Mavacamten is the first first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with obstructive hypertrophic cardiomyopathy (oHCM). II and III of the New York Heart Association symptomatic. Mavacamten was developed to target the hypercontractile phenotype, which plays a critical role in the pathophysiology of the disease.
In phase 2 and 3 clinical trials, mavacamten was well tolerated, reduced left ventricular outflow tract gradients, improved exercise capacity and symptoms, and was associated with improvements in other clinically relevant parameters, such as reported outcomes. by patients and circulating biomarkers. Furthermore, mavacamten treatment was associated with evidence of favorable cardiac remodeling on multimodal imaging studies. Mavacamten substantially reduced guideline eligibility for candidates for septal reduction therapy with oHCM and drug-refractory symptoms.
In this article, we review available efficacy and safety data from completed and ongoing clinical studies of mavacamten in patients with symptomatic oHCM. Longer-term extension studies may help address issues related to the position of mavacamten in current OHCM treatment algorithms, interactions with background therapy, as well as the potential for disease modification beyond relief. symptomatic of left ventricular outflow tract obstruction.
Graphic summary : The path towards the treatment of obstructive hypertrophic cardiomyopathy. (Top left) Hemodynamic observations are demonstrated. Left ventricular (LV) obstruction and symptoms related to LV hypertrophy. (Bottom left) Discovery of genetic variants in approximately 40% of patients. (Middle) Sarcomeres in obstructive hypertrophic cardiomyopathy (oHCM) show excess myosin-actin cross-bridges that are normalized by mavacamten. (Top right) Preclinical observations in mouse and pig models of oHCM. (Bottom right) The two placebo-controlled clinical trials of mavacamten in oHCM. HCM: hypertrophic cardiomyopathy; hsTnT, high-sensitivity troponin T; LA, left atrium; VI, left ventricular; LVOT: left ventricular outflow tract; NT-proBNP, N-terminal pro-B-type natriuretic peptide; CV, quality of life.
Hypertrophic cardiomyopathy ( HCM) is a complex disorder caused by cardiac sarcomere dysfunction resulting in excess cardiac myosin-actin cross-bridges and increased sensitivity to calcium. The main pathophysiological features of HCM include left ventricular hypertrophy (LVH), most commonly affecting the subaortic region of the interventricular septum, microvascular ischemia, myocardial fibrosis, and diastolic dysfunction. Sixty years ago, when the first detailed clinical reports of the disease were published, HCM was considered a rare condition with high mortality and limited treatment options. Today, it is estimated that 1:500 people in the general population have a hypertrophic cardiomyopathy (HCM) phenotype.
Hypertrophic cardiomyopathy is frequently inherited as an autosomal dominant trait with variable penetrance. Pathogenic variations occur most frequently in genes encoding the sarcomeric proteins myosin beta heavy chain 7 (MYH7) and myosin-binding protein C3 (MYBPC3). Pathogenic variants of the genes that encode myosin alter the relaxed state of sarcomeric proteins, causing an increase in cardiomyocyte contractility and energy requirements and altering the relaxation and filling of the left ventricle (LV). About 60% of all HCM patients test negative for sarcomeric variants, some of whom may have a family history of the disease but may have a polygenic etiology. Other patients are sporadic, with no detectable genetic variants or family history. The molecular basis of ventricular hypertrophy has not been established.
Approximately two-thirds of patients with HCM have LV outflow tract obstruction (LVOT), an important determinant of symptoms and outcomes. The hypercontractile phenotype , combined with septal hypertrophy and anatomical abnormalities of the mitral valve apparatus, leads to systolic anterior motion (SAM) of the mitral valve causing mitral-septal contact and subaortic obstruction that is often dynamic and can be intensified by physiological interventions. or pharmacological, such as exercise, the Valsalva maneuver or a beta adrenergic agonist.
Hypertrophic cardiomyopathy has a diverse presentation and clinical course. Some patients may be asymptomatic or mildly symptomatic, while others experience severe symptoms that affect functional ability. The most frequent symptoms are dyspnea on exertion, palpitations, fatigue, presyncope and angina, the latter caused by myocardial ischemia due to thickening of the coronary arterioles and/or increased myocardial energy consumption. Major complications include syncope, recurrent atrial fibrillation, ventricular tachycardia, stroke, heart failure, and sudden death. The placement of an implantable cardioverter-defibrillator may reduce the risk of the latter in high-risk patients.
First-line treatment of obstructive HCM (oHCM) includes oral beta-blockers and/or non-dihydropyridine calcium channel blockers. Both classes of drugs reduce heart rate and their modest negative inotropic actions may provide some reduction in intracardiac obstruction. Disopyramide, an antiarrhythmic, can be added because of its additional negative inotropic action, but its anticholinergic side effects are common limitations. Although these three classes of drugs have been the mainstay of drug treatment for decades, their use is largely supported by observational studies. None address the underlying molecular mechanisms of the disease.
Septal reduction therapy ( SRT), either septal myectomy or alcohol septal ablation is recommended for patients with symptomatic oHCM, who are refractory to medical treatment. Septal reduction therapy substantially improves symptoms and quality of life, but may not be appropriate for patients with severe comorbidities or frailty and others who prefer not to undergo an invasive procedure. To be effective and safe, these procedures require substantial operator experience, which is limited to a few centers of excellence and is not accessible to the majority of patients worldwide. Therefore, medical treatment of oHCM remains an important unmet need.
Mavacamten
Mavacamten is a selective, allosteric and reversible inhibitor of small molecular weight cardiac myosin, which represents the first specific treatment for oHCM targeting the central pathophysiological mechanism of the disease (see Graphical summary). Preclinical studies have shown that mavacamten reduces the likelihood of myosin-actin cross-bridge formation by decreasing the number of myosin heads that can enter the "activation" (energy-generating) state and shifting the myosin population toward a lower state. super relaxed and energy saving "off" mode .
In vivo mouse models that express human myosin mutations and cause oHCM develop age-dependent LVH. Early treatment of these models with mavacamten prevents the development of LVH. Structural studies have shown that while MCH mutations disrupt normal interactions between sarcomere proteins, mavacamten normalizes these interactions and restores physiological function of the sarcomere.
By normalizing the ratio of ’on’ and ’off’ myosin heads , mavacamten reduces sarcomeric hyperactivity and the resulting myocardial hypercontractility by reducing LVOT obstruction and LV filling pressure. Mavacamten has also been shown to reduce maximal strength, Ca2+ sensitivity, myocardial energy demands, and diastolic dysfunction. In a feline model of oHCM, mavacamten was shown to inhibit myosin ATPase and reduce outflow tract obstruction. Additional studies are needed to establish whether mavacamten has further disease-modifying potential for oHCM structural abnormalities.
Phase 1 trials of mavacamten were conducted to determine the pharmacokinetic properties and evaluate its safety and tolerability. The drug is easily absorbed and extensively metabolized, primarily through the cytochrome (CYP) P450 enzymes, CYP2C19, and CYP3A4. The terminal half-life of mavacamten depends on the metabolic status of CYP2C19 and ranges from 6 to 23 days . Inducers and inhibitors of CYP2C19 and CYP3A4 may influence the systemic exposure to mavacamten.
EXPLORER-HCM trial summary
The EXPLORER-HCM trial demonstrated the efficacy of mavacamten in CMOH. In this trial, statistical significance was reached for the primary and secondary endpoints. Nearly 75% of patients exhibited a reduction below the guideline-defined thresholds for invasive SRT (maximum post-exercise LVOT gradient <50 mmHg), and 56% showed even greater relief of obstruction. Mavacamten improved NYHA class, exercise performance, key aspects of health status, and reduced serum NT-proBNP and troponin I levels and was generally safe and well tolerated.
In its review of EXPLORER-HCM, the US Food and Drug Administration (FDA) determined that the number of patients needed to treat to achieve a primary endpoint was 5.2, while the number needed to harm (heart failure or LVEF <30%) was 141.45 The FDA granted mavacamten ’breakthrough therapy’ designation and in April 2022 approved mavacamten for adults with symptomatic oHCM; It has also been approved in Australia, Brazil, Canada, Macau and Switzerland. Applications to other regulatory bodies around the world are being reviewed.
Conclusions Mavacamten is the first cardiac myosin inhibitor approved for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy. It provides a new pharmacological treatment option for patients, which targets the underlying pathophysiology of the disease and is well tolerated in a large majority of patients. Results from ongoing long-term extension studies and real-world experience in clinical practice will expand on the efficacy and safety findings obtained in the clinical trials summarized in this review. Based on available data, mavacamten is beneficial, at least in the short and medium term, in patients with oHCM who remain symptomatic despite single or multiple dose treatment with beta-blockers and calcium channel blockers and may postpone or avoid the need for interventricular septal reduction therapy (SRT). |
