14 September 2023

Cytokinetics Announces Start of ACACIA-HCM, a Pivotal Phase 3 Clinical Trial of Aficamten in Patients With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy

Expanding Development Program to Assess Potential of Aficamten in Additional Patient Population to Inform Increased Utility of Cardiac Myosin Inhibition

Cytokinetics, Incorporated (Nasdaq: CYTK) recently announced that ACACIA-HCM (Assessment Comparing Aficamten to Placebo on Cardiac Endpoints In Adults with Non-Obstructive HCM), a Phase 3 clinical trial of aficamten in patients with symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM), is open to enrollment. Aficamten is a next-in-class cardiac myosin inhibitor in development for the potential treatment of HCM.

“As the first Phase 3 clinical trial of aficamten in non-obstructive hypertrophic cardiomyopathy, ACACIA-HCM represents an important advancement in
the development program for aficamten alongside our two ongoing Phase 3 clinical trials in obstructive HCM,” said Fady I. Malik, M.D., Ph.D., Cytokinetics’ Executive Vice President of Research & Development. “ACACIA-HCM builds on the encouraging findings from Cohort 4 of REDWOOD-HCM, the Phase 2 clinical trial which demonstrated that treatment with aficamten resulted in statistically significant improvements in heart failure symptoms and cardiac biomarkers in patients with non-obstructive HCM. In ACACIA-HCM we look forward to assessing the impact of aficamten in patients with non-obstructive HCM on symptoms and quality of life as well as on other measures of disease burden, including exercise capacity, functional class, cardiac structure and function and cardiovascular outcomes.”

ACACIA-HCM: Clinical Trial Design
ACACIA-HCM is a Phase 3, multi-center, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effect of aficamten compared to placebo on health-related quality of life in participants with symptomatic nHCM. The primary endpoint is the change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score from baseline to Week 36. Secondary endpoints include the change from baseline to Week 36 in maximal exercise performance (peak VO2) and sub-maximal exercise performance (Ve/VCO2), the proportion of patients with ≥1 class
improvement in New York Heart Association (NYHA) functional class, changes in left atrial volume index (LAVI) and NT-proBNP. After the primary analysis at 36 weeks, patients will continue treatment with aficamten or placebo for up to 72 weeks to evaluate additional secondary and exploratory analyses including the time to first cardiovascular event.

ACACIA-HCM is expected to enroll 420 patients, randomized on a 1:1 basis to receive aficamten or placebo. Randomization will be stratified by persistent atrial fibrillation and presence of intracavitary obstruction. At screening, patients enrolled in ACACIA-HCM must have a resting left ventricular outflow tract gradient (LVOT-G) < 30 mmHg and post-Valsalva LVOT-G < 50 mmHg in addition to left ventricular ejection fraction (LVEF) ≥60%, respiratory exchange ratio (RER) ≥ 1.00 and peak VO2 ≤ 90% predicted, NT-proBNP ≥ 300 pg/mL or ≥ 900 pg/mL if atrial fibrillation or atrial flutter are present at screening, NYHA functional class II or III and KCCQ Clinical Summary Score ≥ 30 and ≤ 85.

ACACIA-HCM will consist of two parts, with Part 1 comprising Day 1 to Week 36 and Part 2 comprising Week 36 to Week 72. All participants will complete Part 1. At the end of Part 1, participants will continue into Part 2 until the last randomized participant has completed Part 1. Each patient will receive up to four escalating doses of aficamten or placebo based on echocardiographic guidance. Patients receiving aficamten will begin with 5 mg dosed once daily. At weeks 2, 4 and 6 patients will receive an echocardiogram to determine if they will be up-titrated to escalating doses of 10, 15 or 20mg. Dose escalation will occur only if a patient has an LVEF ≥ 60%. Patients who do not meet escalation criteria will continue to receive their current dose or may be down-titrated if their LVEF is < 50%. Patients who complete ACACIA-HCM will be eligible to participate in an open-label extension clinical trial. Additional information can be found on www.clinicaltrials.gov.

Additional information

Aficamten is an investigational selective, small molecule cardiac myosin inhibitor discovered following an extensive chemical optimization program that was conducted with careful attention to therapeutic index and pharmacokinetic properties and as may translate into next-in-class potential in clinical development. Aficamten was designed to reduce the number of active actin-myosin cross bridges during each cardiac cycle and consequently suppress the myocardial hypercontractility that is associated with hypertrophic cardiomyopathy (HCM). In preclinical models, aficamten reduced myocardial contractility by binding directly to cardiac myosin at a distinct and selective allosteric binding site, thereby preventing myosin from entering a force producing state.
The development program for aficamten is assessing its potential as a treatment that improves exercise capacity and relieves symptoms in patients with HCM as well as its potential long-term effects on cardiac structure and function. Aficamten is currently the subject of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM), a pivotal Phase 3 clinical trial in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM), a Phase 3 clinical trial evaluating aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM, and ACACIA-HCM (Assessment Comparing Aficamten to Placebo on Cardiac Endpoints In Adults with Non-Obstructive HCM), a pivotal Phase 3 clinical trial in patients with symptomatic non-obstructive HCM. Results from SEQUOIA-HCM are expected by the end of 2023. Aficamten received Breakthrough Therapy Designation for the treatment of symptomatic obstructive HCM from the U.S. Food & Drug Administration (FDA) as well as the National Medical Products Administration (NMPA) in China. 

Cytokinetics is a late-stage, specialty cardiovascular biopharmaceutical company focused on discovering, developing and commercializing firstin-class muscle activators and next-in-class muscle inhibitors as potential treatments for debilitating diseases in which cardiac muscle performance is compromised. As a leader in muscle biology and the mechanics of muscle performance, the company is developing small molecule drug candidates specifically engineered to impact myocardial muscle function and contractility. Aficamten is a next-in-class cardiac myosin inhibitor, currently the subject of three Phase 3 clinical trials: SEQUOIA-HCM, evaluating aficamten in patients with obstructive hypertrophic cardiomyopathy (HCM), MAPLE-HCM, evaluating aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM and ACACIA-HCM, evaluating aficamten in patients with non-obstructive HCM. Cytokinetics is also developing omecamtiv mecarbil, a cardiac muscle activator in patients with heart failure.  Additionally, Cytokinetics is developing CK-136, a cardiac troponin activator for the potential treatment HFrEF and other types of heart failure, such as right ventricular failure, resulting from impaired cardiac contractility, and CK-586, a cardiac myosin inhibitor with a mechanism of action distinct from aficamten for the potential treatment of HFpEF. In 2023, Cytokinetics is celebrating its 25-year history of pioneering innovation in muscle biology and related pharmacology focused to diseases of muscle dysfunction and conditions of muscle weakness. For additional information about Cytokinetics, visit www.cytokinetics.com. 


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