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EXPLORER-HCM trial: Mavacamten is a first-in-class cardiac myosin inhibitor that directly targets the underlying pathophysiology of obstructive hypertrophic cardiomyopathy


Mavacamten improves heart function and symptoms in patients with obstructive hypertrophic cardiomyopathy ( HCM ), according to results from the EXPLORER-HCM trial.

Currently available medical treatments for obstructive hypertrophic cardiomyopathy focus on symptom relief, fail to address the underlying causes and are associated with modest efficacy or substantial adverse events.
While surgical septal myectomy and alcohol septal ablation are efficacious, they carry the risks inherent to invasive procedures and require specific expertise.
An effective pharmacological therapy for obstructive hypertrophic cardiomyopathy is therefore an unmet need for those patients with hypertrophic cardiomyopathy who suffer debilitating and life-changing symptoms.

Mavacamten is a first-in-class cardiac myosin inhibitor that directly targets the underlying pathophysiology of hypertrophic cardiomyopathy.
In early clinical trials, Mavacamten led to significant improvements of symptoms, physical function, exercise capacity, and quality of life, and reduced left ventricular outflow tract ( LVOT ) obstruction in patients with obstructive hypertrophic cardiomyopathy.

In the EXPLORER-HCM global phase 3 trial, 251 patients with symptomatic obstructive hypertrophic cardiomyopathy were randomised to once-daily Mavacamten ( 5 mg initially with a two­-step dose titration ) or placebo for 30 weeks.

The primary endpoint was the treatment effect of Mavacamten at week 30 relative to placebo on both symptoms and cardiac function, defined as achieving 1) greater than or equal to 1.5 mL/kg/min improvement in peak oxygen consumption ( peak VO2 ) and greater than or equal to 1 New York Heart Association ( NYHA ) class reduction or 2) greater than or equal to 3.0 mL/kg/min improvement in peak VO2 and no worsening of NYHA class.
Secondary endpoints included change from baseline to week 30 in post-exercise LVOT gradient and patient-reported outcomes such as the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score ( KCCQ-CSS ) and HCM Symptom Questionnaire-Shortness-of-Breath ( HCMSQ-SoB ) subscore.

At week 30, 45 ( 36.6% ) patients on Mavacamten met the primary endpoint vs 22 ( 17.2% ) patients on placebo ( p=0.0005 ).
All secondary endpoints, including post-exercise LVOT gradient and patient-reported outcomes, also demonstrated significant improvements for mavacamten as compared with placebo ( all p less than 0.0006 ).

Safety and tolerability with Mavacamten were similar to placebo. Some 11 serious adverse events were reported in 8.1% of patients on Mavacamten vs 20 events in 8.6% of patients on placebo.
Serious cardiac adverse events occurred in 4 patients treated with Mavacamten ( atrial fibrillation [ AF ], n=2; stress cardiomyopathy, n=2 ) and 4 in the placebo group ( AF, n=3; AF and congestive heart failure, n=1 ).

The results of this pivotal trial support a role for disease-specific therapy for hypertrophic cardiomyopathy, which treats the cause instead of just managing symptoms.
The totality and consistency of the results showed benefit of Mavacamten treatment compared with placebo in patients on background HCM therapy.
Mavacamten has improved functional capacity, LVOT gradient, symptoms, and key aspects of quality of life in patients with obstructive hypertrophic cardiomyopathy and was generally well tolerated. ( Xagena )

Source: ESC ( European Society of Cardiology ) Digital Congress, 2020

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