Highlight
- Aficamten provided rapid, significant, and sustained reductions in left ventricular outflow tract (LVOT) obstruction over 48 weeks in symptomatic obstructive hypertrophic cardiomyopathy (oHCM).
- 82% of patients experienced improvement by at least one NYHA functional class; cardiac remodeling was supported by reductions in left ventricular wall thickness and cardiac biomarkers.
- Combination therapy of aficamten and disopyramide was safe but did not enhance efficacy beyond aficamten alone; disopyramide discontinuation during aficamten treatment appears feasible.
Study Background and Disease Burden
Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by thickened myocardial walls causing LVOT obstruction, leading to symptoms such as dyspnea, chest pain, and exercise intolerance. This condition imparts significant morbidity and mortality risks, including sudden cardiac death and heart failure progression. Pharmacological options have been limited, primarily including beta-blockers, calcium channel blockers, and disopyramide. Disopyramide, a negative inotrope, reduces cytosolic calcium and has been used for decades to manage refractory obstruction. However, optimal long-term treatments with better safety profiles remain a clinical need.
Aficamten (CK-3773274) is a novel, selective cardiac myosin inhibitor that directly reduces hypercontractility by preventing excessive myosin-actin crossbridge formation. Early-phase trials (REDWOOD-HCM and SEQUOIA-HCM) demonstrated its promising hemodynamic and symptomatic benefits. However, robust long-term data on its safety, efficacy, and influence on cardiac structure were lacking, prompting the FOREST-HCM open-label extension study.
Furthermore, the role and safety of concomitant aficamten and disopyramide treatment and the feasibility of withdrawing disopyramide after aficamten initiation warranted investigation, given overlapping mechanisms and potential for simplification of therapy.
Study Design
The FOREST-HCM study is an ongoing phase 2/3, multicenter, open-label extension trial (NCT04848506) enrolling participants from prior aficamten trials, REDWOOD-HCM and SEQUOIA-HCM. Adults with symptomatic oHCM received oral aficamten starting at 5 mg once daily, with titration up to 20 mg guided by echocardiographic measurements of LVOT gradient using the Valsalva maneuver and left ventricular ejection fraction (LVEF).
Separately, a pooled analysis of REDWOOD-HCM Cohort 3, SEQUOIA-HCM, and FOREST-HCM evaluated the safety and efficacy of combined aficamten and disopyramide therapy. Patients were classified into four groups: (1) disopyramide plus aficamten with subsequent aficamten withdrawal, (2) disopyramide plus placebo, (3) aficamten plus disopyramide with subsequent disopyramide withdrawal, and (4) continuous combination therapy with disopyramide and aficamten.
Primary endpoints included changes in resting and Valsalva LVOT gradients, symptomatic improvement via NYHA functional class and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and biomarker changes such as NT-proBNP levels. Safety endpoints encompassed left ventricular function, atrial fibrillation incidence, and adverse events necessitating treatment discontinuation.
Key Findings
From May 2021 to October 2023, a total of 213 patients enrolled in FOREST-HCM, with 46 completing 48 weeks of follow-up (mean age 59.7 years, 56.5% female). Aficamten induced rapid and sustained reductions in mean resting LVOT gradient by 40 ± 34 mm Hg and Valsalva peak LVOT gradient by 53 ± 39 mm Hg at week 48 compared to baseline.
Clinically, 82% experienced at least one NYHA functional class improvement, and 31% achieved a significant 20-point or greater improvement in KCCQ-CSS, reflecting better quality of life and symptom burden relief.
Cardiac remodeling indices showed favorable changes: maximum left ventricular wall thickness decreased by 1.2 ± 1.6 mm (P < 0.0001), left atrial volume index reduced by 3.5 ± 6.6 mL/m2 (P = 0.0008), and lateral E/e' ratio, indicative of diastolic function, improved by 2.2 ± 6.1 (P = 0.02). These changes paralleled reductions in cardiac biomarkers (P ≤ 0.0031), suggesting decreased myocardial stress.
Safety analysis revealed good tolerance of aficamten, with only 2 asymptomatic, transient reductions in LVEF to below 50% (47%-49%) that did not result in treatment discontinuation. No new incidents of atrial fibrillation were recorded.
In the concomitant therapy study involving 93 treatment periods in 50 unique patients, aficamten added to disopyramide markedly reduced LVOT obstruction (resting gradient Δ -27.0 ± 3.6 mm Hg, Valsalva gradient Δ -39.2 ± 5.0 mm Hg; both P < 0.0001) and symptoms (NYHA improvement in 77.8%, KCCQ-CSS increase by 12.3 ± 3.3 points). NT-proBNP levels also declined significantly (ratio 0.35; P < 0.0001). Placebo addition to disopyramide did not produce such effects.
Discontinuing aficamten while continuing disopyramide led to return of obstruction and symptomatic deterioration, with biomarker worsening to baseline. Conversely, withdrawing disopyramide during aficamten therapy did not diminish clinical efficacy. No safety concerns or atrial fibrillation episodes occurred upon disopyramide withdrawal.
Expert Commentary
These findings substantiate aficamten as a potent and durable therapy for symptomatic oHCM, aligning with mechanistic rationale targeting hypercontractility at the sarcomeric level. The documented structural and biomarker improvements suggest potential for reverse remodeling, a critical goal beyond symptomatic relief.
The favorable safety profile addresses concerns associated with earlier negative inotropes, particularly risk of ventricular dysfunction and arrhythmias.
The combination data indicate that while aficamten and disopyramide are safe together, aficamten alone suffices for clinical efficacy. This allows therapeutic simplification and may reduce polypharmacy and adverse effects associated with disopyramide.
Limitations include open-label design and relatively small sample size with 48-week data. Further longer-term randomized controlled trials will confirm durability and mortality impact.
Conclusion
Aficamten offers compelling, sustained hemodynamic and symptomatic benefits in patients with symptomatic obstructive hypertrophic cardiomyopathy over 48 weeks, with favorable cardiac remodeling and excellent tolerability. Combination with disopyramide is safe but clinically redundant, supporting aficamten monotherapy initiation and disopyramide discontinuation when appropriate. These findings mark an important advance in the medical management of oHCM, addressing an unmet need for effective, long-term therapy.
References
Saberi S, et al. Aficamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: 48-Week Results From FOREST-HCM. JACC Heart Fail. 2025 Aug;13(8):102496. doi:10.1016/j.jchf.2025.03.040. PMID: 40540987.
Masri A, et al. Concomitant Aficamten and Disopyramide in Symptomatic Obstructive Hypertrophic Cardiomyopathy. JACC Heart Fail. 2025 Apr 2:102441. doi:10.1016/j.jchf.2025.03.008. PMID: 40285763.
