Getting Hyped for a New Hypertrophic Obstructive Cardiomyopathy Drug Therapy

Volume 15, Issue 2

Hypertrophic obstructive cardiomyopathy (HOCM) is a relatively rare type of cardiomyopathy associated with certain genetic mutations that result in a thickened myocardium.

The septal wall is the most common area of the heart to hypertrophy, and over time, the excessive growth of the myocardial wall can obstruct the left ventricular outflow track (LVOT), which decreases cardiac output and causes symptoms of heart failure. The LVOT obstruction is most pronounced during physical exertion, and due to the thickened heart walls, patients with HOCM tend to have an elevated ejection fraction.

Historically, there have been few effective drug therapies for patients with HOCM. Drugs to slow the heart rate, like beta-blockers and disopyramide, can help manage symptoms. Patients with more severe LVOT obstruction can receive interventions to debulk the heart muscle, either through an open-heart surgery (myomectomy), or through an interventional procedure called an alcohol septal ablation.

In this week’s issue of Talking Therapeutics, we explore the results a pivotal clinical trial of the first agent to directly treat the underlying cause of HOCM.

Point 1: Make Room for Mavacamten

A press release by LianBio indicates:

“Camzyos is an allosteric and reversible inhibitor selective for cardiac myosin. Camzyos modulates the number of myosin heads that can enter ‘on actin’ (power generating) states, thus reducing the probability of force producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross bridge formation and dysregulation of the super relaxed state are mechanistic hallmarks of [HOCM]. Camzyos shifts the overall myosin population towards an energy sparing, recruitable, super relaxed state.”

Mavacamten was studied in the EXPLORER-HCM trial, which showed this drug can improve exercise capacity and health status in patients with HOCM. The primary endpoint of the study “was a 1.5 mL/kg per min or greater increase in peak oxygen consumption (pVO₂) and at least 1 NYHA class reduction, or a 3 mL/kg per min or greater pVO₂ increase without NYHA class worsening.”

This study enrolled 251 patients with HOCM and an LVOT gradient of at least 50 mm Hg. Of the sample, 123 patients were treated with mavacamten and 128 received placebo. More patients receiving mavacamten (37%) vs placebo (17%) met the primary endpoint (difference +19.4%, 95% CI 8.7 to 30.1; P=.0005).

Other endpoints were also improved, including a significant decrease in post-exercise LVOT gradient change, a significant reduction in LV mass index, a significant decrease in LV ejection fraction, and significant improvement in KCCQ score (which measures quality of life).

Mavacamten was well tolerated with no significant long-term treatment-related adverse events.

Point 2: Some Safety Concerns for Pharmacists to Consider

Mavacamten does have some medication-related concerns that pharmacists should be aware of, per the following safety information provided in a press release by Business Wire:

• Use is contraindicated with moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors, and with moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers
• Because of the risk of heart failure due to systolic dysfunction, mavacamten is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CAMZYOS REMS Program
• Mavacamten reduces LV ejection fraction and can cause heart failure due to systolic dysfunction. Echocardiogram assessments of LV ejection fraction are required prior to and during treatment, and initiation of mavacamten in patients with LVEF <55% is not recommended. Interrupt treatment if LVEF is <50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status