New data at CMR 2024 from FOREST-HCM, the open label extension clinical trial of aficamten in hypertrophic cardiomyopathy

In many patients with HCM, the left ventricular hypertrophy that characterizes the disease results in elevated cardiac mass, and left ventricular outflow tract (LVOT) obstruction is often accompanied by mitral valve regurgitation. Patients with HCM may also present with myocardial fibrosis, a strong predictor of abnormal cardiac rhythm and sudden death, and other cardiac structural abnormalities such as increased left atrial volume. Previously presented data from FOREST-HCM showed that prolonged treatment with aficamten was associated with sustained reductions in LVOT gradients with no treatment interruptions for low left ventricular ejection fraction (LVEF) due to aficamten, as well as sustained reductions in cardiac biomarkers and improved symptoms.

New data just presented from the cardiac magnetic resonance (CMR) sub-study in FOREST-HCM show that treatment with aficamten for 48 weeks resulted in favorable cardiac structural remodeling, improvements in cardiac function, and stabilization of myocardial fibrosis. At the time of this analysis, 16 patients in FOREST-HCM had completed a CMR at baseline and at Week 48. Baseline characteristics of the CMR cohort were comparable to the overall patient population in FOREST-HCM.

In this trial, treatment with aficamten for 48 weeks resulted in statistically significant improvements in measures of cardiac structure and function including left ventricular mass index (-11.4 g/m2 ±19.4, p=0.03), maximum left ventricular septal wall thickness (-1.3 mm ±1.8, p=0.02), left atrial volume (-16.3 ml/m2 ±26.4, p=0.05), and mitral regurgitant volume (-12.9 ml ±15.1, p=0.01) and fraction (-9.5% ± 15.1, p=0.05). Additionally, treatment with aficamten stabilized interstitial and replacement myocardial fibrosis, with no increase in the fibrosis mass, as measured by absolute mass of late gadolinium enhancement (-0.6 g ± 5.0, p=0.64).

“These are the first long-term CMR data to emerge from FOREST-HCM, and they demonstrate potential disease modifying effects of aficamten in patients with obstructive HCM,” said Fady I. Malik, M.D., Ph.D., Cytokinetics’ Executive Vice President of Research & Development. “Added to the existing body of evidence from both FOREST-HCM and SEQUOIA-HCM, the pivotal Phase 3 clinical trial of aficamten in oHCM, these data further support the profile of aficamten as a potential next-in-class cardiac myosin inhibitor that is not only associated with statistically significant and clinically meaningful improvements to hemodynamics and symptoms, but that improves the architecture of the heart. We look forward to expanding on these data in the future.”

About the Broad Phase III Clinical Trials Program for Aficamten: The development program for aficamten is assessing its potential as a treatment that improves exercise capacity and relieves symptoms in patients with HCM as well as its potential long-term effects on cardiac structure and function. SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM), was the pivotal Phase III clinical trial in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). The results from SEQUOIA-HCM show that treatment with aficamten significantly improved exercise capacity compared to placebo, increasing peak oxygen uptake (pVO2) measured by cardiopulmonary exercise testing (CPET) by a least square mean difference (95% CI) of 1.74 (1.04 - 2.44) mL/kg/min (p=0.000002). The treatment effect with aficamten was consistent across all prespecified subgroups reflective of patient baseline characteristics and treatment strategies, including patients receiving or not receiving background beta-blocker therapy. Statistically significant (p<0.0001) and clinically meaningful improvements were also observed in all 10 prespecified secondary endpoints. aficamten was well-tolerated with an adverse event profile comparable to placebo.

Treatment emergent serious adverse events occurred in 8 (5.6%) and 13 (9.3%) patients on aficamten and placebo, respectively. Core echocardiographic left ventricular ejection fraction (LVEF) was observed to be less than 50% in 5 patients (3.5%) on aficamten compared to 1 patient (0.7%) on placebo. There were no instances of worsening heart failure or treatment interruptions due to low LVEF.

Aficamten is currently the subject of two ongoing Phase III clinical trials: MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM), evaluating aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM, and ACACIA-HCM (Assessment Comparing Aficamten to Placebo on Cardiac Endpoints In Adults with Non-Obstructive HCM), evaluating aficamten in patients with symptomatic non-obstructive obstructive HCM from the FDA as well as the National Medical Products Administration (NMPA) in China.