Patients with obstructive hypertrophic cardiomyopathy who received a novel cardiac myosin inhibitor drug demonstrated improved oxygen uptake, according to a recent clinical trial results published in the New England Journal of Medicine.
“It is game-changing in terms of establishing this new class of medications, which are designer drugs for hypertrophic cardiomyopathy, in the treatment armamentarium of physicians. We now have more choices to treat patients,” said Lubna Choudhury, MD, professor of Medicine in the Division of Cardiology and a co-author of the study.
Hypertrophic cardiomyopathy, or HCM, is the most common genetic cardiac disorder, affecting one in 500 adults worldwide, according to the Hypertrophic Cardiomyopathy Association. The disease is characterized by thickened, or hypertrophied, walls of the left ventricle, which over time prevents the heart from pumping blood efficiently throughout the body.
More than half of patients with HCM have obstructive HCM, which is caused by abnormal motion of the mitral valve touching the thickened septum — the wall between the left and right ventricles — and obstructs blood flow from the left ventricle to the aorta. Because of this obstruction, patients can experience shortness of beath, fatigue, lightheadedness, chest heaviness and exercise intolerance.
The standard of care for obstructive HCM has included medications like beta blockers, calcium channel blockers, and even surgery. In recent years, Northwestern has participated in several multicenter trials for developing and testing a new class of drugs for HCM called cardiac myosin inhibitors.
These drugs specifically target the contractility of the heart by reducing the interaction between actin and myosin within cardiac muscle cells.
“Hypertrophic cardiomyopathy patients have a very vigorous heart contractility, and we have tried to develop these cardiac myosin inhibitors to try and attack that specific mechanism, to go to the ‘heart of the matter,’ so to speak,” Choudhury said.
In the current phase 3 clinical trial, approximately 280 adults with symptomatic obstructive HCM were randomized to receive varying doses of a cardiac myosin inhibitor drug, aficamten, or placebo for 24 weeks, with dose adjustments based on echocardiography test results.
The primary end point was a change in participants’ peak oxygen uptake over 24 weeks, which was assessed by cardiopulmonary exercise testing. More than 10 secondary endpoints were measured, including a change in participants’ Kansas City Cardiomyopathy Questionnaire clinical summary score, which provides a measure of symptoms and physical limitations associated with heart failure.
At the end of the 24-week trial period, participants who received aficamten showed a significantly greater improvement in peak oxygen uptake than those who received a placebo. The average change in the peak oxygen uptake was 1.8 milliliters per kilogram per minute in the aficamten group compared to zero milliliters per kilogram per minute in the placebo group.
Results for all 10 secondary end points also significantly improved for the aficamten group, and those patients who initially met criteria for surgery and took aficamten no longer met surgical criteria after the 24-week trial period.
“On many levels, this is really a landmark study in the treatment of hypertrophic cardiomyopathy,” Choudhury said. “I think the drug company is very encouraged by the results of this phase 3 trial, and they are going to go to the FDA for approval.”
This work was supported by Cytokinetics.
