Abstract 16842: Obstructive Hypertrophic Cardiomyopathy: Initial Single Ascending Dose Data in Healthy Volunteers and Patients
Introduction: Current therapy for hypertrophic cardiomyopathy (HCM) does not target causal mechanisms. HCM mutations in myosin result in excess left ventricular (LV) contractility, which contributes to development of LV outflow tract obstruction (LVOT), a major cause of limiting heart failure symptoms. MYK-461, a novel oral myosin modulator, decreases contractility, potentially reducing LVOT obstruction in HCM.
Hypothesis: MYK-461 will be well tolerated and decrease LV contractility
Methods: 48 healthy volunteers (HV) received single oral doses (1, 2, 6, 12, 24 or 48 mg) of blinded MYK-461 or placebo (6 active, 2 placebo per dose level). 15 HCM patients received single doses of open label MYK-461 at 48 (n=4), 96 (n=6) or 144 mg (n=5). Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed, the latter by echocardiography.
Results: Dose-dependent reductions in LV contractility (expressed as maximal % change from baseline ± SEM) were observed in both studies and concordant across 3 independent assessments: ejection fraction, fractional shortening, and velocity-time integral (Figure). Two HCM patients had provocable LVOT gradients at baseline (28 and 42 mmHg, respectively) that were abolished after administration of a 96 mg dose of MYK-461 (5 and 9 mmHg, respectively).One HCM patient experienced a serious adverse event (SAE) of asystole associated with a vasovagal episode following a single 144 mg dose which resolved without therapeutic intervention.
Conclusions: MYK-461 was generally well-tolerated following single oral doses up to 48 mg in HV and 144 mg in the majority of HCM patients, with one SAE at the highest dose (~6-10x the anticipated therapeutic daily dose). As proof of mechanism, MYK-461 displayed dose-dependent decreases in LV contractility, associated with elimination of provocable LVOT gradient in 2 HCM patients.
Author Disclosures: M. Maron: None. E. Ashley: Ownership Interest; Significant; Personalis Inc.. T. Blok: None. M. Evanchik: Employment; Significant; MyoKardia. Ownership Interest; Significant; MyoKardia. J. Lambing: Employment; Significant; Myokardia. S. Lester: None. K. Mahaffey: Consultant/Advisory Board; Modest; BAROnova, BI, Bio2 Medical, Epson, Eli Lilly, Johnson & Johnson, Myokardia, Portola, BMS, GSK, Theravance. Other; Modest; All disclosures after August 1, 2013, can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. Research Grant; Significant; Amgen, Daiichi-Sankyo, Johnson & Johnson, Medtronic, Merck, St Jude, Tenax. Consultant/Advisory Board; Significant; AstraZeneca, Cubist, Merck, The Medicines Company. S. Markova: Employment; Significant; Myokardia. A. Owens: None. J. Ritter: None. A. Wang: Research Grant; Significant; Gilead Sciences, Abbott Vascular. J. Fox: Employment; Significant; Myokardia.
- © 2016 by American Heart Association, Inc.