Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy

Ho, Carolyn Y.; Mealiffe, Matthew E.; Bach, Richard G.; Bhattacharya, Mondira; Choudhury, Lubna; Edelberg, Jay M.; Hegde, Sheila M.; Jacoby, Daniel; Lakdawala, Neal K.; Lester, Steven J.; Ma, Yanfei; Marian, Ali J.; Nagueh, Sherif F.; Owens, Anjali Tiku; Rader, Florian; Saberi, Sara; Sehnert, Amy J.; Sherrid, Mark V.; Solomon, Scott D.; Wang, Andrew; Wever‐Pinzon, Omar; Wong, Timothy C.; Heitner, Stephen B.

doi:10.1016/j.jacc.2020.03.064

Cited by 209 publications

(196 citation statements)

References 33 publications

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“…[24][25][26] Similar decreases in cardiac biomarkers were reported in the MAVERICKHCM study in patients with nonobstructive disease, suggesting that gradient reduction might only partly explain the benefit observed in EXPLORERHCM. 20 These effects require further investigation in a translational setting. 16,18 Benefit from mavacamten extended across most pre specified subgroups.…”

Section: Discussionmentioning

confidence: 99%

“…16 In preclinical and early clinical studies, treatment with mavacamten successfully relieved LVOT gradients and improved parameters of left ventricular filling. 15,[17][18][19][20] In the phase 2, openlabel PIONEERHCM study (NCT02842242), mavacamten was well tolerated and significantly reduced postexercise LVOT gradients in obstructive hypertrophic cardiomyopathy. 19 Treatment was also associated with improvements in exercise capacity and New York Heart Association (NYHA) func tional class.…”

Section: Introductionmentioning

confidence: 99%

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Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial

Olivotto¹,

Oręziak²,

et al. 2020

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Background Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. Methods In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1•5 mL/kg per min or greater increase in peak oxygen consumption (pVO 2) and at least one NYHA class reduction or a 3•0 mL/kg per min or greater pVO 2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO 2 , NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial

Olivotto¹,

Oręziak²,

et al. 2020

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“…DISCUSSION It has been proposed that HCM mutations lead to increased sarcomeric output and myocyte hypercontractility [55][56][57][58] . Indeed, mavacamten, an inhibitor of myosin motor activity, is able to prevent development of HCM in mouse models 59 and also shows beneficial effects in clinical trials 7 . Many HCM-causing mutations in myosin affect directly the mechanochemical cycle of the protein resulting in enhanced force generation [60][61] .…”

Section: Mechanical Folding In Missense Mutants Of Cmybp-cmentioning

confidence: 99%

“…These structural changes occur alongside functional defects such as diastolic dysfunction, which can lead to the most severe consequences of the disease including heart failure and sudden cardiac death [4][5][6] . Despite encouraging advances 7 , currently there are no therapies to revert nor prevent HCM pathogenesis and clinical management relies on long-term palliative treatments and surgical procedures [4][5] . The majority of HCM cases are caused by autosomal dominant mutations targeting mechanical proteins of the sarcomere, the basic contractile unit of cardiomyocytes 5,[8][9] (Figure 1a).…”

Section: Introductionmentioning

confidence: 99%

Nanomechanical phenotypes in cMyBP-C mutants that cause hypertrophic cardiomyopathy

Suay-Corredera¹,

Pricolo²,

Velázquez-Carreras³

et al. 2020

Preprint

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Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium caused by mutations in sarcomeric proteins with mechanical roles, such as the molecular motor myosin. Around half of the HCM-causing genetic variants target contraction modulator cardiac myosin-binding protein C (cMyBP-C), although the underlying pathogenic mechanisms remain unclear since many of these mutations cause no alterations in protein structure and stability. As an alternative pathomechanism, here we have examined whether pathogenic mutations perturb the nanomechanics of cMyBP-C, which would compromise its modulatory mechanical tethers across sliding actomyosin filaments. Using single-molecule atomic force spectroscopy, we have quantified mechanical folding and unfolding transitions in cMyBP-C mutant domains. Our results show that domains containing mutation R495W are mechanically weaker than wild-type at forces below 40 pN, and that R502Q mutant domains fold faster than wild-type. None of these alterations are found in control, non-pathogenic variants, suggesting that nanomechanical phenotypes induced by pathogenic cMyBP-C mutations contribute to HCM development. We propose that mutation-induced nanomechanical alterations may be common in mechanical proteins involved in human pathologies.

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“…Mavacamten, der neue, oral verfügbare, allosterische Inhibitor des kardialen Myosins, wird derzeit für die Behandlung einer hypertrophen Kardiomyopathie (HCM) entwickelt. In der MAVERICK-HCM-Studie konnten eine gute Verträglichkeit des Medikaments und eine relevante Absenkung von Herzenzymen, insbesondere NT-proBNP und cTnI, gezeigt werden [21].…”

Section: Mavacamtenunclassified

Medikamentöse Therapie bei Herzinsuffizienz mit erhaltener Pumpfunktion

Trippel¹,

Tschöpe²

2020

Dtsch Med Wochenschr

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Die Herzinsuffizienz mit erhaltener Pumpfunktion verläuft prognostisch so bedrohlich wie bösartige Krebserkrankungen, führt zu häufigen Krankenhausaufenthalten und bringt enorme soziale und ökonomische Kosten mit sich. In der symptom-und risikofaktorenbasierten medikamentösen Behandlung werden meist Diuretika, Renin-Angiotensin-Aldosteron-Inhibitoren (RAASi) und ggf. Antidiabetika eingesetzt. Eine kausale Therapie ist nicht etabliert.

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Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy

Cited by 209 publications

References 33 publications

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial

Nanomechanical phenotypes in cMyBP-C mutants that cause hypertrophic cardiomyopathy

Medikamentöse Therapie bei Herzinsuffizienz mit erhaltener Pumpfunktion

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