Cardiac myosin inhibitor improves exercise capacity in obstructive HCM
ESC Heart Failure 2024 – Treatment with aficamten over 24 week in patients with obstructive HCM resulted in improvement in exercise capacity and significant changes in 10 secondary endpoints including improvements in both KCCQ-CSS and NYHA functional class.
This summary is based on the presentation of Martin Maron, MD (Boston, MA, US) at the ESC Heart Failure Congress 2024 – Aficamten for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy – SEQUOIA-HCM
Introduction and methods
Left ventricular outflow tract (LVOT) obstruction in HCM is a determinant of limiting symptoms, especially exertional dyspnea and reduced exercise capacity. Hypercontractility is an important disease-related mechanism responsible for LVOT obstruction.
There is an unmet need for treatment of obstructive HCM as current first-line medical therapies have limited efficacy and side effects. Aficamten is a novel oral selective cardiac myosin inhibitor, which reduces the excess of myosin cross bridges at the sarcomere level. In the REDWOOD-HCM phase 2 study, it was shown that aficamten reduced LVOT gradients by mitigating cardiac hypercontractility.
In the SEQUOIA-HCM phase 3 trial, patients with oHCM treated with standard of care and LVOT ≥30 mmHg and Valsava ≥50 mmHg, NYHA FC II-III and predicted peak oxygen uptake (pVO₂) ≤90% for age and sex were enrolled. Patients were randomized to aficamten (n=142) or placebo (n=140). Study duration was 24 weeks. Patients in the aficamten group were started on 5 mg once daily starting dose with the opportunity to 5 mg increases up to 20 mg once daily maximum, based on echocardiogram assessment. Primary endpoint was the change in pVO₂ by CPET from baseline to week 24.
Main results
- There was a significant difference in the change in pVO₂ at week 24 between the aficamten group and the placebo group, with a favorable change in the aficamten group (LS mean difference vs placebo was 1.74 mL/kg/min (SE 0.36) (P=0.000002). This is a clinically meaningful change as the risk of death or transplantation in HCM is reduce ~18% for each increase in pVO₂ of 1 mL/kg/min.
- Subgroup analyses showed consistent benefit with aficamten across all prespecified subgroups.
- In the aficamten group, all 10 secondary endpoints, including KCCQ-CSS change, % NYHA class improvement by at least 1 class, Valsava LVOT-G change, guideline eligibility for SRT, and NT-proBNP levels at week 24 were significantly changed compared with the placebo group (all P <0.0001).
Conclusion
In patients with symptomatic oHCM, treatment with aficamten over 24 weeks resulted in clinically meaningful improvements in exercise capacity (pVO₂). Moreover, aficamten treatment resulted in a decreased burden of limiting symptoms based on improvements in both KCCQ-CSS and NYHA FC.
Martin Maron ended his presentation by saying that ‘SEQUOIA-HCM underscores the clinical efficacy of aficamten in the treatment of patients with symptomatic oHCM.
- Our reporting is based on the information provided at the ESC Heart Failure Congress 2024 -