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Mavacamten Promising in Non-Obstructive HCM

— Phase II MAVERICK-HCM trial looked at safety, efficacy of myosin inhibitor

MedpageToday

The investigative agent mavacamten may be safe and effective in patients with non-obstructive hypertrophic cardiomyopathy (HCM), researchers reported.

In the primary safety endpoint of the MAVERICK HCM trial, 10.3% of patients in the mavacamten group experienced one or more serious adverse events (AEs) versus 21.1% of placebo patients, Carolyn Ho, MD, of Brigham & Women's Hospital in Boston, at the virtual American College of Cardiology (ACC) meeting.

Overall, 89.7% of patients on mavacamten experienced treatment-emergent adverse events (TRAEs), although 76% of those TRAEs were considered mild, and 21% were considered moderate, Ho said during an online presentation. In comparison, 68.4% of patients on placebo experienced TRAEs, most commonly palpitations, dizziness, and fatigue.

Ho and colleagues also reported some favorable biomarker changes with mavacamten treatment, specifically statistically significant reductions in serum NT-proBNP (P=0.0005) in the intent-to-treat population. NT-proBNP is a well-established biomarker of cardiac wall stress, associated with increased mortality in HCM patients.

At the conclusion of the 16-week treatment period, the reduction in the geometric mean of NT-proBNP among those receiving mavacamten was 53% versus 1% in the placebo group, the authors stated, adding that a significant drop in NT-proBNP occurred within the first 4 weeks of treatment and was maintained throughout the treatment period.

Mavacamten treatment also resulted in a 34% decrease in the geometric mean of cardiac troponin I levels -- tied to increased incidence of heart failure, atrial fibrillation, and death in patients with HCM -- from baseline to week 16 versus a 4% increase in the placebo group (P=0.009).

"Non-obstructive HCM is especially challenging to treat as there are no proven or approved pharmacological therapies," Ho said. "Thus, for patients who develop symptoms refractory to medications, cardiac transplantation may be the only option."

"Although the primary objective of MAVERICK was to assess the safety and tolerability of mavacamten in non-obstructive HCM, in exploratory analyses we observed an encouraging result with reductions in serum levels of NT-proBNP, a biomarker of hemodynamic stress, and also cardiac troponin I, a biomarker of myocardial injury," she said in a statement. "We believe MAVERICK is the first study to show an improvement in important serum biomarkers in this patient population and suggests that there is potential physiological benefit from the drug."

Mavacamten is a first-in-class myosin inhibitor that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. The agent reduces excessive contractility of the hypertrophic heart, which is characteristic of the disease, Ho explained. The agent has been previously tested in symptomatic obstructive HCM in the trial. The phase III trial in symptomatic HCM is underway.

The phase II trial enrolled 59 patients, randomly assigned 1:1:1 to target mavacamten concentrations of 200 ng/mL, of 500 ng/mL, or to placebo.

The researchers looked at changes from baseline to week 16 in NT-proBNP, peak oxygen uptake (pVO2), New York Heart Association (NYHA) functional class, echocardiographic measures of left ventricular ejection fraction (LVEF) and diastolic function, and composite functional endpoint (≥1.5 mL/kg/min increase in pVO2 and ≥1 NYHA class improvement or ≥3.0 mL/kg/min increase in pVO2 without worsening in NYHA class).

The authors found the following differences in baseline characteristics between the mavacamten groups and placebo group, respectively:

  • NYHA heart failure class II: 33 vs 13 patients
  • NYHA heart failure class III: 7 vs 6 patients
  • Mean pVO2: 20.5 vs 17.9 mL/kg/min
  • Mean NT-proBNP: 821 vs 914 pg/mL
  • Taking beta-blockers: 25 vs 12 patients
  • Taking calcium channel blockers: 10 vs 3 patients
  • Average LVEF: 69% vs 66%

They reported that the average LVEF decreased by 4.1% among patients in the mavacamten groups, and the decrease was larger among patients whose target mavacamten concentration was 500 ng/mL. In the placebo group, the mean LVEF reduction was 2.3%.

In exploratory efficacy results, NT-ProBNP and troponin levels decreased among patients taking mavacamten, while there was little to no change in the placebo group. Additionally, 35% of patients taking mavacamten achieved the composite functional endpoint versus 21% in the placebo group, though the difference was not significant.

Martin Maron, MD, of the Hypertrophic Cardiomyopathy Center at Tufts Medical Center in Boston, commented: "It is pretty clear that mavacamten had an effect in lowering biomarker, but what was frustrating was that it did not translate into a clinical improvement in functional capacity in NYHA class."

Maron also expressed concern about the drops in LVEF in patients who were withdrawn from the study. "About 12% of patients had a striking reduction in LVEF, with an absolute reduction [ranging] from 17% to 35%, showing a lot of individual variability in response to the drug," he explained. "That raises concerns about the translatability of the drug if it were approved into clinical practice."

Disclosures

The study was supported by MyoKardia.

Ho disclosed relevant relationships with MyoKardia, Ambry Genetics, and Novartis.

Maron disclosed relevant relationships with Celltrion, iRhythm, UpToDate, Cytokinetics, Novartis, and Takeda Pharmaceuticals North America.

Primary Source

American College of Cardiology

Heitner B, et al "Mavacamten improves biomarkers of myocardial wall stress and injury in patients with symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM): results from the phase 2 MAVERICK-HCM study" ACC 2020.