Marked health status improvement with mavacamten in obstructive hypertrophic cardiomyopathy
The cardiac myosin inhibitor mavacamten substantially improved health status in patients with symptomatic obstructive hypertrophic cardiomyopathy, with benefits observed early after treatment, according to new data from EXPLORER-HCM.
Presenting new health status data from the trial at the American College of Cardiology Scientific Session, John A. Spertus, MD, MPH, the Lauer/Missouri Endowed Chair and professor at University of Missouri Kansas City and Saint Luke’s Mid America Heart Institute, said mean Kansas City Cardiomyopathy Questionnaire overall summary score differences favoring mavacamten (MyoKadria) were amongst the largest he has observed for any medication, eclipsed only by structural heart interventions.
“There is a very impressive improvement in the symptoms, function and quality of life of [mavacamten]-treated patients and it is really impressive that, when on the medicine, patients get the benefit; when they come off the medicine, benefit goes away,” Spertus told Healio. “It supports a direct cause-and-effect relationship between treatment and improved health status.”
New health status data
As Healio previously reported, treatment with mavacamten, a novel oral allosteric modulator of cardiac myosin, was shown to significantly improve symptoms, quality of life and functional status compared with placebo among participants with symptomatic, obstructive hypertrophic cardiomyopathy. Initial data were presented at the European Society of Cardiology Congress in August 2020.
For the secondary analysis, Spertus and colleagues analyzed data from 251 adults with symptomatic obstructive hypertrophic cardiomyopathy (left ventricular outflow tract gradient 50 mm Hg and New York Heart Association class II–III) who were randomly assigned mavacamten (n = 123) or placebo (n = 88) for 30 weeks, followed by an 8-week washout period. The primary outcome was KCCQ scores, administered at baseline and again at 6, 12, 18, and 30 weeks (end of treatment), as well as at 38 weeks (end of study). Within the cohort, 69% completed the KCCQ at baseline and week 30.
At 30 weeks, change in KCCQ-OS score was a mean 9.1 points greater for participants who received mavacamten vs. placebo (mean score, 14.9 vs. 5.4; 95% CI, 5.5–12.8; P < .0001), with similar benefits observed across all KCCQ subscales. The proportion of patients with a very large change, defined as at least 20 points on the KCCQ scale, was 36% in the mavacamten group vs. 15% in the placebo group, with an estimated absolute difference of 21% (95% CI, 8.8–33.4) and number needed to treat of just five, he said during the presentation.
The observed gains immediately returned to baseline after treatment was stopped and symptoms were no different than placebo-treated patients, Spertus said.
“The magnitude of benefit was surprising,” Spertus told Healio. “It left me wanting to understand: Why? Is it the reduction in the gradient? Is it the change in diastolic function? What is it about the physiology that led to such an impressive improvement in health status? We do not often see this. It is far more important that you alter a patient’s health status than you alter some surrogate biomarker.”
The results were simultaneously published in The Lancet.
Identifying responders
Understanding the clinical importance of a 9.1-point difference in KCCQ scores is difficult, Spertus said, as not all trial participants respond to treatment the same way. He cited several study limitations, including some missing data due to administrative errors with the app used to collect information. He said additional study is needed to determine whether comparable benefits would be seen in patients with less impairment.
Spertus said it is important to identify the responders who will benefit from treatment the most.
“Ultimately, this is a reversal drug, so a clinician can try it and, if the patient responds, you keep going,” Spertus said. “But it is still interesting to figure out [the best responders] to identify new strategies down the road.”
In July, the FDA granted a breakthrough therapy designation to mavacamten for the treatment of patients with symptomatic obstructive hypertrophic cardiomyopathy.
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Perspective
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This study is important. Hypertrophic cardiomyopathy is estimated to affect 1 in 500 individuals in the general population, making it the most common inherited genetic cardiomyopathy. It can be a very disabling condition, associated with poor quality of life, with symptoms that include fatigue, shortness of breath, chest pain and reduced exercise tolerance. Many patients remain symptomatic despite traditional medications used for this condition like beta-blockers, which are not disease-specific, so often surgical (myectomy) or interventional (alcohol septal ablation) therapy becomes necessary for symptom management. There definitely was a need for more effective medical therapy to help patients feel better and have an improved quality of life.
Mavacamten is an exciting advance in the field, as it was the first in its class — a novel therapy that works as a direct myosin inhibitor. The previously pivotal publication from EXPLORER-HCM, which led to its recent FDA approval, showed that mavacamten reduced left ventricular outflow track obstruction and improved some functional measures of exercise capacity such as greater increase in peak oxygen consumption. But a deeper dive into the effects of mavacamten on patient-centered outcomes, such as their quality of life, was needed.
This current analysis examined patient symptoms, physical and social function, and quality of life as measured by the KCCQ, which was a prespecified secondary outcome of the EXPLORER-HCM trial. Both the clinical summary score (KCCQ-CS) and the overall summary score (KCCQ-OS) were examined. The key take-away is that there were significant benefits on quality of life, with the proportional difference in patients having a large symptom benefit improvement of 21% compared with placebo. In other words, this means that for every five patients treated with mavacamten, one would have substantial improvement. That is really important and hopeful. We finally have a new therapy to add to our toolkit for treating patients with obstructive hypertrophic cardiomyopathy that can help alleviate their symptoms to improve their function and quality of life.
A couple of caveats to note: Unfortunately, cessation of therapy was associated with a marked deterioration in KCCQ scores. So, there was no legacy effect of symptom improvement long-term after stopping. Patients would likely need to be adherent to therapy long term.
Additionally, by design, EXPLORER-HCM only enrolled symptomatic patients with obstructive form of hypertrophic cardiomyopathy. Whether this drug would confer benefits in patients with nonobstructive hypertrophic cardiomyopathy forms is not known and would require additional study.
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Spertus JA, et al. Featured Clinical Rearch 1. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).