Christopher Holley, MD Duke University

1. Myosin Modulators:
Omecamtiv and Mavacamten
Christopher Holley, MD, PhD
Associate Director, Duke Cardiovascular Research Center
Duke HF Symposium
October 7, 2021

2. New mechanism for modifying contractility
Omecamtiv mecarbil:
increases contractility
Mavacamten:
Decreases contractility
Kaplinsky E, Mallarkey G. Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil. Drugs in Context 2018.
Actin-myosin
cross-bridging

4. GALACTIC-HF (2021): 8232 pts c HFrEF ≤35%
• OM reduced the composite
outcome of first HF or CV death
• 39.1% v 37%, p = 0.03
• Treatment effect increased with
decreasing EF
• No difference in CV death, all-
cause death, or KCCQ symptom
score
• No major safety issues
Teerlink JR, et al. N Eng J Med 2021;384:105-16.
Dropped by Amgen but Cytokinetics plans to file with FDA

6. Mavacamten is a targeted inhibitor of cardiac myosin that
reduces the number of myosin-actin cross-bridges and decreases contractility
HCM Pathophysiology
Hypercontractility
Impaired relaxation
Altered myocardial energetics
Attenuated hypercontractility
Improved compliance
Improved energetics
Normal contractility
Effective relaxation
Mavacamten: Mechanism of Action
John Spertus, MD, MPH

7. EXPLORER-HCM trial (2020): 251 pts
FDA “breakthrough therapy designation”; under review
Olivotto et al. Lancet. 2020;12(396):759–69

8. Percentage of Participants Who Changed by
Clinically Important Amounts at 30 Weeks
• A greater proportion of patients taking mavacamten achieved a very large clinically meaningful
-point) compared to placebo
• A greater proportion of patients in the placebo arm had no change or deterioration in their health
status at Week 30
36% vs.15%
NNT = ~5
23% vs.9%
NNT = ~7
John Spertus, MD, MPH