Sara Saberi, MD, MS Assistant Professor Inherited Cardiomyopathy Program Frankel Cardiovascular Center University of Michigan Hospital Michigan Medicine

First-in-Class Drug Mavacamten Reduces LVH Associated with Heart Failure and AFib Interview with:

Sara Saberi, MD, MS Assistant Professor Inherited Cardiomyopathy Program Frankel Cardiovascular Center University of Michigan Hospital Michigan Medicine

Dr. Saberi

Sara Saberi, MD, MS
Assistant Professor
Inherited Cardiomyopathy Program
Frankel Cardiovascular Center
University of Michigan Hospital
Michigan Medicine What is the background for this study? Would you briefly explain what is meant by HCM?
How common is it and whom does it affect?

Response: HCM is short for hypertrophic cardiomyopathy, the most common genetic myocardial disorder. It occurs in 1:500 people worldwide and because it is inherited in an autosomal dominant fashion, it affects men and women equally. HCM is characterized by unexplained left ventricular (LV) hypertrophy, hypercontractility, myofibrillar disarray and myocardial fibrosis with associated abnormalities in LV compliance and diastolic function. In some patients, there is progressive adverse cardiac remodeling, associated with chronic heart failure and atrial fibrillation as a result of diastolic dysfunction, left ventricular outflow tract (LVOT) obstruction, or less commonly, LV systolic dysfunction. Current medical management of obstructive HCM (oHCM) is limited to the use of beta blockers and non-dihydropyridine calcium channel blockers, or disopyramide, none of which have been shown to modify disease expression or outcomes after onset.

Mavacamten is a first-in-class, small molecule, selective inhibitor of cardiac myosin specifically developed to target the underlying pathophysiology of HCM by reducing actin–myosin cross-bridge formation. The phase 3 EXPLORER-HCM trial showed that mavacamten improved exercise capacity, LVOT gradients, symptoms, and health status compared with placebo in patients with symptomatic oHCM. At selected study sites, participants were enrolled in a cardiac magnetic resonance (CMR) imaging substudy. CMR is the gold standard for measurement of ventricular mass, volumes and noninvasive tissue characterization, making it an ideal imaging modality to assess the effect of mavacamten on cardiac structure and function in patients with HCM. What are the main findings?
How is Mavacamten different from other drugs for blood pressure or heart failure?

ResponseThirty-five patients were randomized (mavacamten [n=17], placebo [n=18]). Mean age was 60.3 years and 42.9% were female. Patients receiving mavacamten experienced a greater reduction in mean (SD) LVMI, the primary endpoint, from baseline to week 30 versus patients in the placebo group (–17.4 [12.1] g/m2 and –1.6 [7.4] g/m2, respectively); mean between-group difference: −15.8 g/m2 (95% CI, −22.6 to −9.0; P<0.0001). Exploratory endpoints included other measures of LV hypertrophy, left atrial volume, myocardial fibrosis and biomarkers (N‑terminal pro b‑type natriuretic peptide [NT-proBNP] and high-sensitivity cardiac troponin I [hs-cTnI]). There was a statistically significant reduction in each of the exploratory measures of LV hypertrophy that we assessed as compared with placebo: absolute LV mass, absolute intracellular myocardial mass index, and maximal wall thickness. A greater reduction in maximum left atrial volume index was observed with mavacamten versus placebo (mean between-group difference: −10.3 mL/m2 [95% CI, −16.0 to −4.6; P=0.0004]). There was little fibrosis at baseline with no notable within- or between-group changes in late gadolinium enhancement which assesses replacement fibrosis or extracellular volume fraction which assesses interstitial fibrosis. Baseline mean LV ejection fraction was elevated in both groups, as expected in HCM. In keeping with mavacamten’s mechanism of action, we did observe a mild reduction in LV ejection fraction but it remained within normal limits in both groups through week 30. There was a 50% greater reduction in hs-cTnI and 80% greater reduction in NT-proBNP with mavacamten versus placebo (P<0.01). Change in LVMI was positively correlated with change in hs-cTnI (n=31; Rho=0.75 [95% CI, 0.53 to 0.87]).

To summarize, this is the first randomized, controlled clinical trial of a pharmaceutical agent in patients with HCM to show a reduction in left ventricular mass and wall thickness and left atrial volumes, each poor predictors of prognosis in patients with HCM.

Mavacamten is different from other drugs for blood pressure or heart failure in its mechanism of action. It is a selective allosteric inhibitor of cardiac myosin ATPase that reduces actin-myosin cross-bridge formation, thereby reducing contractility and improving myocardial energetics. There are no other currently-available drugs with the same mechanism of action. It is now also differentiated from the other drugs I listed above that we commonly use to treated symptomatic LVOT obstruction in that none of those have been shown to have an impact on cardiac structure or function. Mavacamten had such effects after just 7.5 months of treatment. What recommendations do you have for future research as a result of this study?

Response: We don’t have any data on long-term outcomes in terms of development of atrial fibrillation and congestive heart failure with mavacamten and it will be important to see if the structural and hemodynamic benefits observed with mavacamten translate into better outcomes in the future. It would also be important to see if there is an impact on disease progression if mavacamten is started very early in its presentation or perhaps in pediatric patients with mild phenotypes of HCM, and what its impact would be on disease presentation in those who are genotype positive/phenotype negative. Is there anything else you would like to add? Any disclosures?

Response: This is an incredible time in the field. To see favorable remodeling of the heart with just 30 weeks of treatment with mavacamten is a highly encouraging finding for our patients.

My disclosures: I have received consulting fees from MyoKardia, Inc. 


Mavacamten Favorably Impacts Cardiac Structure in Obstructive Hypertrophic Cardiomyopathy: EXPLORER-HCM CMR Substudy Analysis

Sara Saberi, Nuno Cardim, Mohamad H. Yamani, Jeanette Schulz-Menger, Wanying Li, Victoria Florea, Amy J. Sehnert, Raymond Y. Kwong, Michael Jerosch-Herold, Ahmad Masri, Anjali Owens, Neal K. Lakdawala, Christopher M. Kramer, Mark Sherrid, Tim Seidler, Andrew Wang, Farbod Sedaghat-Hamedani, Benjamin Meder, Ofer Havakuk, and Daniel Jacoby

Nov 2020 Circulation. ;0

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