Amgen Terminates Collaboration on Omecamtiv Mecarbil Due to Suboptimal Phase 3 Results in Chronic Heart Failure

November 23, 2020 /BioonBIOON/ -- Amgen recently announced that it has issued a notice to Cytokinetics to terminate their collaboration and intends to transfer the development and commercialization rights of omecamtiv mecarbil and AMG594.

Omecamtiv mecarbil is a novel selective cardiac myosin activator designed to directly target the heart’s contractile mechanism. This drug has been studied in the Phase 3 GALACTIC-HF trial for the treatment of patients with chronic heart failure with reduced ejection fraction (HFrEF). AMG594 is a selective cardiac troponin activator with a novel mechanism of action, currently in Phase 1 clinical development for the treatment of HFrEF and other types of heart failure.

Preliminary results of the GALACTIC-HF trial were recently presented at the American Heart Association (AHA) 2020 ScientificConferencepublished domestically and simultaneously in the top international medical journal, The New England Journal of Medicine (NEJM). The trial demonstrated that, compared with placebo, among patients receiving standard care,Omecamtiv mecarbil treatment demonstrated statistically significant reductions in the risk of the primary composite endpoint of cardiovascular (CV) death or heart failure events (hospitalization for heart failure and other urgent treatments for heart failure). No reduction in the risk of CV death was observed for the secondary endpoint.

David M. Reese, Executive Vice President of Research and Development at Amgen, stated, “Cardiovascular disease is one of the most significant public health challenges worldwide, underscoring the need for greater innovation in patient care. Our commitment to addressing cardiovascular disease remains unwavering, and we look forward to continuing our close collaboration with the cardiovascular community as we focus on advancing our innovative therapies, including our Lp(a) inhibitor olpasiran (AMG890), which is currently in Phase 2 clinical development. We extend our gratitude to the investigators and patients who participated in the GALACTIC-HF trial. Unfortunately,”The results of the GALACTIC-HF trial failed to meet the high standards we had set for this project.。”

Amgen thanks Cytokinetics and Servier for their productive collaboration over the years and will work closely with them to facilitate a smooth transition of omecamtiv mecarbil. Servier provided funding and strategic support for the project.

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 the 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).

GALACTIC-HF is one of the largest global Phase III cardiovascular outcome 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 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.

Results presented at the AHA Scientific Sessions demonstrated 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 versus 39.1% (n=1,607/4,112) in the placebo group. This effect was observed without evidence of an increase in myocardial ischemic events, ventricular arrhythmias, or cardiovascular or all-cause mortality.

No reduction was observed in the time to cardiovascular (CV) death, a secondary endpoint. Cardiovascular death occurred in 808 patients (19.6%) in the omecamtiv mecarbil treatment group and 798 patients (19.4%) in the placebo group (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 significantly reduced NT-proBNP concentrations by 10% at week 24 (95% CI: 6–14%). The overall safety profile of omecamtiv mecarbil in the GALACTIC-HF trial appeared consistent with data from previous trials. (Bioon.com)

Original Source: Amgen To Transition Development And Commercial Rights For Omecamtiv Mecarbil And AMG 594 To Cytokinetics