Aficamten improves outcomes in obstructive HCM via significant cardiac remodeling
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Key takeaways:
- Aficamten was linked to improved exercise capacity and quality of life for patients with obstructive HCM.
- The benefit was likely due to cardiac remodeling and replacement fibrosis observed on cardiac MRI.
Improvements in exercise capacity and quality of life associated with aficamten coincided with significant cardiac remodeling and replacement fibrosis in patients with obstructive hypertrophic cardiomyopathy, a speaker reported.
Results of a SEQUOIA-HCM substudy were presented at the European Society of Cardiology Congress and simultaneously published in the Journal of the American College of Cardiology.
“Hypercontractility due to excessive myosin-actin interaction increases left ventricular pressure and leads to progressive LV hypertrophy and adverse cardiac remodeling. This is a fundamental mechanism that underlies obstructive hypertrophic cardiomyopathy,” Ahmad Masri, MD, MS, associate professor of medicine in the division of cardiovascular medicine at Oregon Health & Science University, said during a presentation. “Aficamten, as a next-in-class cardiac myosin inhibitor, is currently in development for the treatment of obstructive hypertrophic cardiomyopathy and reduces hypercontractility in the cardiac sarcomere.”
SEQUOIA-HCM included 282 patients with obstructive HCM receiving standard care who were randomly assigned to the cardiac myosin inhibitor aficamten (Cytokinetics) or placebo. The primary endpoint was 24-week change in peak oxygen uptake (peak VO2), and the first hierarchical secondary endpoint was 24-week change in Kansas City Cardiomyopathy Questionnaire score.
As Healio previously reported, aficamten was associated with improved exercise capacity and quality of life compared with placebo in this cohort of patients with obstructive HCM.
For the present substudy, Masri and colleagues used cardiac MRI to assess the impact of aficamten on cardiac structure and function and improvements observed in the main trial.
Fifty SEQUOIA-HCM participants completed the MRI substudy (mean age, 59 years; 35% women; 93% white), of which 21 received aficamten and 29 were assigned to placebo.
On cardiac MRI, the researchers observed reduction in LV mass index (15.4 g/m2; 95% CI, 24.5 to 6.3; P = .001), maximal wall thickness (1.2 mm; 95% CI, 1.8 to 0.6; P < .001), left atrial volume maximum index (12.8 mL/m2; 95% CI, 19 to 6.7; P < .001) and global native T1 (36.8 ms; 95% CI, 68.8 to 4.7; P = .026) from baseline to week 24.
In addition, improvements also were observed for LV extracellular volume mass index (3.9 g/m2; 95% CI, 7 to 0.9; P = .014), absolute myocyte mass index (14 g/m2; 95% CI, 23 to 4; P = .004), LV outflow tract gradient at rest (38 g/m2; 95% CI, 56 to 20; P < .001), LV outflow tract gradient with Valsalva maneuver (47 g/m2; 95% CI, 65 to 30; P < .001), N-terminal pro-B-type natriuretic peptide (85 pg/mL; 95% CI, 89 to 78; P < .001) and a trend toward improvement in NYHA functional class of at least one (OR = 3; 95% CI, 0.99-9.1; P = .05).
“In the SEQUOIA-HCM CMR substudy, treatment with aficamten for 24 weeks resulted in favorable cardiac remodeling, including reduced LV mass, LV wall thickness and left atrial volume index with stable interstitial and replacement fibrosis,” Masri said during the presentation. “The structural changes observed with [cardiac MRI] occurred in conjunction with similar improvements in hemodynamics, symptoms and biomarkers. These data support the need to longitudinal [cardiac MRI] studies to assess treatment response in patients with HCM and to truly try to measure the effects size, when we talk about imaging modalities.”
Reference:
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Masri A. Trial updates and other studies in hypertrophic cardiomyopathy and aortic stenosis. Presented at: European Society of Cardiology Congress; Aug. 30-Sept. 2, 2024; London (hybrid meeting).
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