Cytokinetics Shares New SEQUOIA-HCM Results at ESC Heart Failure 2024 Congress

Cytokinetics, Inc. recently unveiled additional results from the SEQUOIA-HCM trial, a pivotal Phase 3 study of aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). These findings, presented at the Heart Failure 2024 congress, highlighted the effects of aficamten on dosing, safety, and exercise performance. The primary results of the SEQUOIA-HCM trial were also published in the New England Journal of Medicine.

Dr. Stuart Kupfer, Chief Medical Officer at Cytokinetics, emphasized that these additional analyses provide deeper insights into aficamten's benefits beyond the primary and secondary endpoints of the trial. The results support dose down-titration in cases of low left ventricular ejection fraction (LVEF), allowing for individualized dosing and potentially better risk management.

The SEQUOIA-HCM trial data presented by Dr. Caroline Coats revealed no major adverse cardiovascular events associated with aficamten. Serious adverse events were reported in 5.6% of patients in the aficamten group compared to 9.3% in the placebo group, none of which were related to the study drug. Over the 24-week treatment period, patients on aficamten showed a modest reduction in LVEF, which correlated with significant reductions in left ventricular outflow tract gradient (LVOT-G).

Patients were titrated to their target dose of aficamten, with most reaching the higher doses (15 mg in 35.0% and 20 mg in 48.6%). Post-titration, plasma drug concentrations remained stable with low variability. The frequency of LVEF dropping below 50% was low, with only 3.5% of aficamten patients compared to 0.7% of placebo patients experiencing this drop. Importantly, there were no treatment interruptions or worsening heart failure due to low LVEF.

Dr. Gregory Lewis presented the results of a cardiopulmonary exercise testing (CPET) analysis, which showed that aficamten significantly improved peak oxygen uptake (pVO2) and a novel integrated exercise performance metric. Improvements in pVO2 were strongly correlated with other clinical measures, including the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), New York Heart Association (NYHA) Functional Class, and various cardiac function indicators.

The integrated CPET Z-score, representing both maximal and submaximal exercise performance, showed a placebo-adjusted improvement of 0.35. Among aficamten-treated patients, 72.2% experienced an improvement in pVO2, with a notable proportion showing moderate to large improvements. Enhanced exercise performance was linked to better cardiac structure and function, underscoring aficamten's potential clinical significance.

Addressing the pharmacological properties of aficamten, Dr. Coats noted that the drug's design has translated into meaningful clinical benefits, with patients achieving maximal therapeutic effects early in the treatment and adverse events similar to placebo. Dr. Lewis highlighted the comprehensive impact of aficamten on exercise performance and its correlation with cardiac improvements, emphasizing its potential in treating obstructive HCM.

Aficamten, a selective cardiac myosin inhibitor, was developed to reduce myocardial hypercontractility associated with HCM. It has shown promising results in improving exercise capacity and relieving symptoms in HCM patients. The SEQUOIA-HCM trial demonstrated that aficamten significantly increased peak oxygen uptake compared to placebo and was well tolerated.

Cytokinetics continues to explore aficamten's potential in other Phase 3 trials, including MAPLE-HCM, ACACIA-HCM, CEDAR-HCM, and FOREST-HCM. The drug has received Breakthrough Therapy Designation from the U.S. FDA and China’s NMPA for treating symptomatic obstructive HCM.

Hypertrophic cardiomyopathy is a condition where the heart muscle thickens, leading to reduced exercise capacity and other symptoms. It is the most common monogenic inherited cardiovascular disorder, with a significant number of undiagnosed cases in the U.S. Patients with HCM are at risk for various complications, including sudden cardiac death, and a subset may progress to requiring heart transplantation.

Cytokinetics is a biopharmaceutical company specializing in muscle biology and cardiac muscle performance. The company is preparing regulatory submissions for aficamten and continues to develop other cardiovascular treatments, including omecamtiv mecarbil and CK-586.