Mavacamten may improve structural abnormalities of obstructive hypertrophic cardiomyopathy
Mavacamten improved left ventricular hypertrophy, decreased measures of heart stiffness and restored normal mitral valve motion in patients with obstructive hypertrophic cardiomyopathy, according to an analysis of the EXPLORER-HCM trial.
Mavacamten (MyoKardia) is an oral, allosteric modulator of cardiac myosin. This therapy was developed to target the underlying cause of hypertrophic cardiomyopathy.
As Healio previously reported at the virtual European Society of Cardiology Congress, mavacamten improved symptoms, quality of life and functional status compared with placebo in patients with symptomatic, obstructive hypertrophic cardiomyopathy.
The new analysis “builds on our previous observations that treatment with mavacamten led to significant improvement in symptoms, exercise capacity, health status and left ventricular outflow tract gradients,” Sheila M. Hegde, MD, MPH, cardiovascular medicine specialist at Brigham and Women’s Hospital and instructor in medicine at Harvard Medical School, told Healio. “Together, these results support the theory that mavacamten, as a first-in-class myosin inhibitor, impacts key pathophysiologic features of hypertrophic cardiomyopathy. This would represent a significant advance in therapy in this population.”
Researchers reported additional echocardiographic analyses to examine the effect of mavacamten on measures of cardiac structure and function. In total, 244 patients with obstructive cardiomyopathy (mean age, 59 years, 41% women) were randomly assigned to daily mavacamten 2.5 mg to 15 mg or placebo for 30 weeks, with echocardiograms performed every 2 to 4 weeks.
At 30 weeks, patients assigned mavacamten experienced significant reductions compared with placebo in left atrial volume (–7.5 ml/m2), lateral E/e' (–3.8 cm/s), septal E/e' (–3.4 cm/s) and LV mass index (–15.5 g/m2; P for all < .0001), according to the results.
In addition, compared with placebo, more patients assigned mavacamten achieved resolution of mitral valve systolic anterior motion (80.9% vs. 34%; difference; P < .0001) and mitral regurgitation (9% vs. 0%; P = .0006).
The ongoing, long-term extension study, MAVA-LTE, will follow participants of EXPLORER-HCM to evaluate long-term safety and efficacy, according to Hegde. Serial echocardiographic data in this population will provide further insight into the long-term impact of mavacamten on cardiac structure and function, she said.
“There is an ongoing long-term extension study, MAVA-LTE, following the subjects who participated in EXPLORER-HCM to evaluate long-term safety and efficacy, and serial echocardiographic data in this population will provide further insight on the long-term impact on cardiac structure and function,” Hegde said in an interview. “Furthermore, the VALOR-HCM study is enrolling patients with obstructive hypertrophic cardiomyopathy and severe symptoms who are eligible for septal reduction therapy to further investigate the ability of mavacamten to reduce the need for surgical or percutaneous procedures.”
The results were consistent with another imaging study presented at the AHA Scientific Sessions and published in Circulation. In that study of 30 patients from EXPLORER-HCM (mean age, 60 years; 43% women) by Sara Saberi, MD, assistant professor of medicine at the University of Michigan, and colleagues, those assigned mavacamten had a greater reduction in LV mass index at 30 weeks compared with those assigned placebo (mean between-group difference, 15.8 g/m2; 95% CI, 22.6 to 9; P < .0001). The same was true for LV mass (mean between-group difference, 30 g; 95% CI, 43.3 to 16.7; P < .0001).
In July, the FDA granted a breakthrough therapy designation to mavacamten for the treatment of patients with symptomatic, obstructive hypertrophic cardiomyopathy.
References:
- Saberi S, et al. FS.04: High-profile clinical science in CVD. Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).
- Saberi S. et al. Circulation. 2020;doi/10.1161/CIRCULATIONAHA.120.052359.
Perspective
Back to Top
In hypertrophic cardiomyopathy, the main pathology is increased thickness of the septal wall at about the same location as where the blood flows from the left ventricle into the aorta to be pumped to the rest of the body. When the muscle is thick and the ventricle contracts to eject the blood, there is a tendency for that outflow tract to narrow and sometimes close, leading to obstruction of the ventricular outflow.
The original study of mavacamten looked at whether we could reduce the force generated by these muscles so that it does not thicken and obstruct the outflow tract.
Subsequently, researchers looked at the other physiologic characteristics affected by mavacamten, and this analysis revealed that the consequence of such pathophysiological improvement also improved other areas that contribute to the overall clinical manifestation of hypertrophic cardiomyopathy, such as reduction in mitral regurgitation, which was improved due to the altered dynamics of the blood with drug therapy. The analysis by Hegde and colleagues also looked at the size of the left atrium. Left atrial size increases when there is mitral regurgitation due to blood flowing back into the left atrium instead of flowing out into the aorta, and this analysis showed that these secondary endpoints were statistically significant favoring the use of mavacamten.
What is surprising is that the mavacamten not only improved the outflow tract obstruction, but also had positive influence on consequences of that obstruction, which is an added benefit to the patients. Overall, it is in line with what is expected, but it proves efficiency of the drug.
If mavacamten gets approved by the FDA, post-approval studies should look at other factors such as sudden death, which is one of the most feared clinical events in hypertrophic cardiomyopathy and was not mentioned in the Hegde study. Hypertrophic cardiomyopathy in some patients, because of their mutated genes, also results in sudden death. We have a way of screening those patients for this event and then providing treatment, but there are some who are not lucky enough to be diagnosed prior to the event occurring. Sudden death is especially feared among athletes and young adults. Longer-term studies and perhaps a registry would be effective in evaluating this outcome.
The EXPLORER-HCM trial itself moves us forward to provide a medical solution for hypertrophic cardiomyopathy. Initially, in the 1950s and 1960s, patients had surgical options, where the septal thickness was reduced by surgical means. This procedure in itself has had its own consequences. From there, we moved on to using less-invasive alcohol septal ablation, which is injecting alcohol into one of the branches of the coronary artery that supplies that hypertrophic area, cutting off blood supply leading to potential loss of muscle cells and reduction in thickness. Until now, cardiologists and other specialties have not had a specific medical option other than referring the patient for specialized surgical care. What I see happening, if this drug proves to be useful, and these are promising results, is it gives a resource for general cardiologist to start treating these patients before referring them to more invasive, specialized treatments for hypertrophic cardiomyopathy, which is exciting.
Collapse
Hegde SM, et al. Presentation P1732. Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).