Cytokinetics, Incorporated (Nasdaq: CYTK) has announced it will present five scientific analyses related to aficamten, its investigational cardiac myosin inhibitor for hypertrophic cardiomyopathy (HCM), at the upcoming American College of Cardiology (ACC) Annual Scientific Session & Expo in Chicago from March 29-31, 2025.
The presentations will provide new insights into aficamten's metabolism, safety profile when used in combination with standard treatments, and long-term effects on cardiac structure and function in patients with obstructive HCM.
"We are pleased to be sharing several new analyses relating to aficamten at the upcoming ACC Scientific Session & Expo," said Stephen Heitner, M.D., Vice President, Head of Clinical Research at Cytokinetics. "The presentations describe the drug metabolism of aficamten, the safety of combination therapy with the standard of care medication disopyramide, and the effect of longer-term use of aficamten. Together these analyses add to the strong and growing evidence base supporting the potential for aficamten in patients with obstructive HCM and inform how it may be used in clinical practice."
Aficamten's Metabolic Pathway Characterized
A poster presentation on March 29 will detail findings from an open-label, fixed-sequence drug-drug interaction study examining aficamten's metabolism in healthy participants. The study evaluated aficamten with concomitant administration of three strong inhibitors of cytochrome P450 (CYP) pathways: fluconazole, paroxetine, and fluoxetine.
Results showed that aficamten is eliminated through multiple CYP pathways, primarily by CYP2C9 (fraction metabolized [fm]=50%), with additional contributions from CYP3A (fm=26%), CYP2D6 (fm=21%), and CYP2C19 (fm=3%). This multi-pathway metabolism may have important implications for understanding potential drug interactions in clinical practice.
Safety of Combination Therapy with Disopyramide
An oral presentation scheduled for March 31 will present data on the concomitant use of aficamten and disopyramide, a standard treatment for obstructive HCM. The analysis included 50 participants from three clinical trials: REDWOOD-HCM Cohort 3, SEQUOIA-HCM, and FOREST-HCM.
The analysis demonstrated that combination therapy with aficamten and disopyramide was well-tolerated. Importantly, the combination did not result in lower left ventricular outflow tract (LVOT) gradients compared to treatment with aficamten alone. Withdrawal of disopyramide while continuing aficamten did not reduce aficamten's efficacy, while withdrawal of aficamten while on disopyramide resulted in the return of LVOT obstruction and symptoms, with an increase in NT-proBNP levels. No safety events or episodes of atrial fibrillation were reported with either drug withdrawal.
Long-Term Effects on Cardiac Structure and Function
A moderated poster presentation on March 30 will showcase new data from cardiac magnetic resonance (CMR) imaging sub-studies of FOREST-HCM and SEQUOIA-HCM, examining aficamten's effects on cardiac structure and function over 48-72 weeks.
The analysis included 64 patients who completed baseline CMR imaging, with 36 completing follow-up at 72 weeks and 28 at 48 weeks. Longer-term treatment with aficamten resulted in statistically significant improvements in multiple cardiac parameters, including:
- Left ventricular mass index (-9.8 g/m² ±18.1, p<0.0001)
- Maximum left ventricular septal wall thickness (-2.4 mm ±2.3, p<0.0001)
- Left atrial volume (-17.9 ml ±28.3, p<0.0001)
- Mitral regurgitant volume (-18.1 ml ±19.2, p<0.0001) and fraction (-14.2% ±15.6, p<0.0001)
These improvements occurred with stable replacement fibrosis (late gadolinium enhancement mass = -0.3 g ±5.0, p=0.51) and reduced interstitial fibrosis (global extracellular volume = -1.2% ±2.8, p=0.002; Native T1 = -36.6 ms ±55.7, p<0.0001).
Understanding Placebo Effects in HCM Clinical Trials
A poster presentation on March 29 will analyze the placebo effect on Kansas City Cardiomyopathy Questionnaire Overall Summary Scores (KCCQ-OSS) in SEQUOIA-HCM. Among 140 patients randomized to placebo, the median KCCQ-OSS improved by 5.7 points from baseline to Week 24 (p<0.01). After treatment withdrawal from Week 24 to Week 28, scores decreased by only 2.1 points (p<0.01).
These results suggest approximately one-third of the improvement observed in patients receiving placebo was due to a placebo effect, with other improvements potentially attributable to factors such as receiving care at expert centers and changes in patient behavior during trial participation.
Racial Disparities in Non-Obstructive HCM Outcomes
A health economics and outcomes research analysis examining racial/ethnic disparities in non-obstructive HCM will be presented on March 31. The retrospective cohort study included 9,842 adult patients diagnosed with non-obstructive HCM between 2013 and 2021.
The analysis revealed significant disparities in outcomes based on race/ethnicity. Compared to white patients (74.2% of the cohort), Black patients (19.5%) had significantly higher rates of stroke (risk ratio [RR] 1.76), heart failure (RR 1.73), ventricular tachycardia (RR 1.24), sudden cardiac arrest (RR 1.90), cardiovascular hospitalization (RR 1.42), and cardiovascular rehospitalization (RR 1.31), while having a lower rate of atrial fibrillation (RR 0.74; all p<0.001).
All-cause mortality was highest among Black patients (p<0.001), while Asian (2.1%) and Hispanic (4.2%) patients experienced lower rates of adverse outcomes compared to white patients. The researchers emphasized the urgent need to address drivers of race/ethnicity-based disparities in non-obstructive HCM.
Aficamten Development Program
Aficamten is a selective, small molecule cardiac myosin inhibitor designed to reduce myocardial hypercontractility associated with HCM. It works by reducing the number of active actin-myosin cross bridges during each cardiac cycle.
The drug is currently under regulatory review in multiple regions:
- In the U.S., the FDA is reviewing a New Drug Application with a PDUFA target action date of September 26, 2025
- The European Medicines Agency is reviewing a Marketing Authorization Application
- China's National Medical Products Administration is reviewing an NDA with Priority Review
Aficamten is also being evaluated in several ongoing clinical trials, including MAPLE-HCM (comparing aficamten to metoprolol in obstructive HCM), ACACIA-HCM (in non-obstructive HCM), CEDAR-HCM (in pediatric obstructive HCM), and FOREST-HCM (an open-label extension study).
About Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is characterized by abnormal thickening of the heart muscle, which can lead to reduced ventricular filling, limited pumping function, and symptoms such as chest pain, dizziness, shortness of breath, and fainting during physical activity.
HCM affects approximately 280,000 diagnosed patients in the U.S., with an estimated 400,000-800,000 additional patients remaining undiagnosed. Two-thirds of patients have obstructive HCM, where thickening leads to left ventricular outflow tract obstruction, while one-third have non-obstructive HCM.
Patients with HCM face increased risks of cardiovascular complications including atrial fibrillation, stroke, and mitral valve disease. The condition is also associated with potentially fatal ventricular arrhythmias and is one of the leading causes of sudden cardiac death in younger people and athletes.
