Professor Milind Desai

Patients with obstructive hypertrophic cardiomyopathy (HCM) may be able to avoid risky septal reduction surgery by taking the selective cardiac myosin inhibitor mavacamten, according to results presented at the American College of Cardiology’s annual meeting (ACC 2022).

In a small phase 3 trial involving 112 patients with obstructive HCM, there was a striking reduction in the number who were eligible for surgery after 16 weeks of treatment with mavacamten compared to placebo.

In the VALOR-HCM trial, mavacamten was added on to maximally tolerated medical therapy with dose adjustment based on echocardiogram measures of ejection fraction and the LVOT gradient.

At baseline, 93% of patients were NYHA Class III or higher with severe obstruction, but at 16 weeks only 17.9% of patients on mavacamten were found to meet guideline criteria for septal reduction therapy (defined as LVOT gradient of ≥50 mmHg and NYHA Class III–IV), compared with 76.8% of those on placebo.

Patients who received mavacamten in addition to existing drug therapy also showed significant improvements in secondary outcomes of symptoms, quality of life and degree of obstruction  with 63% of patients improving by one and 27% improving by two NYHA classes.

“This is really the first pharmacotherapy that offers a viable medical option for people with obstructive HCM short of needing a procedure,” said study investigator Professor Milind Desai, director of the Hypertrophic Cardiomyopathy Center at the Cleveland Clinic’s Heart Vascular and Thoracic Institute.

“These [procedures] are pretty aggressive therapies. They work well when done in a highly experienced HCM centre where mortality is low, less than 1%, but most centres don’t do enough, and the mortality rate can be high,” he said, noting that one analysis reported the average rate of postoperative mortality to be 5.9%, with rates as high as 15.6% in lower volume centres.

Professor Desai said mavacamten was a selective cardiac myosin inhibitor that has been shown to reduce cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation that results in increased contraction, excessive thickening of the heart muscle and reduced compliance.

The drug was well tolerated, despite concerns that it may reduce hypercontractility. Two patients in the mavacamten group had a drop in ejection fraction to less than 50% and had to stop the drug temporarily until their ejection fraction recovered, but they were able to restart the drug at a lower dose. There were no reported deaths, strokes or heart attacks.

Almost all patients took up the offer to continue therapy in an extension study for three years, Professor Desai noted.

“This is a big win for patients, especially as many people don’t want surgery, are at high risk for complications or don’t have good anatomy for ablation,” he said.

“We are hoping this study will also draw much-needed attention to HCM. This disease is woefully underrecognised. There are not enough HCM experts and not enough proven medical therapies, so there are many opportunities to do better.”

In other findings presented at ACC 2022, mavacamten appeared to maintain good effectiveness and tolerability in an extension study involving 231 patients with HCM who took part in the phase 3 EXPLORER-HCM trial.

The degree of obstruction measured by LVOT gradient was lowered on average by 36 mmHg at 48 weeks (a 74% reduction from baseline) and this reduction was sustained through week 84. At this timepoint, 83.5% of patients 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. 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.

“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 study investigator Dr Florian Rader, co-director of the Hypertrophic Cardiology Clinic at Cedars Sinai, UCLA.

The studies were funded by MyoKardia, Inc., a wholly-owned subsidiary of Bristol Myers Squibb. 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.