Aficamten and Cardiac Remodeling in FOREST-HCM, with Ahmad Masri, MD, MS

New research from the American College of Cardiology (ACC) 2025 Annual Scientific Sessions suggests prolonged treatment with aficamten was associated with favorable cardiac remodeling in obstructive hypertrophic cardiomyopathy (HCM), including reductions in left ventricular (LV) mass, left atrial (LA) volume, and mitral regurgitation (MR), while maintaining myocardial integrity.1

“These are important results. The reason is not the fact that we only change the structure itself, the reason is that every single one of these structural changes, or every single one of these structural abnormalities at baseline has been associated or is associated with adverse outcomes on long-term follow-up,” explained lead investigator Ahmad Masri, MD, MS, director of the Hypertrophic Cardiomyopathy Center at Oregon Health and Science University, in an interview with HCPLive. “As such, the ability for a medication like aficamten to reverse remodel the ventricle in a favorable way, as well as the atrium, gives us clues that, longer term, we should expect to see improvement in patient outcomes, as well as improvement on how patients do in long term that the studies themselves might not be designed to measure.”

Under FDA review for an indication in obstructive HCM, with a decision expected in September 2025, aficamten is a next-generation cardiac myosin inhibitor developed by Cytokinetics. The ACC.25 presentation by Masri examined data from FOREST-HCM, an open-label extension study of patients from the phase 2 REDWOOD-HCM trial and phase 3 SEQUOIA-HCM trial, the latter of which was used in support for the aforementioned application to the FDA.1,2

As part of FOREST-HCM, a 5-year cardiac magnetic resonance (CMR) imaging sub-study was conducted to assess structural and functional changes in patients receiving aficamten.1

Between May 2021 and August 2024, 292 patients with obstructive HCM were enrolled in FOREST-HCM, with 89 (30%) participating in the CMR sub-study. Of these, 31 patients (mean age 62 ±13 years, 58% female) completed both baseline and follow-up CMR. Investigators pointed out 9 patients had their baseline CMR from the SEQUOIA-HCM trial and 72 weeks of follow-up, while 22 had baseline imaging at the start of FOREST-HCM and 48 weeks of follow-up.1

After 48 to 72 weeks, use of aficamten was associated with significant reductions were observed in LV mass index (-10 [SD, 18] g/m²), maximal LV wall thickness (-2 [SD, 2] mm), LA volume (-19 [SD, 24] mL), MR volume (-17 [SD, 21] mL), and MR fraction (-11% [SD, 17]),(P for all <.0001). Investigators pointed out myocardial fibrosis remained stable, as evidenced by unchanged LV late gadolinium enhancement mass (-0.4 [SD, 4] g, P = .48) and global extracellular volume (-0.7% [SD, 2.5]; P = .08). Investigators also called attention to small but statistically significant decrease in LVEF (-4% [SD, 6], P = .0002) was observed from a baseline of 68% (SD, 5%).1

For more on these results, check out our interview with Masri from ACC.25.

Relevant disclosures for Masri include Cytokinetics, Bristol Myers Squibb, BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, BioMarin, and AstraZeneca.

References:

1. Masri A, Cardoso R, Nassif M, et al. EFFECT OF AFICAMTEN TREATMENT FOR UP TO 72 WEEKS ON CARDIAC STRUCTURE AND FUNCTION IN PATIENTS WITH OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY: THE SEQUOIA-HCM AND FOREST-HCM CMR SUB-STUDIES. Presented at: American College of Cardiology (ACC.25) Annual Scientific Session. March 29 – 31, 2025. Chicago, Il.

2. Cytokinetics. Cytokinetics Announces FDA Acceptance of New Drug Application for Aficamten for the Treatment of Obstructive Hypertrophic Cardiomyopathy | Cytokinetics, Inc. Cytokinetics, Inc. Published December 2, 2024. Accessed April 1, 2025. https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-fda-acceptance-new-drug-application-0.