Announcement • Aug 28

Cytokinetics, Incorporated Announces Positive Results From ACACIA-HCM Phase 3 Clinical Trial of Aficamten in Patients with Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy

Cytokinetics, Incorporated announced the primary results from ACACIA-HCM (Assessment Comparing Aficamten to Placebo on Cardiac Endpoints In Adults with Non-Obstructive HCM), the pivotal Phase 3 clinical trial of aficamten in patients with symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM) were presented in a Hot Line Session at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany, and simultaneously published in The New England Journal of Medicine. ACACIA-HCM met both dual primary endpoints, demonstrating statistically significant improvements from baseline to Week 36 compared to placebo in both Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and maximal exercise performance (pVO2). Results for the dual primary endpoint analysis consistently favored aficamten across prespecified subgroups studied. Based on the positive results from ACACIA-HCM, Cytokinetics plans to submit a supplemental New Drug Application to the U.S. Food and Drug Administration (FDA) for aficamten for the treatment of adult patients with symptomatic nHCM in the fourth quarter of 2026. ACACIA-HCM is the first-ever positive clinical trial in non-obstructive HCM. The baseline characteristics of patients enrolled in ACACIA-HCM were well-matched between treatment groups and consistent with a symptomatic nHCM phenotype with substantial disease burden despite normal left ventricular ejection fraction (LVEF). There were two pre-specified primary endpoints, KCCQ-CSS and pVO2, evaluated in parallel. For each endpoint, a p-value of 0.025 or less was considered statistically significant. Compared to placebo, treatment with aficamten demonstrated statistically significant improvements in both dual primary endpoints at 36 weeks. KCCQ-CSS: Change from Baseline to Week 36: Aficamten 11.4 [9.6 – 13.2], Placebo 8.4 [6.6 – 10.2], Aficamten vs Placebo 3.0 (0.5 - 5.5), P-value 0.021. pVO2 (ml/kg/min): Change from Baseline to Week 36: Aficamten 0.64 [0.32 – 0.95], Placebo -0.03 [-0.35 – 0.28], Aficamten vs Placebo 0.67 (0.22 - 1.1), P-value 0.003. Improvements in KCCQ-CSS relative to placebo were noted beyond titration and throughout the treatment period in participants treated with aficamten, such that patients remaining on treatment at 72 weeks demonstrated a least square mean (LSM) change from baseline in KCCQ-CSS of 7.0 points. Of note, following a washout of aficamten for four weeks, the KCCQ-CSS declined from the end of treatment for participants on aficamten to match that in the placebo group. At Week 36, pVO2 increased for participants on aficamten while it remained unchanged for participants on placebo. The treatment effect of aficamten on both dual primary endpoints was consistent across all prespecified subgroups, including baseline LVEF, atrial fibrillation status, genotype, age, sex, whether patients were receiving background beta-blocker therapy and whether patients had intracavitary obstruction at baseline. Statistically significant improvements compared to placebo were observed in key ranked secondary endpoints, including New York Heart Association (NYHA) Functional Class, the composite z-score of two cardiopulmonary exercise testing (CPET) parameters (VE/VCO2 and pVO2), and NT-proBNP, a biomarker of cardiac wall stress. Statistical significance was not met on the endpoints of change from baseline in left atrial volume index or the time to first cardiovascular event for aficamten compared to placebo. Improvement of =1 NYHA class at week 36 – n (%): Aficamten 108 (41.9), Placebo 72 (27.8), Change in composite z-score of two CPET parameters (pVO2 and VE/VCO2) at week 36: Aficamten 0.05 (-0.01 to 0.12), Placebo -0.09 (-0.14 to -0.05), Proportional change in NT-proBNP level at week 36 – pg/ml: Aficamten 0.43 (0.39 to 0.46), Placebo 1.00 (0.93 to 1.08), Change in left atrial volume index at week 36: Aficamten -0.17 (-1.12 to 0.79), Placebo 1.13 (0.19 to 2.08), Time to first cardiovascular event – weeks: Aficamten 68.2 (66.2 to 70.2), Placebo 68.8 (66.9 to 70.7). Aficamten was generally well-tolerated in the study. Non-fatal adverse events that led to early study drug discontinuation occurred in 18 (7.0%) and 5 (1.9%) patients on aficamten and placebo, respectively. Serious adverse events occurred in 52 (20.2%) patients on aficamten compared to 38 (14.7%) patients on placebo. In the time to the first cardiovascular event endpoint, an event (cardiovascular death, heart transplantation or left ventricular assist device, aborted sudden cardiac death, non-fatal stroke, heart failure hospitalization, or cardiac arrhythmia [atrial fibrillation or ventricular tachyarrhythmia] requiring treatment or hospitalization) occurred in 22 (8.5%) patients in the aficamten arm and 20 (7.7%) in the placebo arm. MYQORZO is metabolized primarily by CYP2C9, and to a lesser extent by CYP3A, CYP2D6, and CYP2C19 enzymes. Initiation of medications that inhibit multiple P450 pathways of MYQORZO elimination (eg, fluconazole, voriconazole, or fluvoxamine) or strong CYP2C9 inhibitors, and discontinuation of moderate-to-strong CYP3A inducers may lead to increased blood concentrations of aficamten and increase the risk of heart failure due to systolic dysfunction. Conversely, initiation of medications that induce P450 pathways of MYQORZO (eg, rifampin, moderate-to-strong CYP3A inducers) may lead to decreased blood concentrations of aficamten and potential loss of effectiveness. Assess LVEF 2 to 8 weeks after initiation of such inhibitors or after discontinuation of such inducers and adjust the dose of MYQORZO accordingly. Advise patients of the potential for drug interactions. Advise patients to inform their healthcare provider of all concomitant medications prior to and during MYQORZO treatment. Hypertension (8% vs 2%) was the only adverse reaction occurring in >5% of patients and more commonly on MYQORZO than on placebo in the pivotal trial. MYQORZO is indicated for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) to improve functional capacity and symptoms.

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