, and predicted age- and sex-adjusted baseline peak oxygen uptake (pVO ₂ ) ≤90% by cardiopulmonary exercise test (CPET), coupled with a baseline respiratory exchange ratio ≥1.05. Key exclusion criteria included history of syncope or sustained ventricular tachyarrhythmia during exercise within 6 months before screening, or an inability to exercise on a treadmill or cycle.

Aficamten or placebo was administered once daily. The starting dose of aficamten was 5 mg, with 3 subsequent opportunities to increase by 5-mg increments (at Weeks 2, 4, and 6), up to a maximum dose of 20 mg. At each visit, the site echocardiographic cardiologist determined resting and Valsalva LVOT-G and LVEF and entered these data into the interactive web-response system, which subsequently assigned the appropriate dose of aficamten or matching placebo according to a preprogrammed algorithm. At each titration visit, dose escalation occurred if Valsalva LVOT-G was ≥30 mm Hg and LVEF was ≥55%. At any visit, if LVEF was <50%, the dose was decreased to the next lower dose and no further dose escalation was permitted. If the site-read LVEF was <40%, the drug was temporarily interrupted with the opportunity to restart at the next lower dose after 7 days if LVEF was ≥55%, but this did not occur during the trial. ^,

In the current analysis, patients were grouped according to baseline core laboratory–interpreted Valsalva LVOT-G. The very-high gradient group included enrolled patients with baseline Valsalva LVOT-G ≥100 mm Hg due to typical mitral valve ventricular septal contact, and the high gradient group included enrolled patients with baseline Valsalva LVOT-G ˂100 mm Hg. Primary, secondary, and exploratory endpoints were compared between treatments (aficamten vs placebo) among patients in the very-high gradient group.

The prespecified primary endpoint was proportional change from baseline to Week 24 in aficamten vs placebo patients in Valsalva LVOT-G as assessed by the echocardiography core laboratory.

Secondary endpoints included changes from baseline to Week 24 in (1) absolute Valsalva LVOT-G assessed by the core laboratory; (2) Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS); (3) workload during CPET assessed by the core laboratory; and (4) pVO ₂ by CPET assessed by the core laboratory. Additional secondary endpoints included proportion of patients achieving resolution of very-high Valsalva LVOT-G (<30 mm Hg) at Week 24, proportion of patients with ≥1 class improvement in NYHA functional class at Week 24 compared with baseline, and overall duration of eligibility for SRT during the 24-week treatment period in patients who were eligible at baseline (defined as NYHA class III/IV and resting or Valsalva LVOT-G ≥50 mm Hg). An exploratory endpoint was the geometric mean proportional change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration from baseline to Week 24.

Baseline characteristics were summarized using mean and standard deviation (SD) for normally distributed continuous variables, median and interquartile range (IQR) for right-skewed variables, and counts with percentages for categorical variables. Differences in baseline characteristics were compared using analysis of variance, the Kruskal-Willis test, and Pearson’s χ² test, as appropriate. Within-group changes were assessed using paired t -tests and Wilcoxon signed-rank tests. Treatment effects on secondary endpoints were analyzed using linear regression, adjusted for baseline values of continuous outcomes, randomized treatment, and stratification variables (beta-blocker use and CPET modality). NT-proBNP values were log-transformed prior to inclusion in regression models. The p-values <0.05 were considered statistically significant. Owing to the exploratory nature of these analyses, the 9 p-values pertaining to the tests of efficacy of aficamten were not adjusted for multiple comparisons. Analysis was performed by Brigham and Women’s Hospital Clinical Trials Outcomes Center using STATA version 18.5 (StataCorp, College Station, TX). The overall analysis was prespecified per the SEQUOIA-HCM: Academic Statistical Analysis Plan. The authors, who had full access to the data, vouch for the accuracy and completeness of the data and data analyses.

From February 1, 2022, to May 15, 2023, 543 patients were screened for eligibility at 101 sites in 14 countries, of whom 282 underwent randomization (1:1) to and received aficamten (n = 142) or placebo (n = 140). At baseline, 209 (74%) patients with oHCM had high Valsalva LVOT-G of <100 mm Hg and 73 (26%) had very-high LVOT-G of ≥100 mm Hg.

Baseline characteristics were similar between gradient groups ( Supplementary Table S1 ), except for the following (high vs very-high LVOT-G, respectively): female sex (37% vs 51%), mean ± SD Valsalva and resting gradients (69 ± 21 and 44 ± 21 mm Hg vs 123 ± 25 and 86 ± 28 mm Hg), total workload during CPET (128 ± 39 vs 108 ± 41 W), mean pVO ₂ (18.8 vs 17.5 ml/kg/min), and median NT-proBNP (644 vs 1148 pg/ml).

Of the 73 patients in the very-high gradient group, 33 were treated with aficamten (34.4% received 15 mg and 56.2% received 20 mg of aficamten) and 40 received placebo ( Tables 1 and 2 ). Patients were aged 61.5 ± 13.6 years (range 23 to 82 years), with 3 (4.1%) patients <30 years old and 41 (56.2%) >60 years old; and had heart failure symptoms consistent with NYHA functional class III/IV (n = 22) or class II (n = 51).

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