A Tale of Two Myosin-Targeting Cardiac Drugs: A Rationale for Sarcomere Mechanistic Investigation


Cardiomyopathies refers to diseases of the heart muscle and based on structure and function can be classified into 3 major subtypes, which are dilated, hypertrophic, and arrhythmogenic (reviewed in (1)).  Cardiomyopathies result in distorted cardiac output due to impaired ventricular function, impaired filling, or a combination of both.  Current available pharmacological treatments for adult cardiomyopathies focus on the symptomatic features of the disease rather than targeting the underlying mechanistic defects; thus, they provide little success in altering disease progression.  Cardiomyocytes (cardiac specific muscle cells) change their length and load to generate the contractile force during each heartbeat.  The force generators within cardiomyocytes are cardiac muscle fibers, which are themselves comprised of individual repeating units called sarcomeres (reviewed in (2)). The sarcomere complex is divided into two main components which are the actin thin filaments and the myosin thick filaments.  As abnormal contraction is a major pathologic consequence of cardiomyopathies, an intriguing hypothesis is that specifically targeting sarcomere proteins may be more effective at altering disease progression.

Omecamtiv Mecarbil

The first small molecule drug to specifically act on the sarcomere was Omecamtiv Mecarbil (OM), which targets cardiac myosin (3).  Early studies showed that OM bound the myosin catalytic domain and functioned by promoting and maintaining myosin in an actin-bound force-generating state (4).  Additionally, new crystallographic structural studies showed OM does not alter myosin’s structure; rather, it stabilizes the lever arm in a primed position and increases the number of heads that can bind actin (5).  Decreased cardiac contractility is a common feature of heart failure and dilated cardiomyopathy.  In animal models OM was shown to increase cardiac function through prolonged ejection, but without changing the rate of contraction or enhancing myocardial oxygen metabolism which are both common, negative side-effects of current therapies (4, 6).  A recent phase III study of OM showed a reduction in cardiac events for patients on OM (37%) versus the placebo group (39.1%) (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03); however, there was no overall change in how long patients lived (7).  While these results are a bit dispiriting, it suggests that myosin targeting drugs may provide a benefit, but further investigation is needed.  In that vein, a current study by Tang et al. showed that a mutation F764L in myosin, which promotes dilated cardiomyopathy (DCM), significantly reduced OM’s efficacy in vitro (8). Conversely, another myosin mutation R712L which promotes hypertrophic cardiomyopathy (HCM) responded strongly to OM treatment (9).  Thus, it’s fair to wonder if subsets of patients with underlying genetic mutations would respond more favorably to OM.   These recent studies suggest there is still more to learn about OM and its effect on myosin, force generation in the heart, and ultimately its potential as a therapy for heart failure.  

Figure 1: Omecamtiv Mecarbil and MYK461 interacting with myosin and the downstream effects on actin interaction.