Cardiac Myosin Activation in the Treatment of Congestive Heart Failure: New Therapeutic Options and Review of Literature.

Congestive heart failure (HF) remains a major cause of cardiac-related morbidity and mortality, despite major therapeutic advancements. A newer class of medications has recently been developed which targets the root cause of HF, which is reduced myocardial contractility. This article aims to highlight the cardiac myosin activator class of drugs and the trials to date highlighting their effects on HF outcomes. Copyright:

INTRODUCTION

Heart failure (HF) is defined as a structural or functional impairment of myocardium that consequently results in a failure of the heart to pump blood at a rate commensurate with the needs of the body. HF remains a major cause of morbidity and mortality, with high rates of readmission. In the United States alone, about 6.2 million Americans had HF between 2013 and 2016, and it is anticipated to continue on an upward trajectory as the elderly population continues to increase.[1]

In 2018, HF was mentioned on 379,800 death certificates (13.4%). It has an estimated $30.7 billion dollar health-care cost, which includes the financial burden of health services, medicines to treat HF, and missed days of work.[2] Robust long-term cardiovascular research has helped establish several medications with different mechanisms of action that can effectively treat HF and reduce exacerbations.

Majority of these medications function by inhibiting the compensatory neurohormonal axis and sympathetic drive that is activated when HF occurs.[3] However, no drug has shown to safely target the root causes of HF, which is the initial decrease of systolic dysfunction. In theory, improved myocardial contractility would prevent the activation of neurohormonal axis and sympathetic drive, thus preventing cardiac remodeling and reducing HF.[45]

Recently investigated cardiac myosin activators have shown to improve systolic function and reverse cardiac remodeling, a combined benefit unaccomplished by any previous HF medication. In addition, cardiac myosin activators have inotropic activity without the consequences of systolic calcium accumulation typically seen with other inotropic agents.[67] This review presents the clinical development up to date of available therapeutic cardiac myosin inhibitors, their mechanism of action, data that may or may not support their use, and future prospects.

DISCUSSION

Pharmacology and mechanism of action

Cardiac myosin activators have a rare mechanism of action, which involves directly affecting cardiac sarcomeres rather than enzyme inhibition consequently augmenting cardiac performance without serious adverse effects. Cardiac myosin activators function as myotropes, without changing cardiomyocyte calcium homeostasis.[5] This novel mechanism of action allows it to avoid the deleterious effects, limiting current indirect inotropic mechanisms. Cardiac myosin activators selectively bind to cardiac tissue with no effect on smooth muscle or skeletal muscle myosin. The allosteric binding of myosin activators to myosin results in a conformational change and accelerates the rate-determining step of the cross-bridge cycle, by consequently augmenting the speed of ATP hydrolysis. Once the ATP is hydrolyzed to ADP, this changes the weakly bound actin and myosin to a tightly bound actin and myosin complex.[8910] As a result, more myosin is bound to actin for a longer period. In addition, the accumulation of primed myosin heads generates a stronger force of contraction.[11] The unique mechanism of action allows improvement in systolic function due to prolonged myocardial systole and increased stroke volume (SV) without affecting heart rate and velocity of contraction.

Further research into cardiac myosin activators has also proven their efficacy in reversing cardiac remodeling, consequently reducing the physiological impact of HF. The promising preclinical trials of cardiac myosin activators have supporting its advancement into clinical studies.

THE GLOBAL APPROACH TO LOWERING ADVERSE CARDIAC OUTCOMES THROUGH IMPROVING CONTRACTILITY IN HEART FAILURE TRIAL

The Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial is a large international randomized placebo-controlled clinical trial that evaluated the use of omecamtiv mecarbil (OM) in patients with HF.[12] Overall, the study enrolled 8256 patients with symptomatic chronic HF with reduced ejection fraction (HFrEF) less than <35%. Patients in the OM group received 25 mg, 37.5 mg, or 50 mg twice-daily medication based on plasma levels of the drug. The duration of follow-up was a median of 21.8 months. The primary end point of the study was a composite of time-to-cardiovascular death or first HF event, whichever was to come first. The primary end point occurred in 37.0% of the OM group compared with 39.1% of the placebo group (P = 0.03), showing significant reduction. Secondary end points include measurement of patient-reported outcomes (Kansas City Cardiomyopathy Questionnaire [KCCQ]); cardiovascular death and all-cause death. Interestingly, results show that there was not a significant change in any secondary end point category. Cardiovascular death occurred in 19.6% of the OM group compared with 19.4% of the placebo group (P = 0.86). All-cause death occurred in 25.9% of the OM group compared with 25.9% of the placebo group, and the change in KCCQ total symptoms score at 24 weeks was 23.7 in the OM group compared with 21.2% in the placebo group.[1213]

Overall, the results of the GALACTIC-HF trial showed a decrease in median N-terminal pro-B-type natriuretic peptide level (NT-proBNP) by 10% and a higher median cardiac troponin level of 4 ng//L in the OM group. Despite the small increase in troponin, the incidence of myocardial ischemia, ventricular arrhythmias, and death was similar in the two trial groups. Study limitations were observed in the patient population enrolled in the trial. Only 7% of the patients self-reported as black, and only 21% of the patients were women. Furthermore, while background therapy for patients was generally excellent, only 20% of patients were receiving sacubitril–valsartan at baseline, and only 2.5% were receiving a sodium–glucose cotransporter 2 inhibitor.[14] Thus, it remains indeterminate what treatment value of OM would add in conjunction with these medications. Overall study concludes that OM is superior to placebo and is associated with a reduction in the primary outcome without significant adverse effects.

ACUTE TREATMENT WITH OMECAMTIV MECARBIL TO INCREASE CONTRACTILITY IN ACUTE HEART FAILURE TRIAL

The Acute Treatment with OM to Increase Contractility in Acute Heart Failure (ATOMIC-HF) trial published in 2016 was a double-blind, randomized, placebo-controlled sequential cohort phase IIb study designed to investigate the pharmacodynamic efficacy and safety of intravenous (IV) OM in patients hospitalized for acute HF exacerbations.[15] Patients enrolled in the study were those with HFrEF and hospitalized for acute exacerbation, those with elevated BNP or (NT)-proBNP, those who have dyspnea at rest, or those with minimal effort ≥2 h after IV diuretics. 606 participants were randomized to receive 48 h of placebo or OM in three sequential, escalating-dose cohorts, targeting a mean plasma concentration of 115, 230, and 310 ng/mL. Primary efficacy end point was dyspnea improvement measured using patient-reported 7-level Likert scale through 48 h of IV OM administration. Responders categorized their dyspnea at 6 h by minimally, moderately, or markedly improved, and then again evaluated at 24 and 48 h, and re-categorized as moderately or markedly improved.

Overall, the primary end point of the study was not met. The response rate of dyspnea relief within 48 h did not significantly defer among all groups (3 OM dose groups and pooled placebo: placebo, 41%; OM cohort 1, 42%; cohort 2, 47%; cohort 3, 51%; P = 0.33). Furthermore, none of the secondary outcomes of the study were met either. This included changes in baseline NT-proBNP, length of hospital stay, days alive out of the hospital until day 30, death by any cause or worsening HF within 7 days, dyspnea area under the curve (baseline to 5th day or discharge), and dyspnea by 7-point Likert scale at each scheduled assessment. However, there was suggestion that OM resulted in greater dyspnea relief at 48 h (placebo, 37% vs. OM, 51%; P = 0.034) and through 5 days (P = 0.038) in the high-dose cohort. Despite not meeting primary and secondary end points, the study does reflect a common theme observed in OM studies. There was an increase in left ventricular (LV) ejection systolic time (P < 0.0001) and decrease in end systolic dimension (P < 0.05). Serious adverse events between placebo and OM group on day 30 were statistically similar (placebo: n = 70 [23%] vs. OM: n = 66 [22%]). However, plasma troponin concentrations were higher in OM cohort groups compared with placebo (median difference at 48 h, 0.004 ng/ml) but were not associated with increased myocardial ischemic events.

Overall, ATOMIC-HF trial did not show statistical significance in dyspnea symptoms with OM compared to placebo, and the study remains underpowered to look at clinical outcomes. The serial enrollment of cohorts separated by months significantly limited analysis of the study. It resulted in differences in patient population and placebo response rate, consequently confounding the comparisons of the pooled placebo cohort with the individual OM cohorts.[16]

CHRONIC ORAL STUDY OF MYOSIN ACTIVATION TO INCREASE CONTRACTILITY IN HEART FAILURE TRIAL

Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF) is a phase 2, pharmacokinetic (PK), randomized, placebo-controlled trial with the primary PK objective to dose titrate OM and observe its effects on cardiac function.[17] Patients with symptomatic chronic HF and left ventricular ejection fraction (LVEF) 40% or less were randomly assigned to three different groups. 448 patients were randomized 1:1:1 to receive oral placebo versus patients receiving OM at a fixed dose of 25 mg twice daily, versus patients receiving PK-titrated doses, starting at 25 mg, and increasing to 50 mg based on plasma concentration of the drug. Medications were administered for a total duration of 20 weeks. Patients were visited at weeks 2 and 8 and then every 4 weeks. Intensive PK sampling was performed. Mean maximum concentration of OM at 12 weeks was 200 (standard deviation 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the PK-titration group. The study effectively proved its primary objective by demonstrating stable PK of OM.

Furthermore, the study successfully proved secondary end point by demonstrating improved cardiac function in the OM PK-guided dose-titration group. Systolic ejection time (SET) significantly improved in both OM groups compared to placebo however was markedly more improved in the PK-guided dose-titration group (fixed-dose group: +11 ms, P = 0.007; PK-titration group: +25 ms, P < 0.001). Significant reduction in LV end-systolic and end-diastolic diameters was noted in the OM groups when compared to placebo group. Furthermore, significant reduction in Pro-BNP was noted in the PK-OM groups (fixed-dose group: −822 pg/mL, P = 0.0205; PK-titration group: −970 pg/mL, P = 0.0069), and this effect persisted 4 weeks after discontinuation of the drug. There was an asymptomatic increase in the median plasma troponin of 0.006 ng/ml (95% confidence interval: 0–0.024 ng/ml) in the PK-guided dose-titration group; however, no cases were adjudicated as an episode of myocardial ischemia or infarction. There was no increase significance of cardiac and noncardiac adverse events in placebo versus OM groups. Overall, COSMIC-HF trial demonstrates that OM PK-based dose-titration strategy produced an improvement in cardiac function with a reduction in sympathetic activation and myocardial wall stress when compared to placebo, with no adverse effects. Overall, the trial concluded that OM PK-based dose-titration demonstrated improved cardiac function, reduction in ventricular diameters, and reduction of NT-proBNP when compared to placebo.

Limitations of the study include short duration of exposure and limited number of dosing regimens studied. Furthermore, exclusion of some key patient segments (e.g., very low estimated glomerular filtration rate <30 mL/min/1.73 m2 and systolic blood pressure [BP] >160 mmHg or <90 mmHg or diastolic BP >90 mmHg) limits understanding of adverse events related to OM.[18]

DANICAMTIV

This is a randomized, double-blind, single- and multiple-dose phase 2a trial with the primary objective of determining safety and effectiveness of danicamtiv in patients with HFrEF.[19] The study was optimized by including patients with stable and chronic HFrEF and LVEF on echocardiogram ≤ 35. All patients had quality echocardiogram imaging for accurate EF and were on appropriate medical therapy. The study included 40 patients, 10 of which received placebo and 30 received danicamtiv (50–100 mg twice daily for 7 days).

The danicamtiv group was divided into four different cohorts. Cohort A received medication dose of 75 mg BID based on some PK simulations, and the medication was administered after a 2 h fast, and the patient remained fasting till 2 h after the medication was administered. Cohorts B, C, and D patients received danicamtiv 50, 75, and 100 mg BID, respectively, with food. The primary objective of the study was to investigate the safety and tolerability of single and multiple oral doses of danicamtiv in patients with stable, chronic HFrEF. Overall, the study supported the primary outcome, as danicamtiv was generally well tolerated and no dose-limiting toxicities were observed. Adverse events in the danicamtiv-treated group were mostly mild and reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Adverse events included transient increases in troponin, ventricular extrasystoles, and in two patients, nonsustained ventricular tachycardia (NSVT) episodes which were observed at baseline (before treatment) and again during the study treatment. None of the following adverse effects required medication adjustment and resolved without treatment.

Secondary end points include assessment of the danicamtiv PK profile and evaluation of changes in the following echocardiographic measurements: LVSV, LVEF, LV fractional shortening, and LV SET, after single and multiple doses of danicamtiv. These measurements were assessed in a core laboratory, and readers were blinded to study treatment. Results demonstrate that danicamtiv caused a concentration-dependent increase in LVSV (mean placebo-corrected increase of 7.8 mL [P < 0.01] and 5.7 mL [P < 0.05] at medium and high concentrations, respectively). LVEF did not change significantly. The SET increased in a dose-dependent manner, with a mean placebo-corrected increase of 36 ms (P < 0.01) and 48 ms (P < 0.01) observed at medium and high concentrations, respectively. Furthermore, danicamtiv improved LVSV (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05).

Overall, the study demonstrates that danicamtiv at multiple doses is safe and improves cardiac function in patients with HFrEF. Study limitations include small number of patients and short duration of trial (7 days). The exclusion of patients with very low estimated glomerular filtration rate <30 mL/min/1.73 m2, atrial fibrillation, and advanced HF prevents further understanding of danicamtiv on a more sick population of patients. Furthermore, larger trials of danicamtiv with longer treatment duration are vital to assess optimal dosing, safety, and tolerability.

CONCLUSION

Cardiac myosin activators have demonstrated incremental benefits for patients with HFrEF. The novel mechanism of cardiac myosin activators has allowed them to produce dose-dependent increases in SET, SV, and EF, while simultaneously providing the benefits of ventricular remodeling with a limited adverse event profile.

The ATOMIC-AHF trial demonstrates that IV OM did not improve symptoms of dyspnea; however, no significant adverse side effect profile was noticed. IV OM positively affected key factors by increasing SET and decreasing Left ventricular end systolic volume (LVESV). The COSMIC-HF trial showed that a PK-based dose-titration strategy improved cardiac function compared to placebo and was safely tolerated in patients. There was a notable reduction in NT-proBNP with a minimal troponin increase that was not related to ischemic cardiac events.

This was further studied in the phase III clinical trial, GALACTIC-HF trial. The GALACTIC-HF trial concluded that OM was superior to placebo at improving cardiovascular outcomes. Although there was a slight increase of troponin elevation observed, results demonstrate that the elevation was asymptomatic and not correlated with ischemic events.

At last, danicamtiv, another cardiac myosin activator currently under investigation, has also demonstrated safety of the drug, potential structural benefits toward patients with HFrEF, and improved cardiac function.

With promising results, there is ongoing range of preclinical and clinical research on cardiac myosin activators to gain further insight and understand the scope of treatment.[20] There is great potential for cardiac myosin activators to be implemented in international guidelines after further research and investigation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.