Cytokinetics Announces Additional Data From REDWOOD-HCM Presented at the American Society of Echocardiography 33rd Annual Scientific Sessions
Echocardiographic Data Show Treatment with Aficamten for 10 Weeks Results
In Improved Cardiac Structure, Myocardial Relaxation and Mitral Valve Mechanics
This new analysis investigated changes from baseline in echocardiographic measures of cardiac structure and function after 10 weeks of treatment with aficamten compared with placebo. At baseline, all patients (n=41) enrolled in Cohorts 1 and 2 of REDWOOD-HCM had severe left ventricular outflow tract (LVOT) obstruction, 88% had associated systolic anterior motion (SAM) of the mitral valve, and 90% had mitral regurgitation. SAM occurs when the mitral valve leaflet gets pushed against the interventricular septum during systole, resulting in obstruction of the LVOT and mitral regurgitation.
Measures of cardiac structure, diastolic and mitral valve function (Table 1) improved at Week 10 in patients treated with aficamten. There was a significant reduction in left atrial volume index (p<0.01) and a trend towards a reduction in left ventricular hypertrophy (left ventricular mass index; p=0.06). Treatment with aficamten also resulted in improved ventricular relaxation and filling, as indicated by a reduction in lateral E/e’ (p<0.01) and an increase in lateral e’ (p<0.05). Additionally, treatment with aficamten improved mitral valve dynamics as noted by a reduction in the proportion of patients with SAM (placebo: 92.3% at baseline to 75.0% at Week 10; aficamten: 85.7% at baseline to 35.7% at Week 10; p=0.038 for comparison to placebo) and a trend towards a reduction in those with eccentric mitral regurgitation (placebo: 25.0% at baseline to 33.3% at Week 10; aficamten: 42.9% at baseline to 7.1% at Week 10; p=0.055 for comparison to placebo) at Week 10. Together, these data point to evidence of early signs of improved cardiac function and structure and improved mitral valve dynamics after a 10-week treatment period with aficamten.
Table 1: Measures of Cardiac Structure and Diastolic Function
||Placebo (n=13)||Aficamten (n=28)|
|Left Atrial Volume Index (mL/m2)||31.4 (7.5)||2.2 (1.5)||32.5 (8.1)||-2.9 (1.0)|
|Left Ventricular Mass Index (g/m2)||103.3 (25)||3.3 (3.6)||109.8 (29)||-4.8 (2.4)|
|Mitral E Wave to Lateral Annular
Early Diastolic Velocity Ratio
|17.4 (10)||1.8 (1.1)||13.8 (6.3)||-2.0 (0.8)|
|Mitral Lateral Annular
Early Diastolic Velocity (cm/sec)
|5.8 (2.1)||-0.5 (0.4)||6.7 (2.3)||0.5 (0.3)|
Baseline values are mean (SD) and change from baseline are least square mean (SE)
“Obstructive HCM is a disease characterized by left ventricular hypertrophy, impaired cardiac relaxation, and induced mitral regurgitation,” said
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 long-term effects on cardiac structure and function. Aficamten received Breakthrough Therapy Designation for the treatment of symptomatic obstructive HCM from the
REDWOOD-HCM (Randomized Evaluation of Dosing With CK-274 in Obstructive Outflow Disease in HCM) is a Phase 2, multi-center, randomized, placebo-controlled, double-blind, dose finding clinical trial of aficamten in patients with symptomatic obstructive HCM (oHCM). In Cohorts 1 and 2, patients continued taking background medications exclusive of disopyramide. Results from Cohorts 1 and 2 showed that treatment with aficamten for 10 weeks resulted in statistically significant reductions from baseline compared to placebo in the average resting left ventricular outflow tract pressure gradient (LVOT-G) and the average post-Valsalva LVOT-G. A large majority of patients treated with aficamten achieved the target goal of treatment, defined as resting gradient <30 mmHg and post-Valsalva gradient <50 mmHg at Week 10, compared to placebo. Patients treated with aficamten also saw improvements in heart failure symptoms and reductions in NT-proBNP, a biomarker of cardiac wall stress. Treatment with aficamten in REDWOOD-HCM was generally well tolerated and the incidence of adverse events on aficamten was similar to that of placebo. No serious adverse events were attributed to aficamten, and no treatment interruptions occurred on aficamten. Cohort 3 of REDWOOD-HCM enrolled patients with symptomatic obstructive HCM whose background therapy included disopyramide and, in the majority, a beta-adrenergic blocker. Data from Cohort 3 show that the addition of aficamten to standard of care therapy in more treatment-resistant patients treated with disopyramide resulted in well tolerated, clinically meaningful improvements in LVOT gradients, functional class and cardiac biomarkers supporting inclusion of patients on background therapy with disopyramide in further clinical trials. Cohort 4 of REDWOOD-HCM is enrolling, in an open label fashion, patients with symptomatic non-obstructive HCM receiving background medical therapy with primary objective to determine safety and tolerability of aficamten in patients with non-obstructive HCM.
About Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) becomes abnormally thick (hypertrophied). The thickening of cardiac muscle leads to the inside of the left ventricle becoming smaller and stiffer, and thus the ventricle becomes less able to relax and fill with blood. This ultimately limits the heart’s pumping function, resulting in symptoms including chest pain, dizziness, shortness of breath, or fainting during physical activity. A subset of patients with HCM are at high risk of progressive disease which can lead to atrial fibrillation, stroke and death due to arrhythmias.
This press release contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the "Act").
Senior Vice President, Corporate Communications, Investor Relations
Source: Cytokinetics, Incorporated