Mavacamten — a new disease-specific option for pharmacological treatment of symptomatic patients with hypertrophic cardiomyopathy

Pysz, Piotr; Rajtar-Salwa, Renata; Smołka, Grzegorz; Olivotto, Iacopo; Wojakowski, Wojciech; Petkow−Dimitrow, Paweł

doi:10.33963/kp.a2021.0064

Cited by 8 publications

(3 citation statements)

References 36 publications

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“…Compared to placebo, Mavacamten appears to cause a significant reduction in heart failure symptoms as measured by the NYHA-FC in HCM patients. This is due to its pharmacological mechanism of action, acting as a direct target inhibitor of cardiac myosin, decreasing myosin binding with actin filament, and the excessive contractility that is a feature of HCM [ 23 ]. In EXPLORER-HCM [ 17 ], too, Mavacamten was superior to placebo in improving patient-centered outcomes.…”

Section: Discussionmentioning

confidence: 99%

Analyzing safety and effectiveness of Mavacamten in comparison with placebo for managing hypertrophic cardiomyopathy: a systemic review and meta-analysis

Rangwala,

Fatima,

Ali

et al. 2023

Egypt Heart J

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Background Hypertrophic cardiomyopathy (HCM) is a hereditary myocardial disorder, often due to sarcomere gene mutations, characterized by the left ventricular hypertrophy. Current treatments offer symptomatic relief but lack specificity. Mavacamten, an allosteric inhibitor, has shown significant improvements in HCM patients in trials, reducing the requirement for invasive treatments. This meta-analysis assesses Mavacamten’s efficacy and safety as a targeted HCM intervention. Methods This study examined four randomized controlled trials comparing Mavacamten to placebo in HCM patients. Each trial had a unique primary endpoint, and secondary outcomes included improvements in NYHA-FC, eligibility for septal reduction therapy (SRT) or undergoing it, adverse events (serious and treatment-related), atrial fibrillation, and non-sustained ventricular tachycardia. Statistical analysis involved calculating risk ratios (RRs) and assessing heterogeneity. Results The four included studies showed minimal risk of bias and involved 503 patients with HCM (273 Mavacamten and 230 placebo). Mavacamten significantly increased the primary endpoint (RR 2.15, 95% CI 1.20–3.86, P = 0.01) and ≥ 1 NYHA-FC class (RR 2.21, 95% CI 1.48–3.3, P = 0.0001). Mavacamten group had lower rates of SRT compared to those receiving placebo (RR, 0.30, 95% CI 0.22–0.40; P < 0.00001). No significant differences existed in rates adverse events between the Mavacamten and placebo groups. Conclusions Our study suggests that Mavacamten may have therapeutic benefits for HCM patients, as indicated by its positive impact on certain endpoints. Further research with larger samples, longer follow-up, and comprehensive analysis is needed to understand Mavacamten’s safety and efficacy in HCM patients.

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Section: Discussionmentioning

confidence: 99%

Analyzing safety and effectiveness of Mavacamten in comparison with placebo for managing hypertrophic cardiomyopathy: a systemic review and meta-analysis

Rangwala,

Fatima,

Ali

et al. 2023

Egypt Heart J

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“…Perhaps most promising is the novel allosteric myosin inhibitor mavacamten, which (in contrast to the drugs previously introduced) specifically targets the underlying pathogenic drivers of contractile dysfunction in HCM at the sarcomeric level [ 172 ]. Both the results of EXPLORER-HCM (trial NCT03470545) [ 173 ] and additional studies [ 174 ] have proven mavacamten effective at improving cardiac function in HCM patients, including the reduction of LVOT obstruction gradients. The marked reductions in N-terminal pro B-type natriuretic peptide and cardiac troponin I during mavacamten treatment indicate that the drug may reduce the extent of ischaemic injury in HCM [ 175 ], likely through attenuation of the downstream pro-ischaemic effects of sarcomeric impairment, as shown in Fig.…”

Section: Clinical Perspective: Myocardial Ischaemia In Hcm As a Thera...mentioning

confidence: 99%

Mechanisms and prognostic impact of myocardial ischaemia in hypertrophic cardiomyopathy

Coleman

Ashkir

Raman

et al. 2023

Int J Cardiovasc Imaging

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Despite the progress made in risk stratification, sudden cardiac death and heart failure remain dreaded complications for hypertrophic cardiomyopathy (HCM) patients. Myocardial ischaemia is widely acknowledged as a contributor to cardiovascular events, but the assessment of ischaemia is not yet included in HCM clinical guidelines. This review aims to evaluate the HCM-specific pro-ischaemic mechanisms and the potential prognostic value of imaging for myocardial ischaemia in HCM. A literature review was performed using PubMed to identify studies with non-invasive imaging of ischaemia (cardiovascular magnetic resonance, echocardiography, and nuclear imaging) in HCM, prioritising studies published after the last major review in 2009. Other studies, including invasive ischaemia assessment and post-mortem histology, were also considered for mechanistic or prognostic relevance. Pro-ischaemic mechanisms in HCM reviewed included the effects of sarcomeric mutations, microvascular remodelling, hypertrophy, extravascular compressive forces and left ventricular outflow tract obstruction. The relationship between ischaemia and fibrosis was re-appraised by considering segment-wise analyses in multimodal imaging studies. The prognostic significance of myocardial ischaemia in HCM was evaluated using longitudinal studies with composite endpoints, and reports of ischaemia-arrhythmia associations were further considered. The high prevalence of ischaemia in HCM is explained by several micro- and macrostructural pathological features, alongside mutation-associated energetic impairment. Ischaemia on imaging identifies a subgroup of HCM patients at higher risk of adverse cardiovascular outcomes. Ischaemic HCM phenotypes are a high-risk subgroup associated with more advanced left ventricular remodelling, but further studies are required to evaluate the independent prognostic value of non-invasive imaging for ischaemia.

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“…It has raised hopes for the possibility of managing this potentially lethal intrigue disorder with medicines alone. 10…”

Section: Introductionmentioning

confidence: 99%

Mavacamten: a novel avenue towards hypertrophic obstructive cardiomyopathy

Makhija,

Bansal,

Jakhar

et al. 2024

Int J Basic Clin Pharmacol

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Hypertrophic obstructive cardiomyopathy (HCM) is the most common heterogeneous genetic cardiovascular disorder. Its pathophysiology involves left ventricular hypertrophy, increased fibrosis, hypercontractility, and reduced compliance. The symptomatic obstructive HCM presents as dyspnoea, syncope, chest pain, palpitations, arrhythmias, or sudden death, usually after provocative manoeuvres like exercise. Until April 2022, treatment options were disease non-specific like Beta blockers, Cardio-selective Calcium Channel Blockers, Dipyridamole, and Ranolazine. Mavacamten is a first-in-class, FDA-approved drug molecule for HCM. It works by selective and reversible inhibition of the cardiac myosin ATPase thereby decreasing the formation of actin- myosin cross- bridges in systole and diastole. The excessive actin-myosin cross-bridging is the hallmark of disease and is responsible for the compromised functioning of the heart in both the systole and diastole phase due to left ventricular outflow tract (LVOT) obstruction and increased ventricular filling pressure respectively. Mavacamten acts by producing super-relaxed state of heart which is then translated into decreased LVOT obstruction and improved cardiac filling pressures thereby improving the functional capacity and symptoms in patients with New York Heart Association (NYHA) stage II, and III symptomatic or obstructive heart failure. Mavacamten is administered orally 2.5-15 mg per day with titration guided by lab investigations and clinical symptoms. Its bioavailability is 85%, undergoes metabolism by CYP2C19 and CYP3A4 and is excreted mainly in urine. It is also an enzyme inducer and shows considerable drug interactions. Common adverse effects are dizziness and syncope. Sometimes the drug may worsen heart failure or completely block ventricular function. Mavacamten has raised hopes for the possibility of managing this potentially lethal intrigue disorder with medicines alone.

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Mavacamten — a new disease-specific option for pharmacological treatment of symptomatic patients with hypertrophic cardiomyopathy

Cited by 8 publications

References 36 publications

Analyzing safety and effectiveness of Mavacamten in comparison with placebo for managing hypertrophic cardiomyopathy: a systemic review and meta-analysis

Analyzing safety and effectiveness of Mavacamten in comparison with placebo for managing hypertrophic cardiomyopathy: a systemic review and meta-analysis

Mechanisms and prognostic impact of myocardial ischaemia in hypertrophic cardiomyopathy

Mavacamten: a novel avenue towards hypertrophic obstructive cardiomyopathy

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