Anjali Tiku Owens, MD
Penn cardiologist Anjali Tiku Owens, MD, was a co-author of the recent New England Journal of Medicine report on the Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM (SEQUOIA-HCM) clinical trial (NCT05186818). Aficamten is an investigational small molecule cardiac myosin inhibitor for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Dr. Owens is the Medical Director of Penn Medicine's Center for Inherited Cardiovascular Disease.
Obstructive HCM (oHCM) is among the heritable cardiomyopathies. The condition causes septal thickening in the heart with a reduction in blood flow from the left ventricle to the aorta. The resulting obstruction leads to elevated intracardiac pressure and consequent exercise intolerance and other limiting symptoms among patients with oHCM. Mutations in more than 40 genes have been associated with HCM, with those encoding sarcomeric (muscle) proteins among the most commonly mutated in heritable HCM.
Treatment - Currently, the treatments for HCM include septal reduction therapy, ablations for atrial arrhythmias, and implantable cardioverter defibrillators for those at increased risk for sudden cardiac death and heart transplantation in advanced disease. The general population of patients with oHCM may be prescribed repurposed drugs for arrhythmias and heart failure (i.e., beta blockers, calcium channel blockers, disopyramide, and diuretics). Efficacy of these agents is limited in patients with oHCM, and their side effects are intolerable in many patients. Thus, drugs that meet the standards of safety and efficacy constitute an unmet need in the treatment of the disease. Mavacamten, a novel first-in-class small molecule cardiac myosin inhibitor was recently FDA approved to manage and treat adults with symptomatic heart failure secondary to oHCM. Dr. Owens was a principal investigator for the mavacamten studies EXPLORER-HCM (NCT03470545) and VALOR-HCM (NCT04349072). Mavacamten has demonstrated the capacity to both improve exercise capacity and reduce symptoms in patients with oHCM.
Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy
In the randomized phase 3, double-blind SEQUOIA-HCM clinical trial, aficamten (starting dose, 5 mg; maximum dose, 20 mg) was compared to placebo for 24 weeks in a population of adults with symptomatic oHCM, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in peak oxygen uptake as assessed by cardiopulmonary exercise testing. The prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS); improvement in the New York Heart Association (NYHA) functional class; change in the pressure gradient after the Valsalva maneuver; occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver; and duration of eligibility for septal reduction therapy (all assessed at weeks 12 and 24); as well as change in the total workload as assessed by cardiopulmonary exercise testing at week 24.
Conclusion: Among patients with symptomatic oHCM, aficamten improved exercise capacity over a 24-week treatment period, and was associated with significantly greater improvements by comparison to placebo in all secondary end points. By week 12, the efficacy of aficamten was evident, with significantly greater improvements in left ventricular outflow tract gradients, health status, and symptoms, and an adverse event profile similar to that of placebo.
Visit the Center for Inherited Cardiovascular Disease for more information about the management and treatment of the cardiomyopathies and other heritable heart conditions at Penn Medicine.
Associated Resources:
Research in the Inherited Cardiomyopathies Intensifies at Penn Heart and Vascular