Treatment with aficamten in patients with obstructive hypertrophic cardiomyopathy (oHCM) was associated with broad clinical efficacy across multiple outcome domains, including rapid and sustained decreases in outflow gradients, meaningful improvements in functional class and quality of life, enhanced exercise capacity, and significant reductions in N-terminal pro–B-type natriuretic peptide (NT-proBNP) and hs-troponin concentrations, according to new findings from the SEQUOIA-HCM trial presented as part of HFSA 2024 and simultaneously published in JACC.

SEQUOIA-HCM randomized 282 patients with symptomatic oHCM from 101 academic medical centers in North America, Europe, Israel and China to either aficamten (n=142) or placebo (n=140) for 24 weeks. Initial findings showed improved exercise capacity as assessed by cardiopulmonary exercise testing over a 24-week treatment period compared with placebo.

In the new responder analysis, researchers aimed to characterize the clinical impact of aficamten. Results found that at 24 weeks, patients treated with aficamten vs. placebo showed significant improvement in limiting symptoms (71% vs. 42%), were more likely to have complete hemodynamic response (68% vs. 7%), demonstrated enhanced exercise capacity (47% vs. 24%), and showed a decrease by approximately 50% in NT-proBNP (84% vs. 8%).

Additionally, researchers noted that an improvement in at least one of the outcome measures was achieved in 97% of patients in the aficamten group compared with 59% in the placebo group, and 23% of patients receiving aficamten achieved all four outcomes compared with none in those receiving placebo. Also of note, among the 32 patients in the aficamten group who were eligible for septal reduction therapy, 28 (88%) were no longer eligible at 24 weeks, compared with 15 out of 29 patients (52%) in the placebo group.

“Treatment with aficamten was associated with substantial improvements across a broad range of clinically relevant efficacy measures,” said Martin S. Maron, MD, Ahmad Masri, MD, FACC, et al. “These results underscore the wide-ranging potential of aficamten for treatment of patients with symptomatic oHCM.”

In a related editorial comment in JACC, Torsten B. Rasmussen, MD, PhD, Anne M. Dybro, MD, PhD, and Morten Kvistholm Jensen, MD, PhD, congratulate the authors on their work, but caution that the “substantial treatment effects of placebo in these randomized trials leaves us with a question about the magnitude of these treatment effects.” They suggest that “modification of trial designs, screening procedures, and selection of endpoints could minimize the treatment effects in the placebo groups in future trials.”

Another editorial comment in JACC by Michelle M. Kittleson, MD, PhD, FACC, highlights that these “dives into the SEQUOIA-HCM data provide additional insights into the effects of aficamten in patients with symptomatic obstructive HCM,” but also stresses that many questions remain. “With ongoing clinical trial programs and the future substudies, we will move closer to our ultimate goal—a better understanding of therapeutic options to allow for individualized therapy focused on improving the quality of life and survival of our patients living with symptomatic obstructive HCM,” she writes.