Symptom burden does not influence beneficial effects of aficamten in oHCM
ESC Heart Failure 2025 – A secondary analysis of SEQUOIA-HCM among patients with obstructive hypertrophic cardiomyopathy (oHCM) showed aficamten improved several clinically relevant outcomes, regardless of symptom severity.
This summary is based on the presentation of Iacopo Olivotto, MD (Florence, Italy) at the ESC Heart Failure Congress 2025 - Efficacy and safety of aficamten in patients with obstructive hypertrophic cardiomyopathy and mild symptoms.
Introduction and methods
In patients with obstructive hypertrophic cardiomyopathy (oHCM), the subjectivity and heterogeneity of symptom burden frequently leads to undertreatment of those with objective measures of disease pathology, particularly when symptoms are subtle. Patients with oHCM and mild symptoms who are refractory to first-line medical therapy therefore present an unmet clinical need.
Recently, the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) trial demonstrated treatment with aficamten reduced symptoms and improved functional capacity and quality of life compared with placebo in oHCM patients. In a secondary analysis of the SEQUOIA-HCM trial, the efficacy and safety were examined in oHCM patients stratified by symptom severity at baseline.
The SEQUOIA-HCM trial was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT in which 282 patients with symptomatic oHCM (NYHA class II–III HF symptoms; LV outflow tract (LVOT) gradient ≥30 mmHg at rest and ≥50 mmHg following Valsalva maneuver) and reduced exercise capacity (peak oxygen uptake (pVO₂) ≤90% of predicted) were randomized to aficamten once daily or placebo for 24 weeks, in addition to standard care. The aficamten dose was uptitrated from 5 to 20 mg based on target LVOT gradient and LVEF. In the current analysis, 118 patients with mild symptoms (NYHA class II and KCCQ – Clinical Summary Score (CSS) ≥80) and 150 with moderate-to-severe symptoms (NYHA class II–IV and KCCQ-CSS <80) were included; 14 patients with NYHA class III and KCCQ-CSS ≥80 were excluded.
The primary endpoint was the change in pVO₂ from baseline to 24 weeks. Secondary endpoints included changes from baseline to 24 weeks in NYHA class HF symptoms, KCCQ-CSS, resting and Valsalva LVOT gradients, and NT-proBNP levels, and safety.
Main results
- Among patients treated with aficamten, the placebo-corrected mean change in pVO₂ from baseline to 24 weeks did not differ between participants with mild symptoms (n=62) and those with moderate-to-severe symptoms (n=71) (1.6 mL/kg/min; 95%CI: 0.5–2.7 vs. 1.8 mL/kg/min; 95%CI: 0.8–2.8; P for interaction=0.8).
- The placebo-corrected mean change in KCCQ-CSS with aficamten was 4 points (95%CI: 1–6) in the group with mild symptoms and 10 points (95%CI: 6–15) in the group with moderate-to-severe symptoms (P for interaction=0.02).
- At 24 weeks, 53% of the patients with mild symptoms and 58% of those with more severe symptoms had improved ≥1 NYHA class (P for interaction=0.6).
- There were no differences in the changes in the other secondary endpoints between the 2 symptom groups (all P for interaction>0.05).
- The frequency of treatment-emergent serious adverse events and the incidence of LVEF <50% were low in the 2 treatment groups and in both symptom groups.
Conclusion
In this secondary analysis of the SEQUOIA-HCM trial among patients with symptomatic oHCM, treatment with aficamten resulted in improvements of several clinically relevant outcomes, such as symptom burden and exercise capacity, regardless of symptom severity at baseline.
- Our reporting is based on the information provided at the ESC Heart Failure Congress 2025 and publication of the data in Eur Heart J. -