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SEQUOIA-HCM Trial: Experimental Drug Aficamten Makes Exercise, Everyday Tasks Easier for People With Obstructive Hypertrophic Cardiomyopathy
People with a common heart condition were able to use significantly more oxygen while exercising after taking an investigational drug in an international clinical trial, according to a study published today in the New England Journal of Medicine. The finding was also presented at the European Society of Cardiology’s Heart Failure 2024 meeting in Lisbon, Portugal.
Oregon Health & Science University is part of the randomized, double-blind Phase 3 trial that is evaluating the experimental drug aficamten, which was developed by Cytokinetics to treat the obstructive form of hypertrophic cardiomyopathy, or HCM. Of the 282 adults participating in the trial, 19 enrolled through OHSU — the most of any trial center.
“By having more oxygen available during exercise, patients with obstructive hypertrophic cardiomyopathy can more easily walk, perform household chores, and do other everyday tasks,” said cardiologist Ahmad Masri, M.D., M.S., who co-wrote today’s paper and directs the OHSU Knight Cardiovascular Institute’s Hypertrophic Cardiomyopathy Center. “Our latest clinical trial results suggest aficamten is a promising treatment for HCM.”
HCM affects about 1 in 500 people and is one of the most common causes of sudden death for youth and otherwise healthy athletes. Often caused by inherited gene mutations, it thickens heart muscles and makes it difficult for the heart to work as it should. It causes shortness of breath and reduces people’s ability to exercise. The obstructive form of HCM reduces blood flow out of the heart.
About half of the trial’s participants were given the experimental drug, and the other half took a placebo and served as the study’s control group. Scientists measured the participants’ oxygen levels while they used treadmills or bicycles. Those who took aficamten had a significant increase in their maximum oxygen use — 1.7 milliliters per kilogram per minute more than those in the control group.
Having an increased peak oxygen uptake can improve a patient’s ability to be physically active, whereas reduced oxygen uptake can increase the risk of experiencing heart failure, needing a heart transplant, and dying.
Non-drug treatment options for obstructive HCM include surgery to remove excess heart muscle. In 2022, the Food and Drug Administration also approved mavacamten as the first drug designed to target the underlying cause of obstructive HCM. However, mavacamten may increase the risk of heart failure and it interacts with several commonly used medications. As a result, patients who use mavacamten must also undergo intense monitoring.
More about SEQUOIA-HCM1
A major cause of this in HCM patients is left ventricular outflow tract (LVOT) obstruction, which results in elevated intracardiac pressures. This study demonstrated that aficamten enhanced HCM patients’ exercise capacity with significant improvement in peak oxygen uptake (pVO2), improvement in limiting symptoms, and decreases in LVOT pressure gradients.
“The SEQUOIA-HCM trial demonstrated that aficamten can reliably and safely eliminate LVOT obstruction in patients with obstructive HCM using a simple and stepwise dosing regimen, and was associated with substantial improvements in clinically relevant endpoints such as exercise capacity and symptoms,” said principal investigator Professor Martin Maron of the Lahey Hospital and Medical Center, Burlington, Massachusetts, US. “HCM patients are often on multiple medications, which frequently provide suboptimal benefit, while aficamten was highly effective at providing clinical improvement as combination therapy, but also as monotherapy.”
HCM occurs in approximately one in 200 to 500 individuals, with 70% of patients having obstructive disease.2 The condition causes the walls of the left ventricle to become thick and stiff, which can also result in obstruction to blood flow out of the heart and increased intracardiac pressures.
Aficamten is a cardiac myosin inhibitor that was previously shown to reduce LVOT gradients in a phase 2 trial.3 The phase 3 SEQUOIA-HCM trial evaluated the efficacy and safety of aficamten versus placebo in adults with symptomatic obstructive HCM. The primary endpoint was the change in pVO2, assessed using cardiopulmonary exercise testing, from baseline to week 24. Secondary endpoints at 24 weeks included the change in KCCQ score; the proportion of patients with ≥1 class improvement in New York Heart Association (NYHA); change in Valsalva LVOT gradient; the proportion of patients with Valsalva LVOT gradient <30 mmHg; and eligibility for invasive septal reduction.
SEQUOIA-HCM included 282 patients from 101 sites in 14 countries in North America, Asia, and Europe, making it the largest-ever obstructive HCM trial. All participants had reduced exercise capacity due to obstructive HCM. Patients were randomised 1:1 to aficamten or placebo on top of their background medical therapy. The starting dose of aficamten was 5 mg once daily with opportunities at weeks 2, 4, and 6 to increase the dose in 5 mg increments to a maximum dose of 20 mg. Dose adjustments were made according to left ventricular ejection fraction and LVOT gradients assessed using echocardiography.
The mean increase in pVO2 from baseline to 24 weeks was 1.8 ml/kg/min with aficamten compared to 0.0 ml/kg/min with placebo (least-squares mean difference between groups, 1.7 ml/kg/min; 95% confidence interval [CI] 1.0, 2.4; p<0.001). Regarding secondary endpoints at 24 weeks, aficamten resulted in a least-squares mean difference of 7 points in KCCQ score relative to placebo (95% CI 5, 10; p<0.0001). A ≥1 NYHA class improvement was observed in 58.5% of patients on aficamten and 24.3% of patients on placebo (p<0.0001). Aficamten led to a 50 mmHg greater reduction in Valsalva LVOT gradient versus placebo (95% CI -57, -44; p<0.0001). Some 49.3% of patients on aficamten achieved a Valsalva LVOT gradient <30 mmHg versus 3.6% of patients on placebo (p<0.0001). The aficamten group had 78 fewer days eligible for invasive septal reduction compared with the placebo group (p<0.0001).
Professor Maron said: “It was impressive to see that the beneficial effects of aficamten occurred rapidly and consistently over the treatment period and that the doses could be adjusted effectively and safely using only site read echocardiographic measures. It was also reassuring to see that in the very small number of patients found to have an ejection fraction below 50% on aficamten, there was no associated heart failure or the need for dose interruption, and that the effect on ejection fraction was reversible with treatment discontinuation.”
References and notes
1The ‘SEQUOIA-HCM’ trial will be presented during the session ‘Late Breaking Clinical trials: LVAD, HFpEF and hypertrophic cardiomyopathy’ which takes place on 13 May 2024 in Room 1.
2Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114:2232–2239.
3Maron MS, Masri A, Choudhury L, et al. Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2023;81:34–45.
This research was supported by Cytokinetics.
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