Cytokinetics Announces Results from Dose Escalation Phase of COSMIC-HF Presented at Heart Failure 2017
“The dose escalation phase of COSMIC-HF supported the selection of the optimal formulation of omecamtiv mecarbil based on low peak-to-trough variability in plasma concentration, as well as the implementation of the PK-based dose titration strategy that was employed in the expansion phase of COSMIC-HF recently published in The Lancet,” said Fady I. Malik, MD, PhD, Cytokinetics’ Executive Vice President, Research and Development. “This same formulation is now being used in the ongoing Phase 3 cardiovascular clinical outcomes trial, GALACTIC-HF.”
COSMIC-HF: Dose Escalation Phase Design and Results
COSMIC-HF was conducted in two phases, a dose escalation phase followed by the previously reported dose expansion phase. The dose escalation phase was a randomized, placebo-controlled, multicenter, sequential cohort design. The purpose of the dose escalation phase was to select an oral, modified-release formulation to advance into the dose expansion phase. Approximately 40 patients were randomized 1:1:1:1 to receive placebo or 1 of 3 oral formulations twice daily (BID) (M-F1, M-F2, and SCT-F2) for 7 days in each of two cohorts (25 mg BID Cohort 1; 50 mg BID Cohort 2).
The pharmacokinetics (PK) of the 3 formulations were characterized following the first dose and after 7 days of twice daily dosing. The PK of the three formulations were similar; however, the maximum plasma concentration (Cmax) and exposure over 12 hours (area under the curve or AUC12h) of M-F1 had the lowest coefficient of variability (CV), 23% and 21% respectively, at the 50 mg BID dose compared to the two other formulations. Additionally, the peak to trough fluctuation of this formulation was the lowest (1.14±0.12) as calculated from the ratio of the Cmax measured after dosing to the plasma concentration just prior to dosing (Cmax/Cpredose) at 50 mg BID. The terminal half-life was 24.6±8.7 h (25 mg BID) and 28.6±7.4 h (50 mg BID). Excessive concentrations of omecamtiv mecarbil occurred in one patient taking 50 mg of M-F1 on day 7 (Cmax = 1320 ng/mL) compared with the other subjects (n=9, Cmax: 349 to 654 ng/mL), which was associated with myocardial infarction characterized by symptoms of chest pain and an increased troponin.
Overall, the dose escalation phase and the outlier informed the selection of the MF-1 formulation that was used in the expansion phase of COSMIC-HF and the implementation of PK-guided dose titration to further optimize plasma concentrations of omecamtiv mecarbil in patients with heart failure.
About Heart Failure
Heart failure is a grievous condition that affects more than 23 million people worldwide, about half of whom have reduced left ventricular function. It is the leading cause of hospitalization and readmission in people age 65 and older. Despite broad use of standard treatments and advances in care, the prognosis for patients with heart failure is poor. An estimated one in five people over the age of 40 are at risk of developing heart failure, and approximately 50 percent of people diagnosed with heart failure will die within five years of initial hospitalization.
About Omecamtiv Mecarbil
Omecamtiv mecarbil is a novel cardiac myosin activator. Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into the mechanical force resulting in cardiac contraction. 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
Cytokinetics is a late-stage biopharmaceutical company focused on discovering, developing and commercializing first-in-class muscle activators as potential treatments for debilitating diseases in which muscle performance is compromised and/or declining. As a leader in muscle biology and the mechanics of muscle performance, the company is developing small molecule drug candidates specifically engineered to increase muscle function and contractility. Cytokinetics’ lead drug candidate is tirasemtiv, a fast skeletal troponin activator (FSTA). Tirasemtiv is the subject of VITALITY-ALS, an international Phase 3 clinical trial in patients with ALS. Tirasemtiv has been granted orphan drug designation and fast track status by the U.S. Food and Drug Administration and orphan medicinal product designation by the European Medicines Agency. Cytokinetics is preparing for the potential commercialization of tirasemtiv in North America and Europe and has granted an option to Astellas for development and commercialization in other countries. Cytokinetics is collaborating with Astellas to develop CK-2127107, a next-generation fast skeletal muscle activator. CK-2127107 is the subject of two ongoing Phase 2 clinical trials enrolling patients with spinal muscular atrophy and chronic obstructive pulmonary disease. Cytokinetics is collaborating with Amgen Inc. to develop omecamtiv mecarbil, a novel cardiac muscle activator. Omecamtiv mecarbil is the subject of GALACTIC-HF, an international Phase 3 clinical trial in patients with heart failure. Amgen holds an exclusive worldwide license to develop and commercialize omecamtiv mecarbil with a sublicense held by Servier for commercialization in Europe and certain other countries. Astellas holds an exclusive worldwide license to develop and commercialize CK-2127107. Licenses held by Amgen and Astellas are subject to Cytokinetics' specified co-development and co-commercialization rights. For additional information about Cytokinetics, visit http://www.cytokinetics.com/.
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Cytokinetics Diane WeiserVice President, Corporate Communications, Investor Relations (650) 624-3060