Exploring a novel medical therapy for hypertrophic cardiomyopathy: EXPLORER-HCM and beyond

Take Home Messages
  • Mavacamten represents a first in-class novel therapy for hypertrophic cardiomyopathy, and the first medical therapy targeting HCM pathophysiology
  • EXPLORER-HCM was a double blinded, randomized control trial comparing mavacamten therapy to placebo in patients with obstructive hypertrophic cardiomyopathy. It demonstrated reduced symptom burden compared to placebo and significantly reduced left ventricular outflow tract gradient
  • These are important findings and a big step forward in the management of hypertrophic cardiomyopathy. It is however a relatively small trial, with a focus on symptom burden. Further work is therefore required to ensure long term safety and efficacy of this therapy

In this editorial, I will review the evidence underpinning a new treatment for hypertrophic obstructive cardiomyopathy - the first in class myosin inhibitor, Mavacamten. I will focus on the findings of the recently published phase 3 trial EXPLORER-HCM, as well as highlighting possible future directions.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition characterised by hypertrophy of the left ventricle. Left ventricular hypertrophy (LVH) can occur through multiple mechanisms, including inherited gene mutations; pathophysiological alterations of cardiac preload and afterload; metabolic disorders and infiltrative disease. As a result, there is international disagreement as to how hypertrophic cardiomyopathy should be classified. The 2014 European Society Council (ESC) guidelines use HCM as an umbrella clinical term for left ventricular hypertrophy equalling or exceeding 15 mm in any wall (although HCM may be diagnosed with a lesser degree of wall thickness if other features are present). The ESC view on HCM

aetiology includes causes related to all sarcomeric gene mutations, as well as metabolic disorders such as Anderson-Fabry disease, mitochondrial cardiomyopathies and infiltrative disorders such as cardiac amyloidosis, and excludes only LVH which can be explained by abnormal loading conditions, such as hypertension or aortic stenosis. Many of these diagnoses will be characterised by multi-organ involvement, which is not a restriction to diagnosis of HCM by the European guidelines1.

The recently published American Heart Association/American College of Cardiology guidelines, whilst following the same clinical wall thickness cut-offs as the ESC guidelines, restrict the diagnosis of HCM to hypertrophy of the left ventricle without other organ involvement, which cannot be explained by another cardiac, systemic or metabolic disorder, and for which a sarcomere-related gene mutation has been identified, or a genetic diagnosis remains unresolved2.

For the purposes of this editorial, given that EXPLORER-HCM classifies HCM according to the American guidelines, when referring to HCM pathophysiology, the focus will be on HCM caused by sarcomeric mutations. It is however important to be familiar with the multiple different mechanisms which can lead to left ventricular hypertrophy, as this will aid subsequent investigation and treatment decisions.

Hypertrophic cardiomyopathy was first described by Brock in 19573, and initially labelled as idiopathic hypertrophic subaortic stenosis, reflecting the dynamic left ventricular outflow tract obstruction which characterises the obstructive form of HCM, with reclassification to Hypertrophic Obstructive Cardiomyopathy in the following years4. Another step forward was taken in the 1990s, when mutations in genes encoding sarcomeric proteins were first identified in conjunction with clinical HCM2. Sarcomeres are the contractile units within cardiomyocytes and consist of thick myosin filaments, thin actin/tropomysin filaments, titin filaments which act to maintain structural integrity and troponin complexes coordinating their interaction and calcium binding5. Gene mutations have been identified in all of these sarcomere subunits, and are predominantly inherited in an autosomal dominant fashion6. The most common causal gene mutations are listed in Table 1.

Table 1. Causal Sarcomeric Genes for HCM
GeneEncoded ProteinFunction
MYH7β-Myosin Heavy ChainForce generation
MYBPC3Myosin binding protein-CCardiac Contraction
TNNT2Cardiac Troponin TActin-myosin regulation
TNNI3Cardiac Troponin IInhibition of actin-myosin interaction
TPM1α-tropomysinTroponin interaction with actin
ACTC1Cardiac α-actinActin-myosin interaction
MYL2Regulatory myosin light chainBinding protein of myosin heavy chain
MYL3Essential myosin light chainBinding protein of myosin heavy chain
CSRP3Cysteine and glycine-rich protein 3Z disk protein
Adapted from Marian et al.11
Clinical Manifestations

As previously stated, HCM is clinically defined as the otherwise-unexplained presence on any cardiac imaging modality of LV wall thickness equalling or exceeding 15 mm in any segment, although can also be diagnosed with lesser hypertrophy in the presence of positive genetic testing, or when found in first degree relatives of an index case2. When the latter definition is taken into account, population prevalence is estimated to be up to 1 in 200, although the vast majority of these cases remain undiagnosed7.

The sarcomeric mutations described lead to alterations in multiple molecular signalling pathways, the individual complexities of which are outside the scope of this editorial. Collectively, activation of these pathways, and the incorporation of abnormal proteins into the sarcomere units, lead to cardiomyocyte hypertrophy, increased ventricular interstitial fibrosis and myofibril disarray. These histological changes, in conjunction with alterations in calcium handling, provide a substrate for ventricular tachyarrhythmia, and individuals with HCM are at increased risk of sudden cardiac death (SCD)7.

The risk of SCD varies depending on a number of clinical and genetic characteristics, and has been quantified using the risk prediction model ‘HCM risk-SCD’8, which is recommended in the ESC guidelines for determining the need for internal cardioverter defibrillator (ICD) therapy1. Left ventricular systolic function is most commonly either normal or hyperdynamic, with a reduction in systolic function below 50% indicating a poor prognosis and thought to relate to late stages of the disease9.

Obstructive HCM

The left ventricular hypertrophy seen in HCM is frequently asymmetrical, and can cause dynamic left ventricular outflow tract obstruction (LVOTO), through physical obstruction by septal hypertrophy and by systolic anterior motion of the anterior mitral valve leaflet10. This is assessed by echocardiography demonstrating dynamic pressure gradient change across the LVOT, and can occur at rest in up to a quarter of patients with HCM7, with a larger proportion demonstrating LVOTO on provocation11, either induced by exercise or by using the Valsalva technique12. LVOTO is a hallmark of HCM and its presence is responsible for the majority of symptom burden seen in HCM, as well as increasing the risk of both SCD and progression to heart failure10.

Clinical Symptoms and treatment

Clinical symptoms related to HCM, include exertional angina, breathlessness, palpitations and syncope. These may be a result of outflow tract obstruction, however, may also occur in non-obstructive HCM, related to diastolic dysfunction, intramyocardial ischaemia and brady or tachyarrhythmias.

Current therapies for HCM are predominantly aimed at reducing this symptom burden. In non-obstructive HCM patients with a normal ejection fraction, pharmacological treatment focuses on beta-blockade and calcium channel blockade using non dihydropyridine blocking agents, with the primary aim of increasing LV filling time and reducing diastolic pressure through their negatively inotropic and chronotropic properties, with the additional benefit of reducing tachyarrhythmia incidence. In the presence of reduced EF, conventional therapy with ACE inhibitors and mineralocorticoid receptor antagonists is also indicated13.

In the presence of resting or provocable LVOTO, beta blockade has been shown in several small, historic trials to reduce outflow tract obstruction, and disopyramide may be added if beta blockade alone is insufficient14. If medical therapy fails, invasive therapies to reduce LVOTO include septal myomectomy and alcohol septal ablation. Both of these procedures have been demonstrated to abolish or significantly improve gradients across the LVOT, and significantly improve symptom burden, with low procedural mortality2.

All current therapeutic options for both obstructive and non-obstructive HCM are based only on small trials or observational data14. They are also all focussed on reducing symptom burden, without targeting the pathophysiological processes driving the development of HCM. Explorer-HCM was the first multi-centre randomised control trial to examine a novel therapy with the aim of not only reducing symptom burden, but also targeting the pathophysiological development of hypertrophic cardiomyopathy.


Mavacamten is a small molecule inhibitor of cardiac myosin ATPase. Initially termed MYK-461, it was produced to examine if myosin inhibition, and consequent reduction in sarcomere contractility power, would reduce cardiomyocyte hypertrophy and myocardial fibrosis. This was based on the hypothesis that sarcomeric gene mutations caused increased contractility, not only contributing to the hyperdynamic systolic function that is a characteristic of HCM, but also accelerating myocardial fibrosis, hypertrophy and cellular disarray through activation of multiple molecular signalling pathways15. This initial paper by Green et al not only demonstrated MYK-461 did inhibit cardiomyocyte contractility, but it also reduced LVH, fibrosis and myocardial disarray in a mouse model of HCM15. The success of this small molecule inhibitor gave significant support to the hypothesis that increased sarcomere contractility is the driving mechanism behind HCM pathophysiology, and also highlighted its potential as the first disease modifying treatment for HCM.

A subsequent Phase 2 trial – PIONEER-HCM – demonstrated that MYK-461, now established as mavacamten, could be given safely to patients with obstructive HCM, and suggested that mavacamten reduced LVOT gradients and symptom burden, even when taken in conjunction with beta blockers16. This was a study of just 21 patients, but paved the way for the phase 3 trial, EXPLORER-HCM.



EXPLORER-HCM was an international, double blinded randomised control trial, across 68 centres in 13 countries. A total of 251 adult patients with a diagnosis of obstructive hypertrophic cardiomyopathy, with an LVOT gradient over 50 mmHg at rest as well as NYHA class II-III symptoms, were recruited and randomised to either oral mavacamten or placebo. Concurrent beta blocker or calcium channel blocker use was allowed, although disopyramide use was not. Key exclusion criteria included a history of syncope; sustained VT on exercise; prolonged QT interval; or atrial fibrillation at the time of recruitment. Treatment was continued for thirty weeks, and participants were frequently screened throughout with cardiopulmonary exercise testing (CPET), echocardiography and blood tests to assess mavacamten plasma concentration, with temporary discontinuation of therapy occurring if LVEF reduced to below 50% (16).

Primary and Secondary Outcomes

The primary outcome addressed symptom burden and exercise capacity, and was a composite of either at least a 1.5 ml/kg/min increase in peak minute oxygen consumption (pVO2) with a reduction in NYHA class, or at least a 3.0 ml/kg/min increase in pVO2 with no worsening of NYHA class.

Secondary outcomes were: reduction in post-exercise LVOT gradient at 30 weeks; pVO2; reduction in NYHA class; and other patient-reported symptom scores, including the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness of Breath (HCMSQ-SoB) subscore (17).


Enrolled patients were well matched, with an average age of 58.5, and wide use of background therapy, with 92% taking either a beta blocker or calcium channel blocker. Safety parameters showed no adverse signals, with 97% of patients completing treatment. Seven patients in the mavacamten arm temporarily discontinued therapy due to transient reduction in ejection fraction, but all were able to restart the drug. Only two patients in the mavacamten arm permanently discontinued therapy, one due to atrial fibrillation and one due to syncope. Only one patient in the placebo arm died during the study period.

The composite primary outcome was met by 37% of the mavacamten treatment arm compared with 17% of the placebo arm (p = 0.0005). Within the secondary endpoints, a marked reduction in post-exercise LVOT gradient was observed, with a mean difference in gradient reduction when compared to placebo, of 35.6mmHg (p < 0.0001) observed at 30 weeks. All other secondary endpoints examining exercise capacity and self-reported symptom burden were also met in favour of the mavacamten arm (17).

Further Questions

EXPLORER-HCM is a landmark trial, demonstrating mavacamten can significantly improve symptom burden, exercise capacity and reduce LVOTO in patients with obstructive HCM. This was a relatively short trial and long-term safety data is required, especially regarding the observed issues with LVEF reduction, as it is unlikely echocardiographic follow up could be as rigorous within real world clinical practice as it was under trial conditions. Additionally, younger, non-white patients were under-represented, and the results of EXPLORER-HCM must be interpreted with caution in these patient groups.

Some long term data will eventually be provided by the extension study MAVA-LTE, which will include patients from the phase 2 trial MAVERICK-HCM (18). This trial has also recently been published, and demonstrated that mavacamten reduced NT-proBNP and cardiac troponin I levels in patients with non-obstructive HCM, potentially indicating a reduction in myocardial wall stress, although all findings were exploratory in nature (19), and so further phase 3 trials are required to draw accurate conclusions in this patient group. Finally, although MAVA-LTE will provide longer term safety data for mavacamten, it will not examine hard efficacy outcomes such as mortality. Given the large numbers of patients that would be needed for such a trial, it is unclear if a trial with hard cardiovascular primary endpoints will ever be achievable for a medical therapy in this patient group.

In conclusion, although further studies are required before mavacamten can be incorporated into routine drug therapy for HCM, it represents a hugely important step forward in the much-needed area of disease modifying treatment for inherited cardiomyopathies.



  1. Authors/Task Force members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J [Internet]. 2014 Oct 14;35(39):2733–79. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25173338
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