Omecamtiv Mecarbil Improves Symptoms in Patients with Moderate to Severe Heart Failure

Ultimately, the heart is the most constantly and dramatically moving part of the human body. By a mechanic’s logic, it is therefore most likely to break or need adjustments. Potential pharmaceuticals have been developed to make molecular adjustments to the mechanical cardiomyocyte ratchets. Omecamtiv mecarbil is a selective cardiac myosin activator that acts by increasing the rate of entry of myosin to join actin in the tightened down force-producing state to increase function without any additional cost. Ultimately this molecule increases the systolic duration and stroke volume, while not increasing myocyte calcium.

Amgen and Cytokinetics Incorporated have been examining omecamtiv mecarbil in phase II clinical trials for treatment of patients with chronic heart failure under the moniker COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure). Results were previously presented in late-breaking clinical trial sessions at the American Heart Association (AHA) Scientific Sessions 2015 in Orlando, FL.

Patients were randomized to three groups and treated for 20 weeks: placebo, 25 mg omecamtiv mecarbil bid, and omecamtiv mecarbil titration group (up to 50 mg twice daily). They assessed the effect of omecamtiv mecarbil in chronic heart failure patients treated with stable HF optimal therapies who have with a left ventricular ejection fraction (LVEF) <40%, and elevated natural atrial natriuretic peptides.

John Teerlink, MD, professor of clinical medicine at the University of California San Francisco and director of Heart Failure at the San Francisco Veterans Affairs Medical Center, described additional analysis at the Heart Failure Society of America 2016 Annual Scientific Meeting, in Orlando, FL.

Teerlink explained that the hypothesis behind this study was that treatment with omecamtiv mecarbil would improve symptoms after 20 weeks of therapy. This analysis involved patient-reported baseline system assessment of the severity of the symptoms using the Likert scale and the Kansas City Cardiomyopathy Questionnaire. Researchers observed a significant difference between placebo and omecamtiv mecarbil titration groups, with almost a 5-point improvement after omecamtiv mecarbil treatment. Within this group they saw progressive improvements, but not statistically significant improvement in symptom frequency or burden scores.

In conclusion, Teerlink stated that omecamtiv mecarbil can improve symptoms in chronic heart failure patients, particularly those who are at least moderately symptomatic at baseline. The presentation was well received and highly appreciated by the mostly physician-based audience. The first discussion query was a request for elaboration of correlations with heart rate (HR) changes. Teerlink pointed out that, yes, there was a slight decrease in HR of approximately 2.3 bpm, but the researchers have not completed analysis of this. Next a physician asked about affects atrial natriuretic peptides (ANP).

Teerlink pointed out that they have not done phase III trials yet, but impressively they did see improvements in ANPs at 20 weeks, and ANP continues to go down even 4 weeks post-treatment, thus suggesting omecamtiv mecarbil may be exerting some long-term remodeling effects. They hope this translates into improved mortality. Interestingly, a meta-analysis by Kramer et al, which looked at changes in volumes and outcomes, suggested a 70-80% chance for an eventual change in mortality. But Teerlink said he was “really stepping way out on a ledge” with this statement. That is why we need to do the next trial, according to Teerlink.

So far, researchers have not seen any detriment due to the diastolic changes resulting from omecamtiv mecarbil treatment. Teerlink pointed out that if you are increasing systolate, you must be decreasing diastolate. Moreover, they are affecting approximately 25 ms out of a range of about 1000 ms. So they are actually making a much slower percentage change in terms of diastolate, and their patients tend to have short systolic injection times. In the 1950s and 1960s, these measures were used as metric of heart failure. So, in effect they are effectively normalizing ejection time. At the current phase, the therapeutic potential for omecamtiv mecarbil would appear to have a bright future, according to Teerlink.

Related Coverage:

Larry Allen, MD: Benefits of Shared Decision Making in Heart Failure Patients

Barry Borlaug, Mayo Clinic: Heart Failure With Preserved Ejection Fraction

Larry Allen, MD: The Rebirth in Heart Failure