Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy that cannot be explained by another condition. Clinically, HCM is classified into obstructive (oHCM) and non-obstructive forms depending on whether left ventricular outflow tract obstruction (LVOTO) is present. Approximately two-thirds of patients have oHCM, which carries a higher risk of sudden cardiac death due to impaired blood flow. Traditional treatment approaches, such as beta-blockers, calcium channel blockers, or invasive procedures, can provide symptomatic relief but have limitations in efficacy and long-term outcomes. Therefore, novel and targeted therapies remain a key focus in HCM management.

Aficamten (CK-3773274), developed by Cytokinetics, is a next-in-class, oral, selective cardiac myosin inhibitor (CMI). Its mechanism of action is to reduce sarcomere hypercontractility by allosterically inhibiting myosin ATPase activity, thereby alleviating pathological hypertrophy, LVOTO, and myocardial fibrosis. Compared with mavacamten, the first FDA- and EMA-approved CMI, aficamten was designed with optimized pharmacologic features including a half-life of ~3.4 days, low pharmacokinetic variability, metabolism via multiple CYP450 pathways (reducing drug-drug interaction risks), absence of teratogenicity, and a shallow dose-response curve providing a wide therapeutic window. Preclinical models and clinical studies suggest that aficamten not only improves symptoms and cardiac function but may also reverse structural changes in the heart. The FDA accepted its NDA in December 2024, with a PDUFA action date of December 26, 2025.

The ESC Congress 2025 together with World Congress of Cardiology has been held in Madrid, Spain, from August 29 to September 1, 2025. At this meeting, results from the landmark MAPLE-HCM trial, evaluating aficamten in oHCM, along with other important data, has been presented.

MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM)

MAPLE-HCM is a global Phase 3 multicenter, randomized, double-blind, double-dummy, and head-to-head trial designed to compare the efficacy of aficamten vs metoprolol in participants with symptomatic oHCM. A total of 175 symptomatic oHCM patients were enrolled across 71 centers worldwide and randomized 1:1 to receive either aficamten or metoprolol for 24 weeks.

At 24 weeks, the change in the peak oxygen uptake was 1.1 ml per kilogram of body weight per minute (95% confidence interval [CI], 0.5 to 1.7) in the aficamten group and −1.2 ml per kilogram per minute (95% CI, −1.7 to −0.8) in the metoprolol group. Patients who received aficamten had significantly greater improvements in New York Heart Association (NYHA) class, Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), left ventricular outflow tract gradient, N-terminal pro–B-type natriuretic peptide (NT-proBNP) level, and left atrial volume index than patients who received metoprolol. No significant difference in left ventricular mass index was observed. Adverse events appeared to be similar in the two treatment groups.

Figure 1. MAPLE-HCM primary endpoint, source: reference [1]

REDWOOD-HCM, SEQUOIA-HCM, and FOREST-HCM Trials: Incidence and Impact of Atrial Fibrillation in oHCM with Aficamten

1) Incidence of Atrial Fibrillation (AF) Across REDWOOD-HCM, SEQUOIA-HCM, and FOREST-HCM

This analysis evaluated AF incidence among 173 patients with oHCM who participated in either the REDWOOD-HCM or SEQUOIA-HCM studies and subsequently received ≥48 weeks of aficamten treatment in the FOREST-HCM open-label extension. [2]

Findings showed that the annualized incidence of AF in aficamten-treated patients was only 1.5%, consistent with the predicted incidence based on HCM risk models. The low rate of new-onset AF during long-term aficamten treatment suggests that aficamten may be a safe and effective therapeutic option for patients with oHCM, including those with a history of atrial fibrillation.

2) FOREST-HCM Study

The FOREST-HCM trial is a Phase II/III open-label extension designed to assess the long-term safety and durability of aficamten in symptomatic oHCM. A total of 296 patients were enrolled, with a mean follow-up duration of 62 weeks. [3]

Key results included:

• Rapid and sustained hemodynamic response: Within 12 weeks of treatment, both resting and Valsalva-induced LVOT gradients declined substantially, remaining stable throughout long-term follow-up. In most patients, Valsalva-induced LVOT gradients were maintained below 30 mmHg, meeting criteria for hemodynamic response.

• Preserved cardiac function: Mean LVEF decreased only slightly, with average reductions of less than 5%. Importantly, no patients experienced an LVEF <40%, indicating a preserved safety margin.

• Biomarker improvements: NT-proBNP levels declined significantly by week 12 (mean reduction of 532 pg/mL) and remained low during follow-up. High-sensitivity troponin I also decreased by 3.4 ng/L at week 12, reflecting reduced myocardial stress.

• Symptomatic and quality-of-life benefits: Patients reported meaningful symptomatic relief and sustained improvements in health-related quality of life measures.

Long-term treatment with aficamten in symptomatic oHCM results in early, marked, and durable reductions in LVOT gradients, improvements in clinical symptoms, and favorable biomarker trends, while maintaining good safety and tolerability.

Conclusion

At this year’s meeting, the next-generation CMI aficamten demonstrated breakthrough value in the management of hHCM, supported by robust clinical evidence and distinct therapeutic advantages. Aficamten not only has the potential to redefine first-line treatment strategies for oHCM, but also sets a new benchmark for precision therapy in HCM with its profile of high efficacy, safety, and convenience.

About Huateng Pharma

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References:

[1].Aficamten or Metoprolol Monotherapy for Obstructive Hypertrophic Cardiomyopathy. New England Journal of Medicine. Published August 30, 2025. DOI: 10.1056/NEJMoa2504654

[2]. Low Incidence of Atrial Fibrillation in Patients with Obstructive HCM Treated with Aficamten: An Analysis from the REDWOODHCM, SEQUOIA-HCM and FOREST-HCM Trials, Heart Rhythm (2025), doi: https://doi.org/10.1016/ j.hrthm.2025.08.031.

[3].Efficacy and safety of long-term treatment with aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy: results from FOREST-HCM.ESC 2025