Cardiac Myosin Inhibitors as a Novel Treatment Option for Obstructive Hypertrophic Cardiomyopathy: Addressing the Core of the Matter

mid- ventricular, and post- SRT phenotypes. Patients with heart failure with preserved ejection fraction also represent a future target for CMIs given their mechanism of action. Finally, in the minority of patients who present or progress to end- stage disease (defined as a left ventricular ejection fraction ≤50%), CMIs and SRT are contraindicated and/or not beneficial, and standard of care therapies are not typically effective. In these scenarios, advanced heart failure therapies are required. CMs indicates cardiac myosin inhibitors; G−, genotype negative; G+, genotype positive; HFpEF, heart failure with preserved ejection fraction; ICD, internal cardioverter defibrillator; LVAD, left ventricular assist device; nHCM, non- obstructive hypertrophic cardiomyopathy; NYHA, New Yok Heart Association; oHCM, obstructive hypertrophic cardiomyopathy; P−, phenotype negative; P+, phenotype positive; and SRT, septal reduction therapies.

Currently, SRT are largely confined to patients with oHCM who have advanced symptoms, as defined by New York Heart Association (NYHA) Class III or IV. 7 Increasing evidence suggests that SRT are safe in experienced centers, allowing consideration for patients with NYHA Class II symptoms. However, in a nationwide study of 6386 septal myectomies performed in the United States between 2003 and 2011, 60% of hospitals performed ≤10 procedures over the 9-year period and in-hospital mortality was as high as 15.6% in the lowest surgical volume tertile. 8 Even in the highest tertile, in-hospital death, need for permanent pacing, stroke, bleeding, and acute renal failure were not negligible (3.8%, 8.9%, 1.9%, 1.7%, and 9.4%, respectively). 8 Worldwide, many patients with oHCM are managed in institutions with limited or no expertise in SRT.
The initial approach to treatment of symptomatic patients with oHCM includes beta-blockers (BB), nondihydropyridine calcium channel blockers (CCB), and disopyramide. 7 BB and CCB act as weak negative inotropes and are often insufficient to control symptoms. 9 In addition, these agents are commonly associated with side effects and chronotropic incompetence. Disopyramide is employed as a second-line therapy, is safe and often effective in expert hands, but its use is limited by anticholinergic side effects and efficacy may diminish with time, so that SRTs ultimately become necessary. Disopyramide also suffers from supply shortages and lack of confidence by physicians, many of whom are reluctant to use class I anti-arrhythmic agents in structural heart disease. Notably, none of these time-honored medications have undergone rigorous evaluation with large multicenter randomized clinical trials (Table). [9][10][11][12][13][14][15][16] A recent crossover trial showed that BB decrease LVOT gradients and improve symptoms but without improving peak oxygen consumption (pVO 2 ). 12 Importantly, SRTs are effective in palliating symptoms and possibly improving longevity in oHCM patients, but do not address the core mechanisms of disease at the functional and energetic level. Thus, the natural evolution of the cardiomyopathic process is not affected. In a survey-based study of 753 patients (with a median age at survey of 64 years) undergoing myectomy, 26% reported new onset of atrial fibrillation (AF) during follow-up, increasing to 37% among those followed over 10 years. 17 As AF is an important marker of disease progression, and a predictor of adverse outcome in HCM, this observation challenges the notion of myectomy as a definitive treatment. This is consistent with data from the SHARE (Sarcomeric Human Cardiomyopathy Registry) on 4591 patients, showing a substantial and progressive burden of HCM-related morbidity in both obstructive (28%) and nonobstructive patients (including those undergoing SRT) mainly driven by heart failure and AF. 18 Thus, in accepting the status quo, we accept the lack of effective diseasemodifying strategies for our patients.
The 2020 American College of Cardiology/American Heart Association HCM guidelines have placed significant emphasis on shared decision-making in HCM across multiple domains, including treatment approaches. 7 Diversifying treatment strategies is the best way of empowering patients and promoting personalized care. In the current standard-of-care approach, it is assumed that all oHCM patients are willing to undergo SRT, have insurance plans that cover them in seeking care at an experienced center, and are able to afford the cost of travel for themselves and their family members, as well as the time off required for recovery from SRT. Such pre-requisites to getting excellent care at the few expert centers promote healthcare inequality by inadvertently excluding patients with lower socioeconomic status, lower education level, those who cannot advocate for themselves, and patients living with disabilities.
Over the past 2 decades, the need for more effective and less invasive therapies combined with advances in our understanding of HCM pathophysiology have set the stage for developing new agents targeting the molecular basis of the disease. HCM-associated mutations affecting sarcomere protein genes have been shown to cause myocardial hyper-contractility, due to excessive availability of myosin heads ready to form cross-bridges with actin, with a reduced proportion remaining in the energy-sparing super-relaxed state not available for engagement. This is thought to represent the core pathophysiological abnormality ultimately generating the HCM phenotypes, from compensatory hypertrophy to diastolic impairment, from LVOTO to arrhythmias, and from energy depletion to fibrosis. Inhibiting the myosin ATPase via selective cardiac myosin inhibitors (CMI) counters this state of things by reducing the number of myosin heads available for engagement with resultant return to a normal or quasinormal contractile state, relief of LVOT obstruction, decrease in wall stress, and improvement in lusitropy. 19 Currently, there are 2 main CMIs currently in various stages of development, mavacamten and aficamten. In a murine model harboring heterozygous pathogenic mutations in the cardiac myosin heavy chain, chronic administration of mavacamten suppressed the development of ventricular hypertrophy, cardiomyocyte disarray and myocardial fibrosis, and attenuated hypertrophic and profibrotic gene expression. 20 These potent and protean effects support a disease-modifying potential for CMI. The Table summarizes  Several controlled studies have been performed or are underway with CMI-at a rate unparalleled in HCM in over 4 decades. The more mature trials to date have focused on symptomatic patients with oHCM. Mavacamten, the first-in-class CMI, has been employed in the phase 2, open label PIONEER-HCM trial (Pilot Study Evaluating MYK-461 in Subjects with Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction). The study included 2 oHCM cohorts: cohort A (mavacamten 10-20 mg/day without background medical therapy) and cohort B (mavacamten 2-5 mg/day allowing concomitant BB administration). Mavacamten was highly effective in reducing LVOT gradient and improved pVO 2 , causing minor decreases in LVEF at higher plasma concentration. 14 These findings led to the phase III EXPLORER-HCM trial (Clinical Study to Evaluate Mavacamten  in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy), a randomized placebo-controlled 30-week on treatment trial of mavacamten in 251 patients with oHCM, on the background of BB and CCB (>90% of subjects). 16 The trial met its primary endpoint in a highly significant fashion: an improvement in pVO 2 by 3.0 mL/kg per minute without worsening in NYHA class or improvement of pVO 2 by 1.5 mL/kg per minute and at least one NYHA class reduction was observed in 37% of patients on mavacamten versus 17% of patients on placebo (P<0.0001). Mavacamten was generally safe and well tolerated, with a general adverse event profile comparable to placebo.
Masri and Olivotto CMI in oHCM Only one sudden death occurred, in the placebo arm.
A total of 7 patients on mavacamten developed systolic dysfunction, which was reversible with appropriate washout. 16 The finding of increased incidence of atrial fibrillation on mavacamten in PIONEER-HCM was not confirmed in EXPLORER-HCM where atrial fibrillation incidence as a treatment emergent adverse event was 2% in the mavacamten group as compared with 3% on placebo. 15,16 The analysis of multiple pre-specified secondary endpoints in Explorer-HCM demonstrated marked and consistent improvement in LVOT gradient, symptomatic status and quality of life. Notably, 65% of patients on mavacamten had improvement by ≥1 NYHA class by week 30, as compared with 31% on placebo, and 50% of patients on mavacamten achieved NYHA class I as compared with 21% on placebo. 16 These changes were associated with marked and sustained reduction in circulating levels of N-terminal pro-brain natriuretic peptide and high sensitivity troponin I in the active treatment arm. Of note, oHCM patients on BB treatment receiving mavacamten showed a modest increase in peak VO 2 , due to the blunted heart rate response, despite an amelioration in performance shown by the consistent improvement in minute ventilation/carbon dioxide production (VE/VCO 2 ) slope-which is heart rate independent. Post-hoc analyses are awaited to understand the characteristics and predictors of patients who did not respond to mavacamten.
Overall, mavacamten was effective, with a number needed to treat of 2, 3, and 4 at 30 weeks, respectively, for the endpoints of LVOT gradient reduction ≤50 mm Hg, improvement in NYHA by ≥1 class, and improvement to NYHA class I. 21 While such proportion of responders may be seen to compare unfavorably with published SRT results, it must be emphasized that patients enrolled in EXPLORER-HCM were not immediate candidates for SRT (operative referral being an exclusion criterion), and that about two-thirds were in NYHA class 2, while only the remaining third were in class 3. In addition, the results of a prospective doubleblind placebo-controlled, randomized trial cannot be compared with those from retrospective SRT studies, in view of inherent limitations of the latter. SRTs have never been formally tested in a rigorous controlled environment, and likely never will. However, the considerable placebo effect seen in EXPLORER-HCM serves as an important reminder to use caution when interpreting observational as compared to controlled data. Because of these caveats, randomized controlled trials are needed, such as the ongoing VALOR-HCM trial (A Study to Evaluate Mavacamten in Adults with Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy, NCT04349072), whose primary aim is precisely that of assessing whether mavacamten may reduce or postpone the need for SRT (Figure and Table).
Quality of life analysis provided further insight into the efficacy of mavacamten in EXPLORER-HCM. In a recently published pre-specified sub-analysis, 22   mavacamten group versus 15% in the placebo group, with an estimated absolute difference of 21% (95% CI 8.8-33.4) and a number needed to treat of 5 (95% CI 3-11). Thus, mavacamten markedly improved symptoms, physical and social function and quality of life in patients with oHCM, to a degree surpassing that of most successful cardiovascular drugs, and resembling the effects of invasive interventions such as transcatheter aortic valve replacement. 22 A small EXPLORER-HCM cardiac magnetic resonance sub-study comparing 17 treated patients versus 18 on placebo, showed significant positive remodeling over the 30-week trial period, characterized by decreased left ventricular mass, wall thickness, and left atrial volume index. In the light of concomitant improvement in echocardiographic diastolic function and circulating biomarkers, these changes can be interpreted as beneficial and promising in terms of longterm evolution of the disease, particularly as they were not associated with any increase in replacement or interstitial fibrosis, as measured by late gadolinium enhancement imaging and extracellular volume fraction. 23 Notably, similar, positive signals have emerged in a small pilot study in nonobstructive HCM patients, suggesting that the benefits observed in EXPLORER-HCM are not solely due to the marked reduction in LVOTO, Figure. The landscape of current and future applications of cardiac myosin inhibitors (CMI) for the whole spectrum of hypertrophic cardiomyopathy. Currently, the most mature application for CMI is symptomatic oHCM with NYHA class II/III, where mavacamten is under regulatory review (green boxes). Other possible future applications of CMIs include disease modifying strategies in asymptomatic individuals (denovo and post-SRT), in oHCM who are referred for SRT, and in nHCM with septal, apical, mid-ventricular, and post-SRT phenotypes. Patients with heart failure with preserved ejection fraction also represent a future target for CMIs given their mechanism of action. Finally, in the minority of patients who present or progress to end-stage disease (defined as a left ventricular ejection fraction ≤50%), CMIs and SRT are contraindicated and/or not beneficial, and standard of care therapies are not typically effective. In these scenarios, advanced heart failure therapies are required. CMs indicates cardiac myosin inhibitors; G−, genotype negative; G+, genotype positive; HFpEF, heart failure with preserved ejection fraction; ICD, internal cardioverter defibrillator; LVAD, left ventricular assist device; nHCM, non-obstructive hypertrophic cardiomyopathy; NYHA, New Yok Heart Association; oHCM, obstructive hypertrophic cardiomyopathy; P−, phenotype negative; P+, phenotype positive; and SRT, septal reduction therapies. but reflect direct effects on the myocardium. 24 While mavacamten is still under review by the United States Food and Drug Administration for official registration, 2 ongoing 5-year extension studies (NCT03496168 and NCT03723655) will shed more light on the long-term safety and efficacy of the drug in HCM patients.
Aficamten is the second CMI undergoing clinical trials: it has a shorter life compared with mavacamten, achieves steady state within 2 weeks, and appears to have a wide therapeutic window. 25 In the phase II randomized placebo-controlled sequential cohort REDWOOD-HCM (Randomized Evaluation of Dosing with CK-3773274 in Obstructive Outflow Disease in HCM) trial, high-dose aficamten (10-30 mg daily) had a favorable safety profile and led to 93% response rate (defined as a final resting LVOT gradient ≤30 mm Hg and Valsalva LVOT gradient ≤50 mm Hg) compared with 8% in the placebo arm. 13 The ongoing REDWOOD-HCM Cohort 3 of open-label aficamten on the background of disopyramide is fully enrolled, with data expected soon (NCT04219826). Based on the data from REDWOOD-HCM Cohorts 1 and 2, the phase III SEQUOIA-HCM trial is set to start enrolling.
The development of ground-breaking, diseasespecific therapies, represent a major opportunity for HCM patients, in the attempt to improve longevity, minimize morbidity, and improve quality of life. However, it would be wrong to view these novel therapeutic options as competitors to currently available treatments: they are just another arrow to our bow. As discussed earlier, providing more options ultimately means allowing patients the possibility of choosing the therapy that best suits their needs, values and circumstances. At the same time, we must be aware that early enthusiasms should be tempered by caution until we learn more about their long-term efficacy and safety, as well as their cost-effectiveness. Many open questions remain regarding CMI, ranging from potential benefits in non-obstructive HCM, individual variability in response in different ethnic groups, and their potential in preventing phenotype development in HCM mutation-carriers.
In the specific case of oHCM, it is early to say if and how much CMI will impact current practice including SRT referrals. A hypothetical transition of invasive interventions from a default strategy to a therapy for selected non-responders to CMI might represent a major advancement, certainly welcomed by patients. Beyond the laudable goal of improving hemodynamic parameters and symptoms, the Holy Grail lies in the possibility that CMI may effectively address the core mechanism of HCM, influence its substrates and prevent its natural course. Mapping this uncharted territory will require intense and prolonged efforts. Nevertheless, favorable clinical evidence is rapidly accumulating with CMI as well as its functional counterpart omecamtiv mecarbil-a myosin activator effective in heart failure with reduced ejection fraction. 26 With additional trials underway and molecules in development, it is fair to say that the newborn strategy of myosin modulation is here to stay in cardiovascular medicine.

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