SEQUOIA-HCM: Aficamten demonstrates clinical efficacy in obstructive HCM

In patients with obstructive hypertrophic cardiomyopathy (HCM), treatment with aficamten resulted in clinically meaningful improvements in exercise capacity and symptoms compared with placebo. The rapid and durable responses observed in the phase 3 SEQUOIA-HCM study underscore the clinical efficacy of aficamten in this population.

“Left ventricular outflow tract obstruction frequently leads to exertional dyspnoea and a decreased exercise capacity in patients with HCM,” explained study presenter Dr Martin Maron (Lahey Hospital and Medical Center, MA, USA). “Hypercontractility is a disease-related mechanism largely responsible for this obstruction.” Current first-line therapies for obstructive HCM have limited efficacy and important adverse events. The novel, investigational, selective, cardiac myosin inhibitor aficamten reduces left ventricular contractility and has delivered promising results in patients with obstructive HCM [1,2]. In the phase 3 SEQUOIA trial (NCT05186818), 282 participants with obstructive HCM were randomised 1:1 to aficamten plus standard-of-care or placebo plus standard-of-care. It is the largest obstructive HCM trial to date. The main inclusion criteria were: left ventricular outflow tract gradient ≥30 mmHg and Valsalva manoeuvre ≥50 mmHg; NYHA class II or III; and predicted peak oxygen uptake (pVO₂) ≤90% for age and sex. The primary endpoint was change in peak oxygen uptake (pVO₂) by cardiopulmonary exercise testing (CPET) from baseline to week 24 [3].

The mean absolute change in pVO₂ from baseline to week 24 was +1.8 mL/kg/min with aficamten versus 0.0 mL/kg/min with placebo. The difference in least squares mean change was 1.74 mL/kg/min (95% CI 1.0–2.4; P=0.000002) significantly favouring the experimental arm over the placebo arm. “For each 1 mL/kg/min increase in pVO₂ the risk of death or transplantation was reduced by about 18%,” added Dr Maron. “Our result passed the threshold of a clinically meaningful difference.”

Aficamten was superior to placebo with respect to change in pVO₂ across subgroups. Moreover, a benefit was observed for all secondary endpoints, which included KCCQ-CSS, NYHA functional classification improvement, and NT-proBNP levels.

“Robust functional and symptomatic improvements and relief from obstruction were observed as early as 2 weeks,” concluded Dr Maron, “and these remained durable throughout the treatment period.”

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   1. Chuang C, et al. J Med Chem. 2021;64:14142–52.
   2. Maron MS, et al. J Am Coll Cardiol. 2023;81:34–45.
   3. Maron MS, et al. Aficamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy: SEQUOIA-HCM, an international multicenter phase 3 trial. Late breaking clinical trials: LVAD, HFpEF and hypertrophic cardiomyopathy, Heart Failure 2024, 11–14 May, Lisbon, Portugal.

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Posted on 16 July 202416 July 2024