Cytokinetics presents additional data from SEQUOIA-HCM at the European Society of Cardiology Congress 2024.

These presentations were accompanied by simultaneous publications in leading cardiac journals, three in the Journal of the American College of Cardiology and one in the European Heart Journal.

“As we continue to dissect data from SEQUOIA-HCM, the expanding body of evidence reinforces the effects of aficamten on clinical outcomes, symptom burden, cardiac biomarkers and cardiac structure and function,” said Stephen Heitner, M.D., Vice President, Head of Clinical Research. “Key data presented and published show that treatment with aficamten appears to improve the architecture of the heart in patients with obstructive HCM, suggesting potential for disease modification. These data reinforce the primary analyses of SEQUOIA-HCM which are central to our rolling NDA submission for aficamten expected to be completed during this third quarter.”

Data from SEQUOIA-HCM CMR Sub-Study Show Treatment with Aficamten is Associated with Favorable Cardiac Remodeling: Ahmad Masri, M.D., MS, Director of the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University presented data from the cardiac magnetic resonance (CMR) sub-study in SEQUOIA-HCM. The data were simultaneously published in Journal of the American College of Cardiology. Of the 282 patients with obstructive HCM who participated in SEQUOIA-HCM, 57 patients participated in the CMR-sub-study and 50 patients completed the study, including 21 patients who received aficamten and 29 patients who received placebo. Baseline characteristics of patients enrolled in the CMR sub-study were comparable to the overall patient population in SEQUOIA-HCM.

The primary endpoint in the CMR sub-study was the change from baseline to Week 24 in left ventricular mass index (LVMI) from baseline. Treatment with aficamten significantly improved LVMI (-15.4 g/m2, p=0.001) and resulted in favorable cardiac remodeling as demonstrated by reductions in left ventricular maximal wall thickness (p<0.001), left atrial volume index (lavi) (p><0.001), and extracellular volume mass index (ecvi) (p="0.014)," while replacement fibrosis (late gadolinium enhancement [lge]) remained stable. these observed structural changes are suggestive of ongoing favorable remodeling and occurred in conjunction with improvements in clinical endpoints including resting and valsalva left ventricular outflow tract gradient (lvot-g), nt-probnp and nyha functional class. a cmr sub-study is also being conducted in forest-hcm, the ongoing open-label extension clinical trial of aficamten, to evaluate cardiac remodeling associated with long-term treatment with aficamten, as well as in acacia-hcm, the pivotal phase iii clinical trial of aficamten in patients with non-obstructive hcm.

Aficamten Improves Echocardiographic Measures of Cardiac Structure and Function Without Negatively Impacting Systolic Function: Sheila Hegde, M.D., M.P.H., Cardiovascular Medicine Specialist, Division of Cardiovascular Medicine, Brigham and Women’s Hospital presented data from an analysis of the impact of treatment with aficamten on echocardiographic cardiac structure and function from SEQUOIA-HCM. The data were simultaneously published in Journal of the American College of Cardiology. As previously reported, treatment with aficamten significantly improved gradients by approximately 60%, improving placebo-corrected resting LVOT-G -40 mmHg (55 to 20 mmHg with aficamten) and Valsalva LVOT-G -50 mmHg (86 to 35 mmHg with aficamten) , with no significant adverse changes in left ventricular systolic function, as measured by left ventricular ejection fraction (LVEF) (-4.8%, 95% CI -6.4 to -3.3; p<0.001). aficamten also improved measures of left ventricular structure and function including maximal wall thickness, septal wall thickness, inferolateral wall thickness, left ventricular mass index, and left ventricular end systolic volume index, with no change in left ventricular end diastolic volume index. aficamten also improved lavi as well as left ventricular relaxation and filling as indicated by an increase in lateral e’ velocity and decrease in lateral e e’, findings consistent with an improvement in diastolic function . The improvements in these echocardiographic measures were each associated with improvements in pVO2, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and NT-proBNP, demonstrating that the effects of aficamten on cardiac function and structure were associated with improvements in exercise capacity, symptoms and quality of life.

Aficamten Improves Symptom Burden and Quality of Life in Patients with Obstructive HCM: John A. Spertus, M.D., M.P.H., Professor, Daniel J. Lauer Missouri Endowed Chair in Metabolic and Vascular Disease Research, Clinical Director, University of Missouri Kansas City Healthcare Institute for Innovations in Quality and Saint Luke’s Mid America Heart Institute presented results from an analysis of the effect of treatment with aficamten on patient symptom burden, including the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and the Seattle Angina Questionnaire Summary Score (SAQ-SS) from SEQUOIA-HCM. The data were simultaneously published in Journal of the American College of Cardiology. At 24 weeks, aficamten significantly improved KCCQ-OSS by 7.9 points (95% CI 4.8 to 11; p<0.001). very large improvements in kccq-oss ( greater than 20 points) were achieved by 30% of patients treated with aficamten compared to 12% of patients treated with placebo (number needed to treat (nnt)="5.8)." similarly, aficamten significantly improved saq-ss scores by 7.8 points (95% ci 4.7 to 11; p><0.001), with 31% of patients treated with aficamten experiencing a very large improvement ( greater than 20 points) compared to 14% of patients on placebo (nnt="5.8)." no significant heterogeneity was observed in improvements in kccq-oss and saq-ss according to patient baseline characteristics, including the severity of disease or level of symptom burden. even in patients with minimal angina at baseline, saq-ss scores improved after 24 weeks of treatment with aficamten. These results indicate that treatment with aficamten significantly improves patient health status including symptoms, function and quality of life.

Aficamten Improves Cardiac Biomarkers Including NT-proBNP and hs-cTnI: Caroline Coats, M.D., Ph.D., Lead Clinician, West of Scotland Inherited Cardiac Conditions Service, Honorary Senior Lecturer, School of Cardiovascular and Metabolic Health, University of Glasgow presented results from a pre-specified secondary analysis from SEQUOIA-HCM related to NT-proBNP and high sensitivity cardiac troponin (hs-cTnI), cardiac biomarkers indicative of cardiac wall stress and myocardial injury. The results were simultaneously published in the European Heart Journal. Higher baseline concentrations of NT-proBNP and hs-cTnI were associated with worse baseline echocardiographic measures of disease severity including resting and Valsalva LVOT-G, LVEF and left ventricular wall thickness. Treatment with aficamten for 24 weeks resulted in an 80% reduction in NT-proBNP (p<0.001) and a 43% reduction (p><0.001) in hs-ctni . both measurements returned to baseline after washout. baseline measurements of nt-probnp and hs-ctni were not correlated with change in pvo2 such that treatment with aficamten significantly improved pvo2 irrespective of baseline biomarkers. baseline nt-probnp and hs-ctni also did not predict future instances of lvef><50%. however, at 24 weeks, improvements in nt-probnp and hs-ctni were strongly associated with improvements in lvot-g, pvo2 and kccq. improvements in nt-probnp were shown to closely mirror improvements in pvo2, which was not directly related to the reduction in lvot-g, indicating that nt-probnp may serve as an independent surrogate for change in pvo2. additionally, changes in nt-probnp as early as week 2 were strongly associated with changes in valsalva lvot-g, kccq-css, lavi and lateral e e’ at week 24, indicating that early improvements in nt-probnp may be a signal of future treatment effect. These results indicate that NT-proBNP may be a potentially useful tool to monitor functional and symptomatic improvements in response to treatment with aficamten.

See- Masri A, et al. "Effect of Aficamten on Cardiac Structure and Function in Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM CMR Substudy". JACC. 2024.

See-Hegde S, et al. "Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy". JACC. 2024.

See- Sherrod C, et al. "Effect of Aficamten on Health Status Outcomes in Obstructive Hypertrophic Cardiomyopathy: Results from SEQUOIA-HCM ". JACC. 2024.

See-Coats CJ, et al." Cardiac Biomarkers and Effects of Aficamten in Obstructive Hypertrophic Cardiomyopathy: The SEQUOIA-HCM Trial". Eur Heart J. 2024.