FDA Approves Mavacamten for Obstructive Hypertrophic Cardiomyopathy

The FDA has approved mavacamten (Camzyos) for the treatment of adult patients with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (oHCM).

Mavacamten is a first-in-class, oral, allosteric modulator of cardiac myosin designed to decrease contractile function and improve VO2 in patients with oHCM, which often results in dynamic left ventricular outflow tract (LVOT) obstruction. oHCM thickens the heart walls and makes it more difficult for the heart to expand normally and fill with blood. Mavacamten aims to target the underlying pathophysiology of the condition.

“This is a first-in-class medicine specifically for patients living with symptomatic obstructive HCM,” said Milind Desai, MD, MBA, director of the Hypertrophic Cardiomyopathy Center and director of clinical operations in Cleveland Clinic’s Heart Vascular & Thoracic Institute, in a press release. "With this FDA approval, US cardiologists now have a new pharmacological option for eligible patients that targets the underlying pathophysiology of the disease.”

The EXPLORER-LTE study found that treatment with mavacamten provides sustained improvement in LVOT gradients, as well as NYHA Class and N-terminal pro brain natriuretic peptide (NT-proBNP) levels, according to data presented at the American College of Cardiology 2022 Scientific Sessions.Mavacamten has previously been found to reduce cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation that results in hypercontractility, left ventricular hypertrophy, and reduced compliance.

“This approval builds on decades of cardiovascular leadership and reflects our steadfast commitment to people impacted by cardiovascular disease,” said Samit Hirawat, MD, executive vice president and chief medical officer, Global Drug Development, Bristol Myers Squibb, in a press release. “We are proud to bring this first-of-its kind medicine to patients, which may help to address an unmet need in the US in the symptomatic NYHA class II-III obstructive HCM treatment landscape.”

The EXPLORER-LTE trial included a cohort of the MAVA-LTE study, the largest and longest evaluation of mavacamten in patients with symptomatic obstructive HCM. EXPLORER-LTE enrolled 231 of the 244 patients who were eligible for the long-term extension study at the end of the phase 3 parent trial, EXPLORER-HCM.

More than 200 patients remained on study for more than 48 weeks and 67 patients reached 84 weeks. Clinically meaningful improvements were sustained in LVOT gradients, NYHA Class, and NT-proBNP levels at 48 weeks and up to 84 weeks. The safety profile remained consistent with EXPLORER-HCM and no new safety signals were observed during longer term follow-up. The exposure-adjusted event rates were also stable or lower in this cohort.

All participants in the EXPLORER-LTE cohort started therapy on 5 mg of mavacamten daily and dose adjustments were made at weeks 4, 8, and 12 based on echocardiography measures of Valsalva LVOT gradient and left ventricular ejection fraction (LVEF). Dose adjustment was also possible at week 24 following site-read echocardiography assessment of LVOT gradient after exercise.

As of the August 2021 interim analysis cutoff date, 94% of patients remained on mavacamten. Furthermore, resting LVOT gradient decreased from baseline by an average of -35.6 mmHg plus or minus 32.6 mmHg at week 48. Similar reductions persisted throughout the extension period and up to 84 weeks.

Similarly, the Valsalva LVOT gradient decreased from baseline by an average of -45.3 mmHg plus or minus 35.9 mmHg at week 48, with sustained efficacy persisting throughout the extension period. Serum NT-proBNP levels decreased from baseline by a median of -480 ng/L at week 48.

Furthermore, at week 48, 67.5% of patients improved by 1 or greater NYHA Class from baseline, with 60.2% improving by 1 NYHA Class and 7.3% improving by 2 classes. Improvements in NYHA Class were first observed at week 12 and showed sustained improvement through week 48, according to the study. Resting LVEF also decreased from baseline by -7% plus or minus 8.3% at week 48.

Safety data showed that 10 participants (4.3%) permanently discontinued due to treatment-emergent adverse events (TEAEs) and 26 (11%) discontinued temporarily for any reason and resumed treatment thereafter. Of these, 12 (5.2%) had LVEF 50% or higher, 2 of which were considered TEAEs, and all recovered an LVEG of 50% or less without further AEs.

“The approval of Camzyos represents a significant milestone for appropriate symptomatic obstructive HCM patients and their families, who have long awaited a new treatment option for this chronic and progressive disease,” said Anjali T. Owens, MD, Medical Director of the Center for Inherited Cardiac Disease and an assistant professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania. “As a lead US investigator on the EXPLORER-HCM study, I’m grateful to the patients and their families whose participation in the trial played a key role in this approval.”

Reference

U.S. Food and Drug Administration Approves Camzyos™ (mavacamten) for the Treatment of Adults With Symptomatic New York Heart Association Class II-III Obstructive Hypertrophic Cardiomyopathy (HCM) to Improve Functional Capacity and Symptoms. Bristol Meyers Squibb. April 28, 2022. https://news.bms.com/news/details/2022/U.S.-Food-and-Drug-Administration-Approves-Camzyos-mavacamten-for-the-Treatment-of-Adults-With-Symptomatic-New-York-Heart-Association-Class-II-III-ObstructiveHypertrophic-Cardiomyopathy-HCM-to-Improve-Functional-Capacity-and-Symptoms/default.aspx