RARE Daily

Cytokinetics Reports Positive Results for HCM Drug

May 13, 2024

Rare Daily Staff

Cytokinetics reported results from SEQUOIA-HCM, the pivotal phase 3 clinical trial of its experimental therapy aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy.

The study’s principal investigator presented the results in a late-breaking session at Heart Failure 2024, an International Congress of the European Society of Cardiology, and simultaneously published in the New England Journal of Medicine.

Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) becomes abnormally thick (hypertrophied). The thickening of cardiac muscle leads to the inside of the left ventricle becoming smaller and stiffer, and thus the ventricle becomes less able to relax and fill with blood. This ultimately limits the heart’s pumping function, resulting in reduced exercise capacity and symptoms including chest pain, dizziness, shortness of breath, or fainting during physical activity. HCM is the most common monogenic inherited cardiovascular disorder. A subset of patients with HCM are at high risk of progressive disease leading to dilated cardiomyopathy and heart failure necessitating cardiac transplantation.

Aficamten is an investigational selective, small molecule cardiac myosin inhibitor discovered following an extensive chemical optimization program that was conducted with careful attention to therapeutic index and pharmacokinetic properties, and as may translate into next-in-class potential in clinical development if approved. Aficamten was designed to reduce the number of active actin-myosin cross bridges during each cardiac cycle and consequently suppress the myocardial hypercontractility that is associated with hypertrophic cardiomyopathy (HCM). In preclinical models, aficamten reduced myocardial contractility by binding directly to cardiac myosin at a distinct and selective allosteric binding site, thereby preventing myosin from entering a force producing state.

The results from SEQUOIA-HCM showed that treatment with aficamten for 24 weeks significantly improved exercise capacity compared to placebo, increasing peak oxygen uptake measured by cardiopulmonary exercise testing by 1.8 ml/kg/min compared to baseline in patients treated with aficamten versus 0.0 ml/kg/min in patients treated with placebo.

The treatment effect of aficamten was consistent across all prespecified subgroups, including age, sex, patient baseline characteristics, and in patients receiving or not receiving background beta-blocker therapy.

Statistically significant improvements were observed in all 10 prespecified secondary endpoints, with functional and symptomatic improvements occurring within two weeks of initiating treatment with aficamten and sustained throughout the treatment period.

Aficamten was well-tolerated in SEQUOIA-HCM with an adverse event profile comparable to placebo.

“The results from SEQUOIA-HCM demonstrate that treatment with aficamten is associated with statistically significant, rapid and sustained improvements in exercise capacity, symptoms, cardiac function and cardiac biomarkers in patients with obstructive HCM,” said Fady Malik, Cytokinetics’ executive vice president of research and development. “We believe these results are strongly supportive of the potential approval of aficamten, and we look forward to submitting regulatory filings in both the U.S. and Europe later this year.”

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