Date: 2016-11-30
Type of
information: Publication of results in a medical journal
phase: 2
Announcement: publication of results in The Lancet
Company: Amgen (USA - CA)
Product: omecamtiv mecarbil
Action
mechanism: myosin activator. Omecamtiv mecarbil is a novel cardiac myosin activator. It activates cardiac muscle contractility and operates to strengthen heart function in patients with systolic dysfunction. Cardiac myosin activators are thought to accelerate the rate-limiting step of the myosin enzymatic cycle and shift the enzymatic cycle in favor of the force-producing state. Preclinical research has shown that cardiac myosin activators increase contractility in the absence of changes in intracellular calcium in cardiac myocytes.
Omecamtiv mecarbil is being developed by Amgen in collaboration with Cytokinetics . Amgen holds an exclusive, worldwide license to omecamtiv mecarbil and related compounds, subject to Cytokinetics' specified development and commercialization rights. Servier has exercised an exclusive option granted by Amgen for the commercialisation of omecamtiv mecarbil in Europe , as well as the Commonwealth of Independent States, including Russia .
Disease: chronic heart failure
Therapeutic
area: Cardiovascular diseases
Country: Australia, Belgium, Bulgaria, Canada, Czech Republic, Germany, Hungary, Italy, Lithuania, Netherlands, Poland, UK, USA
Trial
details:
- COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure) was a double-blind, randomized, placebo-controlled, multicenter, Phase 2 trial designed to evaluate an oral formulation of omecamtiv mecarbil in chronic heart failure patients with reduced ejection fraction. The trial consisted of two parts, a dose escalation phase and a larger and longer expansion phase. The dose escalation phase, which completed in 2013, assessed the pharmacokinetics and tolerability of three oral modified-release formulations of omecamtiv mecarbil and was used to select one formulation for further evaluation in the expansion phase. In the dose escalation phase, 96 patients were randomized 1:1:1:1 to placebo or one of three oral modified-release formulations of omecamtiv mecarbil in two cohorts (25 mg twice daily or 50 mg twice daily). Each patient cohort was followed for 35 days.
The expansion phase evaluated 448 chronic heart failure patients with reduced ejection fraction who were dosed with the selected oral formulation of omecamtiv mecarbil for 20 weeks and followed for a total of 24 weeks. Patients were randomized 1:1:1 to receive either placebo or treatment with omecamtiv mecarbil 25 mg twice daily or 25 mg with dose escalation to 50 mg twice daily, depending on plasma concentrations of omecamtiv mecarbil after two weeks of treatment. The pharmacokinetic-based dose titration strategy was designed to maintain patient exposure to omecamtiv mecarbil in a targeted plasma concentration range; approximately 53 percent of patients in the dose titration group were escalated to a dose of 50 mg twice daily.
The primary endpoints for the expansion phase were to assess the maximum and pre-dose plasma concentration of omecamtiv mecarbil. The secondary endpoints were to assess changes from baseline in systolic ejection time, stroke volume, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, heart rate and NT-proBNP (a biomarker associated with the severity of heart failure) at week 20, as well as the safety and tolerability of omecamtiv mecarbil including incidence of adverse events from baseline to week 24.
COSMIC-HF was not designed to assess the impact of omecamtiv mecarbil on cardiovascular outcomes in heart failure patients. (NCT01786512)
Latest
news:
- • On November 30, 2016, Amgen and Cytokinetics announced The Lancet published results from a Phase 2 clinical trial evaluating omecamtiv mecarbil in patients with chronic heart failure. The COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure) trial met its primary pharmacokinetic objective and showed statistically significant improvements in all pre-specified secondary measures of cardiac function in the treatment group receiving pharmacokinetic-based dose titration. The results were initially presented as a Late-Breaking Clinical Trial at the American Heart Association (AHA) Scientific Sessions 2015.
- The trial, which evaluated 448 patients with chronic heart failure and left ventricular systolic dysfunction, showed that dose titration controlled patient exposure to omecamtiv mecarbil. Patients were randomized 1:1:1 to receive either placebo or treatment with omecamtiv mecarbil dosed as 25 mg twice daily or 25 mg with dose escalation to 50 mg twice daily, depending on plasma concentrations of omecamtiv mecarbil after two weeks of treatment.
- The pharmacokinetic-based dose titration strategy was designed to maintain patient exposure to omecamtiv mecarbil in the targeted plasma concentration range. Approximately 53 percent of patients in the dose titration group were escalated to a dose of 50 mg twice daily.
- Following 20 weeks of treatment, statistically significant improvements were observed in all pre-specified secondary endpoint measures of cardiac function in the dose titration group, compared to placebo. Systolic ejection time increased by 25.0 msec (p<0.0001), stroke volume increased by 3.6 mL (p=0.0217) and heart rate decreased by 3.0 beats per min (p=0.0070). Left ventricular end-systolic and end-diastolic dimensions decreased by 1.8 mm (p=0.0027) and 1.3 mm (p=0.0128), respectively, and were associated with statistically significant reductions in left ventricular end-systolic and end-diastolic volumes. N-terminal pro-brain natriuretic peptide (NT-proBNP) decreased by 970 pg/mL (p=0.0069). In pre-specified exploratory analyses of the dose titration group, placebo-corrected reductions in NT-proBNP persisted four weeks after stopping omecamtiv mecarbil, decreasing further to 1,306 pg/mL (p=0.0006). The data also showed increases in fractional shortening at week 20 compared to placebo in the dose titration group.
- Adverse events (AEs), including serious AEs, in patients on omecamtiv mecarbil were comparable to placebo. The incidence of adjudicated deaths (3 percent died on placebo, 1 percent died on omecamtiv mecarbil 25 mg twice daily, 2 percent died on omecamtiv mecarbil dose titration), myocardial infarction (1 percent on placebo, 0 percent on omecamtiv mecarbil 25 mg twice daily, 1 percent on omecamtiv mecarbil dose titration) and unstable angina (0 percent on placebo, 1 percent on omecamtiv mecarbil 25 mg twice daily, 0 percent on omecamtiv mecarbil dose titration) was similar. Other cardiac AEs were generally balanced between placebo and active treatment groups. In patients receiving omecamtiv mecarbil compared to placebo, cardiac troponin increased by 0.001 ng/mL and 0.006 ng/mL (median change from baseline at week 20) in the 25 mg twice daily group and dose titration group, respectively. Events of increased troponin (n=278 across all treatment groups) were independently adjudicated and none were adjudicated as an episode of myocardial ischemia or infarction.
Is
general: Yes
