Amgen’s Novel Cardiac Myosin Activator Omecamtiv Mecarbil Meets Primary Composite Endpoint in Phase 3 Trial for Chronic Heart Failure

November 16, 2020 /BioValleyBIOON/ -- Amgen, in partnership with Cytokinetics and Servier, recently announced at the American Heart Association (AHA) 2020 ScientificConferenceThe primary results of the GALACTIC-HF trial, a pivotal Phase 3 clinical study evaluating omecamtiv mecarbil for the treatment of chronic heart failure, were announced. The findings were simultaneously published in the New England Journal of Medicine (NEJM).

Omecamtiv mecarbil is a novel selective cardiac myosin activator designed to directly target the heart’s contractile mechanism. Currently, omecamtiv mecarbil is under development for the treatment of chronic heart failure with reduced ejection fraction (HFrEF). This May, the United StatesFDAGranted Fast Track Designation (FTD) for omecamtiv mecarbil in the treatment of HFrEF.

GALACTIC-HF is one of the largest global Phase III cardiovascular outcomes trials conducted to date in the field of heart failure treatment. It enrolled 8,256 patients with heart failure with reduced ejection fraction (HFrEF) receiving standard-of-care therapy across 35 countries. These patients had New York Heart Association (NYHA) functional class II–IV symptoms, a left ventricular ejection fraction (LVEF) ≤35%, elevated natriuretic peptide levels, and either were hospitalized for heart failure at the time of study enrollment or had been hospitalized for heart failure or visited an emergency department for heart failure within one year prior to screening. The study aimed to evaluate whether the addition of omecamtiv mecarbil to standard-of-care therapy could reduce the risk of heart failure events (hospitalization for heart failure and other urgent treatments for heart failure) and cardiovascular (CV) death in patients with HFrEF.

The results showed that omecamtiv mecarbil met the primary composite efficacy endpoint: after a median follow-up of 21.8 months, omecamtiv mecarbil significantly reduced the risk of the primary composite endpoint of cardiovascular (CV) death or heart failure events (hospitalization for heart failure or other urgent treatment for heart failure) compared with placebo in patients receiving standard care (HR=0.92; 95% CI: 0.86, 0.99; p=0.025). The first primary endpoint event occurred in 37.0% (n=1,523/4,112) of patients in the omecamtiv mecarbil group and 39.1% (n=1,607/4,112) of patients in the placebo group. When this effect was observed, there was no evidence of an increase in myocardial ischemic events, ventricular arrhythmias, or cardiovascular or all-cause mortality.

Among the broadest and most diverse patient populations enrolled in contemporary heart failure trials, a statistically significant reduction in the composite risk of heart failure events or cardiovascular death was observed, with no notable imbalance in the overall incidence of adverse events across treatment groups. The GALACTIC-HF trial included both hospitalized and outpatient participants, with a higher proportion of subjects exhibiting moderate-to-severe heart failure symptoms, as well as reduced ejection fraction, systolic blood pressure, and renal function.

No reduction was observed in the time to cardiovascular (CV) death, a secondary endpoint. A total of 808 patients (19.6%) in the omecamtiv mecarbil treatment group and 798 patients (19.4%) in the placebo group died from cardiovascular causes (HR=1.01; 95% CI: 0.92–1.11; p=0.86). According to the multiple testing control procedure, the change from baseline to Week 24 in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall symptom score, stratified by randomization setting (mean difference [95% CI] for hospitalized patients: 2.50 [0.54, 4.46]; for outpatients: -0.46 [-1.40, 0.48]; combined p=0.028), did not reach the prespecified statistical significance threshold (p=0.002) in the prespecified analysis. No other secondary endpoints were met according to the prespecified statistical analysis.

In most prespecified subgroups, the efficacy of omecamtiv mecarbil was consistent, with a potentially greater treatment effect observed in patients with lower left ventricular ejection fraction (LVEF ≤28%, n > 4000, HR = 0.84; 95% CI: 0.77–0.92; interaction p = 0.003). Compared with placebo, omecamtiv mecarbil also reduced NT-proBNP concentrations by 10% (95% CI: 6–14%) at week 24.

In the GALACTIC-HF trial, the overall safety profile of omecamtiv mecarbil appeared consistent with data from previous trials. Adverse events related to the study drug and treatment discontinuations were balanced across treatment groups. Overall, the incidence rates of myocardial ischemia, ventricular arrhythmias, and death were similar in the treatment and placebo groups. Furthermore, there were no significant differences in changes in systolic blood pressure from baseline to week 24 or week 48 between the omecamtiv mecarbil group and the placebo group. At both time points, patients in the omecamtiv mecarbil group exhibited a slight but significant decrease in heart rate compared with those in the placebo group. Compared with the placebo group, the median concentration of cardiac troponin I increased by 4 ng/L (95% CI: 3–5; limit of detection: 6 ng/L) from baseline in the omecamtiv mecarbil group.

GALACTIC-HFClinical TrialsJohn Teerlink, Chair of the Executive Committee, Professor of Medicine at the University of California, San Francisco, and Director of Heart Failure at the San Francisco Veterans Affairs Medical Center, stated, “As the global population continues to age, heart failure remains an increasingly significant clinical and economic burden. The results of the GALACTIC-HF study demonstrate that omecamtiv mecarbil, as a selective cardiac myosin activator, can meaningfully improve patient outcomes. The findings also indicate that patients with heart failure in the large, pre-specified subgroup with severely reduced systolic function may derive greater benefit from this novel investigational drug, an observation consistent with the drug’s primary pharmacological mechanism of enhancing cardiac function.”

Fady I. Malik, Ph.D., Executive Vice President of Research and Development at Cytokinetics, stated: “GALACTIC-HF is a landmarkClinical Trial“We are pleased that it enrolled the broadest range of inpatients and outpatients among contemporary heart failure trials. Omecamtiv mecarbil demonstrated positive effects on the overall primary efficacy endpoint and was particularly beneficial in patients with reduced ejection fraction, without increasing the overall incidence of adverse events. We look forward to continuing discussions with Amgen regarding the next steps for this program to determine its future direction.”

Molecular structure of omecamtiv mecarbil (Image source: Wikipedia)

Heart failure is a serious condition affecting more than 26 million people worldwide, approximately half of whom have reduced left ventricular function. It is a leading cause of hospitalization and readmission among individuals aged 65 years and older. Despite the widespread use of standard therapies and advances in care, the prognosis for patients with heart failure remains poor. It is estimated that approximately one in five people aged 40 years and older is at risk of developing heart failure, and among those diagnosed, about half die within five years of their initial hospitalization.

Omecamtiv mecarbil is a novel, selective cardiac myosin activator that binds to the catalytic domain of myosin. Preclinical studies have demonstrated that cardiac myosin activators can increase myocardial contractility without affecting intracellular calcium concentrations in cardiomyocytes or myocardial oxygen consumption. Cardiac myosin is a cytoskeletal motor protein in cardiomyocytes that is directly responsible for converting chemical energy into the mechanical force that drives myocardial contraction.

Currently, omecamtiv mecarbil is being developed for the treatment of heart failure with reduced ejection fraction (HFrEF) through a collaboration between Amgen and Cytokinetics, with funding and strategic support from Servier. The team is conducting a comprehensive Phase III clinical development program, which includes two Phase III trials: (1) the GALACTIC-HF trial, evaluating the impact of omecamtiv mecarbil versus placebo on cardiovascular outcomes in patients; and (2) the METEORIC-HF trial, assessing the effect of omecamtiv mecarbil versus placebo on patients’ exercise capacity (evaluated using cardiopulmonary exercise testing). (Bioon.com)