Cardiac myosin inhibitors for hypertrophic cardiomyopathy: shedding light on their clinical potential

1. Introduction

Hypertrophic cardiomyopathy (HCM) is an inherited condition with an estimated global prevalence of 1 in 500 adults and is characterized by left ventricular, non-dilated hypertrophy in the absence of another secondary underlying cause [1,2]. With an autosomal dominant pattern of inheritance, the pathophysiology of HCM is related to more than 2000 variants in genes responsible for cardiac sarcomere function. Through excess availability of myosin heads and reduced proportion of the energy-sparing relaxed state, these gene mutations may promote myocardial hypercontractility, impaired relaxation, and energetics and consequently result in myocardial hypertrophy [3]. Furthermore, myocardial fiber disarray along with hypertrophy and interstitial fibrosis creates an arrhythmogenic substrate, leading to the well-known and clinically associated phenomenon of sudden cardiac death [4]. Aside from arrhythmia, dynamic left ventricular outflow tract obstruction (LVOTO) can be seen in 70% of HCM patients, owing to systolic anterior motion of an oftentimes elongated mitral valve leaflet toward a hypertrophied interventricular septum [5]. Diastolic dysfunction (from an increase in chamber stiffness paired with impaired relaxation) along with myocardial ischemia (from small vessel disease and perforating artery compression) ultimately results in reduced coronary perfusion [6]. Clinically, this diverse pathophysiology manifests most commonly as dyspnea, chest pain, exertional syncope, arrhythmias, or sudden cardiac death.

2. Therapeutic options for hypertrophic cardiomyopathy

Over the past two decades, there has been an expansion of pharmacotherapeutic options for patients with HCM, most comprehensively housed within national centers of excellence. The most recent guidelines on the management of HCM call for a melody of treatment strategies, taking symptomology and obstructive gradient into consideration [1,2]. Historically, treatment has revolved around reduction of symptoms and the reduction of risk of sudden cardiac death through medical management with beta-blockers, non-dihydropyridine calcium channel blockers and disopyramide, and implantation of defibrillators in high-risk patients [1]. In cases of persistent symptoms despite pharmacotherapy, septal reduction therapy (SRT) is advised through alcohol septal ablation and septal myectomy [1]. Although alcohol septal ablation and septal myectomy data have shown mortality rates of less than 1% and 1–3%, respectively, they require highly experienced centers and personnel to achieve such success. Less experienced or low volume centers show mortality rates of up to 16%, suggesting that there simply are not enough centers performing the invasive procedures with the desired outcomes [7]. This has been the driving force behind the development of alternative noninvasive therapies. Targeted drug therapy, specifically novel cardiac myosin inhibitors (CMI), such as mavacamten and aficamten, is being investigated to not only improve longevity and minimize morbidity but also potentially suppress the development and progression of HCM.

3. Novel cardiac myosin inhibitors in clinical trails

Mavacamten, a CMI, was engineered as an allosteric and reversible inhibitor selective for modulating the number of myosin heads in the off or relaxed state by inhibiting the cardiac myosin adenosine triphosphatase (ATPase) [3,8]. This increases the length of the total time of the ATPase cycle, ultimately leading to a reduction in the force of myocardial contraction [9]. Additionally, mavacamten has been shown to stabilize the relaxed state of the beta-cardiac myosin, reducing the interaction between actin and myosin and again working to suppress cardiac contractility. Of note, chronic mavacamten infusion has led to suppression of the phenotype development including ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis in mouse models [3].

To date, four key clinical trials (Table 1) have investigated the effects of mavacamten in HCM – PIONEER-HCM, MAVERICK-HCM, EXPLORER-HCM, and VALOR-HCM. The PIONEER-HCM study (a multicenter, phase II, open-label trial) demonstrated that mavacamten has beneficial effects in reduction of LVOTO and improvement of exercise capacity in symptomatic patients [10]. It evaluated dosing in two cohorts: one with mavacamten dosed 10–20 mg/day without previous medical therapy, and another where mavacamten was dosed at 2–5 mg/day with concurrent beta blocker administration. The left ventricular outflow tract (LVOT) gradient and maximal oxygen consumption peak VO2 were tested at 12 weeks. Ultimately, the LVOT gradient was significantly reduced in patients that had received the higher dose of mavacamten [10]. Subsequently, MAVERICK-HCM study (a multicenter, double-blind, phase II, randomized, placebo-controlled trial), conducted in symptomatic non-obstructive HCM patients, revealed significant decreases in troponin-I and NT-proBNP, as well as improvement in echocardiographic parameters in patients receiving mavacamten as compared to placebo [11].

Table 1. Clinical trials assessing the efficacy and safety of the novel cardiac myosin inhibitor mavacamten, in patients with hypertrophic cardiomyopathy.

Trial name and year	Design	Participants, drug, and doses	Primary endpoint	Key findings
PIONEER-HCM 2019	Open-label, nonrandomized, phase 2 trial	Total: 21 patients with symptomatic HOCM. Cohort A: MAV 10–20 mg/day Cohort B: MAV 2–5 mg/day + BB	Change in post-exercise LVOT gradient after 12 weeks, compared to baseline	MAV decreased mean post-exercise LVOT-gradient and resting LVEF in both cohorts. MAV increased mean pVO2 in both cohorts.
MAVERICK-HCM 2020	Multicenter, double-blind, placebo-controlled, dose-ranging phase 2 study	Total: 59 patients with symptomatic nHCM, LVEF ≥55%, NT-proBNP ≥300 pg/ml. MAV doses of 2.5, 5, 10, or 15 mg/day, to target plasma levels of 200 ng/ mL (n = 19) or 500 ng/mL (n = 21) versus placebo (n = 19).	Efficacy and safety of MAV	Study underpowered to detect clinical benefit. Compared to placebo: MAV reduced NT-proBNP and cTnI.
EXPLORER-HCM 2020	Multicenter, phase 3, randomized, double-blind, placebo-controlled trial	Total: 251 patients with HCM, with LVOT gradient ≥50 mm Hg and NYHA II–III symptoms. MAV (2.5–15 mg (n = 123), titrated to maintain LVOT gradient <30 mm Hg and drug plasma concentrations 350–700 ng/mL versus placebo (n = 128) for 30 weeks.	Improvement in exercise pVO2 of ≥1.5 mL/kg/min and reduction of at least one NYHA class OR Improvement in exercise pVO2 of ≥3.0 mL/ kg/min without NYHA class worsening.	Significantly more patients in MAV group met primary endpoint compared to placebo group. Significantly greater reductions in post-exercise LVOT gradient, pVO2, and improved symptom scores in MAV group compared to placebo.
VALOR-HCM 2022	Phase 3, randomized, double-blinded, parallel-assignment, placebo-controlled trial	Total: 112 patients with HOCM, randomized to MAV (5 mg daily), or placebo, titrated up to 15 mg.	Proportion of patients proceeding with SRT or remaining guideline-eligible after 16 weeks of treatment.	After 16 weeks, a significantly lower proportion (18%) of MAV patients met guideline criteria or underwent SRT, as compared to placebo (77%).

BB: beta blocker; cTnI: cardiac troponin-I; HCM: hypertrophic cardiomyopathy; HOCM: hypertrophic obstructive cardiomyopathy; LVEF: left ventricular ejection fraction; LVOT: left ventricular outflow tract; MAV: mavacamten; NT-proBNP: N-terminal pro-B type natriuretic peptide; NYHA: New York Heart Association; pVO2: peak oxygen consumption; SRT: septal reduction therapy.

These results drove the EXPLORER-HCM study (a multicenter, phase III, double-blind, randomized, placebo-controlled trial) that assessed the efficacy and safety profile of mavacamten over a 30-week period for symptomatic obstructive HCM [12]. This was defined as having a peak LVOT gradient of ≥50 mmHg and New York Heart Association (NYHA) class II–III symptoms. The trial determined the primary endpoints as an increase of ≥1.5 mL/kg/minute peak oxygen consumption (pVO2) and a reduction of at least one NYHA functional classification or a 3.0 mL/kg/minute in pVO2 and no worsening of NYHA class. Findings revealed that 37% of patients on mavacamten met the primary outcome, with 20% of patients achieving both a ≥ 3.0 mL/kg per min increase in pVO2 and ≥1 improvement in NYHA class compared with only 8% of placebo, and roughly 50% of patients on mavacamten achieving NYHA class I upon trial completion as compared with 21% on placebo. One of the more encouraging findings, however, was that 27% of patients receiving mavacamten therapy showed a reduction in all LVOT gradients to less than 30 mmHg as well as reached NYHA class I classification (termed complete response). Only 1% of placebo achieved this complete response [12].

Most recently, the VALOR-HCM trial had findings that were complementary to those of the EXPLORER-HCM trial, as it assessed the safety and efficacy of adding mavacamten to maximally tolerated medical therapy patients with more severely symptomatic (NYHA class II–III) obstructive HCM, this time over a 16 week period [13]. The same inclusion criteria were considered as in the EXPLORER-HCM trial; however, the patients recruited in VALOR-HCM were referred within the past 12 months for SRT or were actively considered for scheduling the procedure. Again, the study found an improvement in NHYA class (1 or more) in 63% of patients receiving mavacamten compared to 21% of placebo. Resting and Valsalva-induced LVOT gradients were also significantly reduced when compared to placebo [13].

An increased incidence of atrial fibrillation was seen as a potential adverse effect of mavacamten based on the findings of the PIONEER-HCM trial [10]. However, this was not confirmed in the EXPLORER-HCM trial, as the incidence of atrial fibrillation was only 2% in the mavacamten group but 3% in the placebo arm [12]. The most common adverse effect noted in all trials was related to a dose-dependent reversible decrease in left ventricular ejection fraction (LVEF). The PIONEER-HCM study showed a decrease to 34–49% with higher plasma concentrations of the drug [10]. This recurred in both the EXPLORER-HCM and VALOR-HCM studies [12,13]. EXPLORER-HCM noted LVEF reductions below 50% in 7 patients and VALOR-HCM noted the same in 2 patients [12,13]. In all cases and trials, there was recovery upon temporary drug discontinuation. Given this propensity of mavacamten to reduce cardiac contractility and cause systolic dysfunction, it is only available through a Risk Evaluation and Mitigation Strategy (REMS) called CAMZYOS REMS Program in the United States [14].

Aside from mavacamten, other myosin inhibitors are also being developed and tested. Among these is aficamten, a myosin inhibitor and allosteric modulator binding to a different regulatory site, with a reduced half-life and potentially fewer drug-drug interactions than mavacamten owing to no substantial CYP inhibition or induction [15]. The SEQUOIA-HCM study (a phase III trial) is currently enrolling patients to evaluate the effects of aficamten on health status and cardiopulmonary exercise capacity in patients with hypertrophic obstructive cardiomyopathy.

4. Expert opinion

Novel CMI may significantly change management and alter the risk/benefit discussion of invasive therapies for HCM, and mavacamten is the first of its kind to show promise in this regard. CMI may now fit into management of several HCM patient subsets: (1) as initial pharmacotherapy for patients with newly diagnosed HCM, (2) patients on traditional medications, (3) patients failing traditional medications/wish to avoid medications who move to SRT, (4) ideal candidates for SRT, especially at extremes of age, who should move to SRT instead of traditional medications, and (5) patients post-SRT with residual LVOT gradients.

Future studies of CMI should focus on evaluating the prevention of symptoms and progression of diseases in individuals with gene positivity or mild phenotype positivity who are asymptomatic. Randomized controlled trials of CMI are needed in this population. Furthermore, diversification of the study pools will be crucial to ensure generalizability of the findings, particularly to underrepresented backgrounds, as the trials presented here had an overwhelming majority of Caucasian participants.

The introduction of CMI may streamline the playing field of therapeutic options for HCM, focusing on these medications and the proven SRTs for patients who fail medical treatment. Given widespread phenotypical variability in patients with HCM, clinical management will remain challenging, and a personalized and individualized approach will be necessary. For these reasons, national centers of excellence should remain a mainstay of the landscape to work alongside community cardiologists in caring for these complex patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.