An investigational, first-in-class agent showed hypothesis-generating promise in symptomatic adults with nonobstructive hypertrophic cardiomyopathy (HCM), a condition lacking in good treatment options, in an early dose-finding study.
The 40 patients, who had been randomly assigned to receive the cardiac myosin inhibitor mavacamten (formerly MYK-461, MyoKardia) for 16 weeks, vs 19 given placebo, usually tolerated the drug well and showed significant improvements in cardiomyopathy-related biomarkers, researchers report in the June 2 issue of the Journal of the American College of Cardiology.
Patients on mavacamten showed significant dose-dependent reductions in cardiac troponin I (cTnI), a marker for myocardial injury, and of N-terminal proB-type natriuretic peptide (NT-proBNP), which reflects myocardial wall stress.
Both findings suggest a degree of physiologic improvement on the drug, and it may be important that both biomarkers are prognostic in heart failure and HCM, observe the authors, led by Carolyn Y. Ho, MD, Brigham and Women's Hospital, Boston.
The phase 2 trial, MAVERICK-HCM, wasn't powered to show potential drug effects on clinical outcomes or even functional surrogates, like exercise capacity or NYHA class.
But in an exploratory analysis, treatment with mavacamten appeared to improve symptoms and functional capacity in patients with the most severe disease, as indicated by echocardiographic measures of diastolic function and elevations in cTnI.
"Those people seemed to have some hint of clinical efficacy," Ho told theheart.org | Medscape Cardiology. "It's hypothesis-generating and interesting to think about in terms of who are the best patients to target — which patients with nonobstructive HCM may most benefit from mavacamten."
An effective drug therapy for nonobstructive HCM, "has been quite elusive. There's a real unmet need for that cohort." And, in contrast to options for patients with the obstructive form of HCM, "there's no physiological or mechanical target for invasive therapy," she said.
"So people with nonobstructive HCM who are severely symptomatic have really just been adrift without effective therapies."
"The biomarker data are striking and suggest a physiological benefit," write Jane E. Wilcox, MD, and Elizabeth M. McNally, MD, PhD, in a linked editorial. "These findings represent a rigorous, well-designed phase 2 study that has offered a glimmer of hope in a high-risk nonobstructive HCM population with limited available therapies."
In contrast, "a one-sized approach does not fit all, and high-risk subgroups of an already highly selected population (59 nonobstructive-HCM patients enrolled after screening over 150 patients) may not be reflective of physiology across the entire spectrum of nonobstructive disease," caution the editorialists, from Northwestern University, Chicago.
The main report describes mavacamten as a "small molecule, allosteric inhibitor of cardiac-specific myosin adenosine triphosphatase. It specifically reduces excessive cross-bridging with actin, which is believed to be an important contributor to the pathological hypercontractility associated with HCM." It therefore targets what is believed to be one of HCM's underlying pathophysiologic mechanisms.
The drug is also under development for the obstructive form of HCM, for which it performed favorably in the 251-patient EXPLORER-HCM trial, MyoKardia recently announced along with cursory top line results. Ho is on that trial's steering committee.
The phase 3 EXPLORER-HCM trial, the company said, showed a significant benefit from mavacamten for a primary end point reflecting changes in peak VO2 and symptoms, as well as secondary functional, hemodynamic, and quality-of-life end points.
MAVERICK-HCM randomized 19 and 21 patients to receive mavacamten uptitrated to plasma levels of 200 ng/mL and 500 ng/mL, respectively, and 19 to receive placebo. For entry, they were required to be 18 years or older with nonobstructive HCM with NYHA class 2 or 3 symptoms, elevated NT-proBNP, increased left ventricular (LV) wall thickness, an LV ejection fraction of at least 55%, and a family history of HCM.
The drug was said to be well tolerated in all patients except five who showed reversible declines in LV ejection fraction to less than 45%. Serious adverse events, which included atrial fibrillation, occurred in 10.3% of mavacamten recipients and 21.1% of those on placebo. Treatment-associated adverse events of any kind, usually mild and self-limiting, were seen in 90% and 68%, respectively. The most common among those receiving mavacamten were palpitations, dizziness, and fatigue, the group reports.
The geometric means for NT-proBNP fell by 53% for those receiving mavacamten and 1% for those on placebo (P = .0005), and for cTnI declined 34% and rose 4%, respectively (P = .009).
"These patients tend to be the most challenging patients to take care of clinically, just because we have so little to offer, other than transplant. So trying to address that unmet need is not going to be met certainly in one step by one trial," Ho told theheart.org | Medscape Cardiology.
"Key will be trying to figure out who best to target, who are those responders, what are their characteristics, and how can we identify that information and be able to treat in a more precise, proactive manner."
MAVERICK-HCM was supported by MyoKardia, which "was involved in the study design and interpretation of the data, analysis, writing of the report, and in the decision to submit the manuscript for publication." Ho discloses consulting for MyoKardia and serving on an advisory board for Ambry Genetics. Disclosures for the other authors are in the report. Wilcox discloses serving as a speaker for and receiving honoraria from Medtronic, serving on an advisory board for Cytokinetics, and serving as a speaker or consultant for Boehringer Ingelheim. McNally discloses serving as a consultant for Amgen, AstraZeneca, Pfizer, Tenaya Therapeutics, Cytokinetics, and Invitae.
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Cite this: Mavacamten Phase 2 Results Hopeful in Nonobstructive Hypertrophic Cardiomyopathy - Medscape - May 26, 2020.