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Aficamten in symptomatic obstructive hypertrophic cardiomyopathy: the FOREST-HCM long-term study
Key result
Extended aficamten in obstructive HCM yields sustained clinical improvements with low rates of AF and LVEF<50%.
- MD -62
- P<0.0001
- n=296
Figures
Why the study?
The safety and efficacy of extended aficamten treatment in symptomatic obstructive hypertrophic cardiomyopathy were not established.
Does extended aficamten treatment safely improve hemodynamics and symptoms in patients with symptomatic obstructive hypertrophic cardiomyopathy?
Key Points
- To evaluate the long-term safety, tolerability, and efficacy of extended aficamten treatment in patients with symptomatic obstructive hypertrophic cardiomyopathy.
- Open-label extension study (FOREST-HCM, NCT04848506) enrolling patients with symptomatic obstructive hypertrophic cardiomyopathy who completed a parent aficamten trial.
- Included N = 296 patients (mean age 61 ± 12.3 years, 44.3% female) followed for a median duration of 51.6 weeks (IQR 41.5, 70.8) with 352 patient-years of cumulative exposure between May 2021 and August 2024.
- Aficamten significantly reduced the Valsalva left ventricular outflow tract gradient from baseline by 56 ± 43 mmHg at Week 12 and 62 ± 33 mmHg at Week 96 (both P < 0.0001), with modest reductions in left ventricular ejection fraction (-3% ± 6% and -5% ± 5%).
- Functional improvements occurred in 69% of patients at Week 12 and 93% at Week 96 who gained ≥1 NYHA class, alongside KCCQ-CSS gains of 15 ± 16 and 16 ± 16 points.
- Treatment-emergent serious adverse events occurred in 36 (12.2%) patients with zero treatment-related deaths or heart failure, while LVEF < 50% occurred in 10 (3.4%) patients with no episodes dropping below 40%.
Structured PICO
Does extended aficamten treatment safely improve hemodynamics and symptoms in patients with symptomatic obstructive hypertrophic cardiomyopathy?
P
Population
296 patients with symptomatic obstructive hypertrophic cardiomyopathy who completed a parent aficamten study, followed for a median of 51.6 weeks.
I
Intervention
Extended aficamten treatment (oral selective cardiac myosin inhibitor)
O
Outcome
Valsalva left ventricular outflow tract gradient, left ventricular ejection fraction (LVEF), NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score, and safety events at Weeks 12 and 96surrogate
Main Result
Mean Difference: -62
p-value: p=<0.0001
Extended aficamten treatment in symptomatic obstructive hypertrophic cardiomyopathy provides sustained improvements in left ventricular outflow tract gradients and symptoms with a favorable long-term safety profile.
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“What we are seeing is actually a rapid, pretty robust and sustained reduction in outflow obstruction with maintenance of LV systolic function over that time period, along with significant improvements in how patients report to us that they feel in terms of assessments by KCCQ.”
“Patients with non-obstructive HCM have no effective medical therapies and lack an apparent therapeutic target like reducing or eliminating the LVOT obstruction, underscoring the need for a therapy to address the underlying cause of the disease. The results from Cohort 4 of REDWOOD-HCM demonstrate that treatment with aficamten is well-tolerated and associated with significant improvements in heart failure symptoms and cardiac biomarkers in patients with non-obstructive HCM and support the advancement of aficamten into a pivotal Phase III clinical trial in patients with non-obstructive HCM.”
“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. 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.”
Implication
Strengthens case for long-term aficamten in symptomatic oHCM; extends randomized trial data with durable cohort safety and efficacy.
Abstract
BACKGROUND AND AIMS: Aficamten is a next-in-class, oral selective cardiac myosin inhibitor that ameliorates hypercontractility in hypertrophic cardiomyopathy (HCM). This study assessed the safety and efficacy of extended aficamten treatment in symptomatic obstructive HCM (oHCM). METHODS: Patients completing a parent aficamten study were eligible to enrol in FOREST-HCM (NCT04848506), an open-label study evaluating long-term aficamten treatment. RESULTS: Patients with oHCM (N = 296; mean age ±SD 61 ± 12.3 years, 44.3% female) enrolled between May 2021 and August 2024. Cumulative exposure was 352 patient-years; median follow-up 51.6 (IQR 41.5, 70.8) weeks. At Weeks 12 and 96, aficamten reduced Valsalva left ventricular outflow tract gradient by 56 ± 43 and 62 ± 33 mmHg from baseline (both P < 0.0001), with minimal reduction in left ventricular ejection fraction (LVEF) (-3% ± 6% and -5% ± 5%); 69% and 93% of participants had at least one NYHA class improvement; Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score improved by 15 ± 16 and 16 ± 16 points. Treatment-emergent serious adverse events (TESAEs) occurred in 36 (12.2%) patients; no deaths, heart failure, or events considered related to aficamten were reported. One (0.3%) patient terminated therapy due to a TESAE (ischemic colitis). LVEF<50% occurred in 10 (3.4%) patients [exposure-adjusted incidence rate (EAIR): 2.9 per 100 patient-years] with 2 having non-serious mild/moderate dyspnoea. No treatment interruptions for LVEF<50%, and no events of LVEF<40% occurred. New-onset atrial fibrillation occurred in seven (2.4%) patients (EAIR 2.0 per 100 patient-years). CONCLUSIONS: Extended aficamten treatment in patients with symptomatic oHCM yielded early and sustained hemodynamic and clinical responses with low incidences of new-onset atrial fibrillation and LVEF<50%.
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Cite This Study
Tower‐Rader et al. (2025) studied symptomatic obstructive hypertrophic cardiomyopathy (oHCM) (n=296). Aficamten was evaluated on Valsalva left ventricular outflow tract gradient at Week 96 (MD -62, p=<0.0001). Extended aficamten treatment in symptomatic obstructive hypertrophic cardiomyopathy reduced Valsalva left ventricular outflow tract gradient by 62 mmHg from baseline at 96 weeks (P<0.0001).