Extension study shows mavacamten’s efficacy and safety in treating hypertrophic cardiomyopathy

Use of mavacamten, a novel cardiac myosin inhibitor, to treat people with symptomatic obstructive hypertrophic cardiomyopathy (HCM), a condition that results in excess thickening of the heart muscle, resulted in continued benefits in patient quality of life and outcomes over an extended period of time, according to interim data from the EXPLORER-HCM extension study presented at the American College of Cardiology's 71st Annual Scientific Session. Specifically, researchers said mavacamten was associated with significant and sustained improvements in left ventricular outflow tract (LVOT) gradients, which is the degree of obstruction, health status, symptoms with exertion and a key blood marker for heart failure.

"These data are very consistent with the initial trial results—obstruction in the heart was relieved, two-thirds of patients felt better and disease severity improved," said Florian Rader, MD, co-director of the Hypertrophic Cardiology Clinic at Cedars Sinai and the study's lead author, adding that this is the largest and longest report of mavacamten treatment in obstructive HCM. "The thickening caused by HCM can obstruct blood flow out of the heart, which results in burdensome symptoms and poor quality of life for many patients. Based on these results, the drug doesn't lose its effectiveness over time and appears to be safe and well tolerated long term."

MAVA-LTE is an ongoing, dose-blinded five-year extension study that includes 231 of 244 patients who completed treatment in the phase 3 EXPLORER-HCM trial. Results from EXPLORER-HCM showed significant improvements in patients' health status, symptoms, exercise capacity and quality of life among those taking mavacamten compared with placebo after 30 weeks. The MAVA-LTE study was designed to collect longer-term data. At data cutoff for this analysis, patients were 60 years old on average and 39% were female.

Patients initially were provided 5 mg of once daily mavacamten after stopping the drug (called a wash out period). Patients ultimately could take 2.5, 5, 10 or 15 mg, with dose adjustments at weeks four, eight and 12 and again at 24 weeks based on local site read echocardiograms, which looked at the degree of obstruction by gradient and checked for normal ejection fraction (>50%). If the gradient was above 30 mmHg, patients were eligible to increase the dose to further reduce the gradient and obstruction. If patients showed signs of reduced left ventricular ejection fraction (<50%), a measure of how much blood the heart pumps out, treating physicians were advised to lower the dose or temporarily stop the medication. Most patients were on 5 mg or 10 mg, with only 15% on the 15 mg dose.

The median follow-up was 62 weeks and ranged from one to 124 weeks, signifying that not all patients had been taking mavacamten at the designated 48- or 84-week follow-up, which are reported in this interim analysis. In patients who were assessed at these time points, 206 at 48 weeks and 66 at 84 weeks, the degree of obstruction measured by LVOT gradient was lowered on average by 36 mmHg at 48 weeks (a 74% reduction from baseline); this reduction was sustained through week 84. At week 84, 83.5% of patients who had follow-up at that time point had LVOT gradients less than 30 mmHg, which is considered the cutoff for having obstructed blood flow out of the heart.

In terms of NYHA class, 68% of patients improved by at least one class designation, with the most dramatic change in Class I, which means no significant exertional symptoms. At baseline, only 6% of patients were in Class I, but that percentage jumped to 55% of patients by week 48. In contrast, 29% of patients were in Class III, showing noticeable limitation with physical activity at the start of the study; the proportion of people in this class dropped to 4.9% at 48 weeks. At baseline, almost everyone (94% of patients) had some degree of shortness of breath with exercise; by 48 weeks, only 45% of patients reported feeling this way. In addition, the heart failure marker NTproBNP decreased by 480 ng/L at week 48 and 488 ng/L at week 84—a 63% reduction. NTproBNP is released by the heart in the setting of elevated pressure in the heart (i.e., heart failure); Rader said that large changes of this marker indicate a significant improvement in heart failure in these patients.

Mavacamten was well tolerated with no new or unexpected adverse events reported, Rader said. Thirty-four (14.7%) patients reported a serious adverse event, however Rader said only a few of these were deemed to be related to mavacamten. Twenty-six patients had to temporarily discontinue treatment, 12 of whom because their ejection fraction fell below normal. Twenty patients restarted mavacamten, including eight who had ejection fraction. There were three deaths during the study period—one from a cardiac arrest, one from a heart infection and one from a heart attack, all of which were deemed unrelated to mavacamten.

There have been limited medication options for HCM and many patients end up having to go through surgical removal of a portion of the thickened heart muscle or undergo alcohol septal ablation to reduce the obstruction. Although these invasive treatment options are effective, they also have risks. Mavacamten is the first medication specifically designed to relieve this obstruction and as the data shows, it helps patients feel better, and they are able to live a more active life. If this medication continues to be effective over time, it may also help keep patients from having to undergo an invasive procedure or open-heart surgery to relieve the obstruction."

Florian Rader, MD, co-director of the Hypertrophic Cardiology Clinic at Cedars Sinai and study's lead author

HCM is the most common genetic heart condition. It's estimated to affect 1 in 500 adults, yet many patients remain undiagnosed. Changes in certain genes allow the heart muscle to get too thick ("hypertrophy" means to thicken). In some cases, the left ventricular outflow tract (LVOT), where blood leaves the heart, becomes obstructed by the thickened heart muscle, forcing the heart to work harder and leaving people unable to do even simple tasks without feeling winded and fatigued. Obstructive HCM is also associated with heightened risks of atrial fibrillation, stroke, heart failure and, although rare, sudden cardiac death.

Mavacamten is currently under review with the U.S. Food and Drug Administration for use in obstructive HCM, with a decision expected at the end of April 2022.

The study was funded by MyoKardia, a wholly owned subsidiary of Bristol Myers Squib.

For more information on HCM, visit www.CardioSmart.org/HCM.

Rader will be available to the media in a press conference on Sunday, April 3, at 11:15 a.m. ET / 15:15 UTC in the Room 103AB.

Rader will present the study, "Updated Cumulative Results of Treatment with Mavacamten from the EXPLORER-LTE Cohort of the MAVA-LTE Study in Patients with Obstructive Hypertrophic Cardiomyopathy," on Sunday, April 3, at 9:45 a.m. ET / 13:45 UTC in the Main Tent, Hall D.

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