Primary results from SEQUOIA-HCM presented in late breaking clinical trial session at the European Society of Cardiology Heart Failure 2024 Congress and published in the New England Journal of Medicine

SEQUOIA-HCM  enrolled 282 patients with obstructive HCM. The baseline characteristics of patients in SEQUOIA-HCM were well-matched between treatment groups and consistent with a symptomatic patient population that had high resting and post-Valsalva gradients (mean [SD]; 55.1 [29.6] and 83.1 [32.3] mmHg, respectively) reflective of substantial burden of disease. Background therapies consisted of beta-blockers (61.3%), calcium channel blockers (28.7%), and disopyramide (12.8%), with combination background therapies permitted.

The results from SEQUOIA-HCM showed that treatment with aficamten for 24 weeks significantly improved exercise capacity compared to placebo, increasing peak oxygen uptake (pVO2) measured by cardiopulmonary exercise testing (CPET) 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 (least square mean (LSM) difference [95% CI] of 1.74 mL/kg/min [1.04 - 2.44]; p=0.000002).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. Compared to baseline, at Week 24 patients treated with aficamten experienced significant improvements in post-Valsalva left ventricular outflow tract gradient (LVOT-G) with an LSM difference of -50 mmHg (p<0.0001) versus placebo. aficamten also substantially reduced the burden of symptoms compared with placebo, with a significant improvement observed in kansas city cardiomyopathy questionnaire clinical summary score (kccq-css) (lsm difference="7" points; p><0.0001) and with 34% of patients experiencing greater than 1 class improvement in new york heart association (nyha) functional class (p><0.0001) . treatment with aficamten substantially reduced the proportion of patients eligible for septal reduction therapy (srt). among those eligible for srt at baseline, over the duration of 24 weeks of treatment, patients receiving aficamten spent 78 fewer days eligible for srt compared with those treated with placebo (p><0.0001). additionally, from baseline to week 24, treatment with aficamten reduced nt-probnp, a biomarker of cardiac wall stress, by 80% relative to placebo.

The prespecified exploratory responder analysis in SEQUOIA-HCM showed that treatment with aficamten improved both exercise capacity and symptoms, with 60 (42%) of 142 patients treated with aficamten achieving the composite responder endpoint of (1) greater than 1.5 mL/kg/min increase in pVO2 and greater than 1 NYHA Functional Class improvement, or (2) Greater than 3.0 mL/kg/min increase in pVO2 and no worsening of NYHA Functional Class, compared to 19 (14%) of 140 patients treated with placebo, equating to a placebo-corrected difference of 28.7% (95% CI, 18.8, 38.6; p<0.0001).

“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 I. Malik, M.D., Ph.D., Cytokinetics’ Executive Vice President of Research & Development. “With no treatment interruptions due to low LVEF, aficamten appeared safe and well-tolerated. 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. I would like to thank the patients, investigator teams, and our staff for their tireless work to bring these results forward.”

“These results are remarkable, not only because of the magnitude of effect on clinical measures of disease, but also for the consistency observed across patient subgroups, including patients taking beta-blockers at baseline, which in real-world practice represents a large portion of patients with obstructive HCM,” said Martin Maron, M.D., Director, Hypertrophic Cardiomyopathy Center, Lahey Hospital and Medical Center, and Principal Investigator of SEQUOIA-HCM. “If approved, aficamten is a potentially transformational treatment which may reliably and safely address the most important treatment goals in obstructive HCM including relieving limiting symptoms and enhancing exercise capacity resulting in substantial improvements in quality of life.”

Aficamten was well-tolerated in SEQUOIA-HCM with an adverse event profile comparable to placebo. Treatment emergent serious adverse events occurred in 5.6% and 9.3% of patients on aficamten and placebo, respectively. Core echocardiographic left ventricular ejection fraction (LVEF) was observed to be less than 50% in 5 patients (3.5%) on aficamten compared to 1 patient (0.7%) on placebo. One of the 5 patients on aficamten with low LVEF had LVEF less than 40% following infection with COVID-19 but did not interrupt treatment as the site-read LVEF remained greater than 40% and the patient did not have symptoms of heart failure due to systolic dysfunction. Overall, there were no instances of worsening heart failure or treatment interruptions due to low LVEF.

See- "Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy"- Authors: Martin S. Maron, M.D., Ahmad Masri, M.D., Michael E. Nassif, M.D., Roberto Barriales-Villa, M.D., Ph.D., Michael Arad, M.D., Nuno Cardim, M.D., Ph.D., Lubna Choudhury, M.D., +26, for the SEQUOIA-HCM Investigator. Published May 13, 2024 DOI: 10.1056/NEJMoa2401424.