Topline phase 3 results were positive for aficamten (Cytokinetics), an investigational cardiac myosin inhibitor, in the treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM), the company announced.
Results of the Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM (SEQUOIA-HCM) show that treatment with aficamtem significantly improved exercise capacity compared with placebo, as well as all secondary endpoints, and was well tolerated.
"Cardiac myosin inhibition represents an exciting new therapy option for patients with symptomatic obstructive HCM, and I am pleased to see these impressive results from SEQUOIA-HCM," said Martin S. Maron, MD, Director, Hypertrophic Cardiomyopathy Center, Lahey Hospital and Medical Center, Burlington, Massachusetts; Tufts University School of Medicine; and National Principal Investigator of SEQUOIA-HCM.
"A therapy like aficamten that improves exercise capacity in a clinically meaningful manner, absent low LVEF events that interrupt treatment, should be a welcome addition for HCM patients, as well as the clinicians who treat them," Maron said.
Aficamten is an investigational selective, small-molecule cardiac myosin inhibitor designed to reduce the number of active actin-myosin cross-bridges during each cardiac cycle and consequently suppress the myocardial hypercontractility associated with HCM, the company noted.
The results of SEQUOIA-HCM showed treatment with aficamten significantly improved exercise capacity compared with placebo, increasing peak oxygen uptake measured by cardiopulmonary exercise testing by a least square mean difference of 1.74 (95% CI, 1.04-2.44) mL/kg/min (P = .000002).
The treatment effect was consistent across all prespecified subgroups based on baseline characteristics and treatment strategies, including patients receiving or not receiving background beta-blocker therapy.
Statistically significant (P < .0001) and "clinically meaningful" improvements were also seen in all 10 prespecified secondary endpoints, including Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at weeks 12 and 24, the proportion of patients with ≥ 1 class improvement in New York Heart Association functional class at weeks 12 and 24, change in provoked left ventricular outflow tract gradient (LVOT-G), and proportion < 30 mmHg at weeks 12 and 24, as well as exercise workload and guideline-eligibility for septal reduction therapy.
Treatment was well-tolerated with an adverse event profile comparable to placebo, the company said. Treatment emergent serious adverse events occurred in 8 (5.6%) and 13 (9.3%) patients on aficamten and placebo, respectively. Core echocardiographic left ventricular ejection fraction (LVEF) was observed to be < 50% in five patients (3.5%) on aficamten compared with one patient (0.7%) on placebo. There were no instances of worsening heart failure or treatment interruptions due to low LVEF.
"The results from SEQUOIA-HCM meet our high expectations for both efficacy and safety, demonstrating that aficamten added to standard of care therapy had a positive impact on exercise capacity as well as rapid and sustained effects on symptoms and functional class in patients with obstructive HCM while maintaining the safety and tolerability that we have previously observed," said Fady I. Malik, MD, PhD, Cytokinetics' Executive Vice President of Research & Development.
"We believe these results are consistent with those observed in REDWOOD-HCM, the phase 2 clinical trial of aficamten, and FOREST-HCM, the ongoing open label extension clinical trial," Malik said.
Full results from the trial will be presented at a medical meeting in 2024, the company noted.
The development program for aficamten includes two other ongoing phase 3 trials: Metoprolol vs Aficamten in Patients With LVOT Obstruction on Exercise Capacity in HCM (MAPLE-HCM), comparing aficamten and metoprolol as monotherapy in patients with obstructive HCM, and Assessment Comparing Aficamten to Placebo on Cardiac Endpoints in Adults With Nonobstructive HCM (ACACIA-HCM), evaluating the drug in patients with symptomatic nonobstructive HCM.
Aficamten received Breakthrough Therapy designation for the treatment of symptomatic obstructive HCM from the US Food and Drug Administration as well as the National Medical Products Administration in China.
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