Mavacamten in Symptomatic Hypertrophic Cardiomyopathy

Corresponding Author

Hypertrophic cardiomyopathy (HCM), typically characterized by significant and asymmetrical hypertrophy of the myocardium, remains the most common genetic disorder with an autosomal-dominant inheritance pattern in cardiology; however, not all individuals who are diagnosed with HCM carry an identified sarcomere mutation encoding dysfunctional sarcomeric proteins.¹ Although patients with such condition often present with a wide range of nonspecific symptoms, up to one-sixth of them may eventually develop severe heart failure (NYHA functional class III or IV), with up to one-fourth of them receiving implantable cardioverter-defibrillators during clinical follow-up.²

Because of the unique dynamic anatomic susceptibility, it has been reported that 60% to 70% of individuals with phenotypic HCM may develop left ventricular outflow tract (LVOT) obstruction—defined as an LVOT gradient of ≥30 mm Hg at rest or with physiological provocation.¹ Obstructive HCM (oHCM) has shown significant associations with higher risks of malignant ventricular arrhythmias and sudden cardiac death, and is closely linked to the onset of atrial fibrillation and heart failure. When mechanism-specific treatments are not available, traditional pharmacological treatments such as β-blockers and nondihydropyridine calcium channel blockers as first-line agents, and disopyramide, may offer a certain degree of efficacy in terms of reducing LVOT gradients and alleviating symptoms in patients with symptomatic oHCM. However, such therapeutic interventions are often accompanied by adverse effects, meaning that patient subsets are often considered as candidates for surgical myectomy or percutaneous alcohol septal ablation procedures, as further alternatives.

An oHCM therapy that is both mechanism- and disease-specific—being based on regulating cardiac function at the sarcomere level—has recently become clinically available. Mavacamten, a novel and first-in-class oral medication that was designed to specifically modulate cardiac myosin ATPase, showed substantial clinical benefits in the randomized, double-blind, and placebo-controlled phase 3 EXPLORE-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) trial.³ Patients with symptomatic oHCM (NYHA functional class I-III, n = 231) who received oral mavacamten showed significant improvements in exercise capacity, LVOT obstruction, NYHA functional class, and health status, with these results being sustained in the open-label extension until week 180.⁴ Notably, the imaging-based findings correlated well with clinical improvements, reinforcing the mechanistic underpinnings of cardiac myosin inhibitor therapy in terms of altering the natural course of oHCM. In the VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) trial, mavacamten also produced durable improvements in LVOT gradients, N-terminal pro–B-type natriuretic peptide levels, and NYHA functional classes and improved quality of life metrics.⁵ Both the REDWOOD-HCM (Randomized Evaluation of Dosing With CK-3773274 in Obstructive Outflow Disease in HCM)⁶ and SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM)⁷ trials, which evaluated aficamten in North American, European, and global populations, respectively, confirmed rapid and sustained reductions in LVOT gradient, in parallel with improvements to NYHA functional classes and N-terminal pro–B-type natriuretic peptide levels. In the SEQUOIA-HCM trial, the drug significantly raised peak oxygen consumption, as an indicator of improved exercise capacity. One meta-analysis focusing on oHCM analyzed 5 randomized controlled trials involving 767 patients (mavacamten: 30.4%; aficamten: 22.2%; placebo: 47.4%) with a median follow-up period of 24 weeks reported that the cardiac myosin inhibitors were associated with improved NYHA functional class, peak LVOT at rest and during the Valsalva maneuver, health status, and similar safety outcomes vs a placebo.⁸

Despite the significant breakthrough of mavacamten as an emerging pharmacologic treatment option for oHCM (Table 1), substantial knowledge gaps persist regarding the effects and safety profiles of oral mavacamten in Chinese patients, and those of other Asian ethnicities—both of which represent potential markets that were underrepresented in the early worldwide trials of the drug. Although the sample size was much smaller (n = 81), the substantial improvements in LVOT obstruction, NYHA functional class, and health status vs placebo that were observed in the Chinese patients of the EXPLORE-CN (A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM) trial were generally consistent with previous trials, with no safety-related signals reported.⁹ Notably, cardiac magnetic resonance imaging datasets were available in the EXPLORE-CN trial, providing valuable and mechanistic insights into the cardiac remodeling (eg, cardiac mass, volume, fibrosis) that takes place during mavacamten treatment in Chinese patients.

Table 1.

Comparison of Key Findings in Cardiac Myosin Inhibitors Phase II and III Trials

Study Name	Drug	Population	Imaging/Clinical Findings	Imaging Modality	Key Outcome(s)
EXPLORER-HCM1	Mavacamten	Global, oHCM	↓ LVOT gradient, ↓ LVMI, ↓ LAVI, ↓ wall thickness, ↑ diastolic function	CMR	Improved NYHA functional class, NT-proBNP, symptoms
EXPLORER-CN2	Mavacamten	Chinese, oHCM	↓ LVOT gradient, ↓ LVMI, ↓ wall thickness, ↓ LAVI, ↓ fibrosis	CMR	Improved NYHA functional class, quality of life
VALOR-HCM3	Mavacamten	USA, oHCM	↓ LVOT gradient	TTE	Improved NYHA functional class, NT-proBNP, cardiac troponin I, quality of life
REDWOOD-HCM4	Aficamten	North American and European, oHCM	↓ LVOT gradient	TTE	Improved NYHA functional class, NT-proBNP
SEQUOIA-HCM5	Aficamten	Global, oHCM	↓ LVOT gradient	TTE	Improved pVO2, NYHA functional class, NT-proBNP, quality of life

CMR = cardiac magnetic resonance; LAVI = left atrial volume index; LVMI = left ventricular mass index; LVOT = left ventricular outflow tract; NT-proBNP = N-terminal pro–B-type natriuretic peptide; oHCM = obstructive hypertrophic cardiomyopathy; pVO₂ = peak oxygen uptake; TTE = transthoracic echocardiography.

In the global EXPLORER-HCM cardiac magnetic resonance study,¹⁰ no notable changes were reported in terms of the global mass of late gadolinium enhancement by 6 SDs at week 30. In this issue of JACC: Asia, Tian et al¹¹ showed that greater reductions from baseline indicators were observed in patients who were given mavacamten vs a placebo (mavacamten: n = 39; placebo: n = 19) in terms of left ventricular mass index, maximal left ventricular wall thickness, and maximal left atrial volume index, after 30 weeks. Although the precise mechanism remains to be determined, this study also reported a reduction in global late gadolinium enhancement by 6 SDs mass, indicating a reduced total burden of myocardial fibrosis with relatively small sample sizes. Notably, the extent of fibrosis at the baseline appeared to be greater in the EXPLORER-CN trial vs the earlier EXPLORER-HCM one. This suggests a potential antifibrotic effect of mavacamten in addition to underscoring the reproducibility of its structural and functional benefits, which may need to be confirmed in further studies with larger sample size across populations of varying ethnicities.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.