Cytokinetics, Inc. (CYTK): Cytokinetics: Clinical Investigators’ Opinions On …
Pending the results of the ongoing COSMIC-HF trial in 1H, 2014, I believe that the ATOMIC-AHF results support moving omecamtiv mecarbil into Phase III. With success in the Phase III, omecamtiv mecarbil would likely be a several billion drug. I regard …http://seekingalpha.com/article/1672892-cytokinetics-clinical-investigators-opinions-on-atomic-ahf-trial-results?source=google_news
Omecamtiv mecarbil (INN), previously codenamed CK-1827452, is a cardiac specific myosin activator. It is clinically tested for its role in the treatment of left ventricular systolic heart failure. Systolic heart failure is characterised as a decreased cardiac output (<40% ejection fraction), due to decreased stroke volume, resulting in the inability to meet the metabolic demands of the body. The loss of contraction is caused by a reduced number of effective actin-myosin cross bridges in the left ventricular myocytes. One possible underlying mechanism is altered signal transduction that interferes with excitation-contraction coupling. A decreased cardiac output causes peripheral hypotension and activation of the sympathetic nervous system. This in turn stimulates the cardiac myocytes excessively, eventually leading to left ventricular hypertrophy, characteristic of chronic heart failure. Some symptoms of systolic heart failure are fatigue, peripheral oedema, dyspnoea, exercise intolerance and breathlessness. Current inotropic drug therapies such as dobutamine, are palliative and not a cure. They also cause many adverse effects including arrhythmias related to increased myocardical oxygen consumption, desensitization of adrenergic receptors and altering intracellular calcium levels. Thus systolic heart failure is considered malignant, however the novel mechanism of Omecamtiv Mecarbil is a hopeful long-term resolution.
Mechanism of action
Cardiac myocytes contract through a cross-bridge cycle between the myofilaments, actin and myosin. Chemical energy in the form of ATP is converted into mechanical energy which allows myosin to strongly bind to actin and produce a power stroke resulting in sarcomere shortening/contraction. Omecamtiv Mecarbil specifically targets and activates myocardial ATPase and improves energy utilization. This enhances effective myosin cross-bridge formation and duration, while the velocity of contraction remains the same. It also increases the rate of phosphate release from myosin, thereby accelerating the rate-determining step of the cross-bridge cycle, which is the transition of the actin-myosin complex from the weakly bound to the strongly bound state. The overall result of Omecamtiv Mecarbil is an increase in left ventricular systolic ejection time, sarcomere shortening and stroke volume, while the systolic pressure remains the same. This causes a decrease in heart rate while myocardial oxygen consumption is unaffected. The increased cardiac output is independent of intracellular calcium and cAMP levels. Thus Omecamtiv Mecarbil improves systolic function by increasing the systolic ejection duration/stroke volume, without consuming more ATP energy, oxygen or altering intracellular calcium levels causing an overall improvement in cardiac efficiency.
Experimental studies on rats and dogs, proved the efficacy and mechanism of action of Omecamtiv Mecarbil. Current clinical studies on humans have shown there is a direct linear relationship between dose and systolic ejection time. The dose-dependent effects persisted throughout the entire trial, suggesting that desensitization does not occur. The maximum tolerated dose was observed to be an infusion of 0.5 mg/kg/h. Adverse effects, such as ischemia, were only seen at doses beyond this level, due to extreme lengthening of systolic ejection time. Thus due to the unique cardiac myosin activation mechanism, Omecamtiv Mecarbil could safely improve cardiac function within tolerated doses. Omecamtiv Mecarbil effectively relieves symptoms and enhances the quality of life of systolic heart failure patients. It drastically improves cardiac performance in the short term, however the hopeful long term effects of reduced mortality have yet to be studied.
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- ^ a b Bers, DM (Jan 2002). “Cardiac excitation-contraction coupling”. Nature 415 (6868): 198–205. doi:10.1038/415198a. PMID 11805843.
- ^ a b c Shen YT, Malik FI, Zhao X, Depre C, Dhar SK, Abarzúa P, Morgans DJ, Vatner SF (Jul 2010). “Improvement of cardiac function by a cardiac myosin activator in conscious dogs with systolic heart failure”. Circ Heart Fail 3 (4): 522–7. doi:10.1161/CIRCHEARTFAILURE.109.930321. PMID 20498236.
- ^ a b c Malik F, Teerlink J, Escandon R, Clake C, Wolff A (2006). “The Selective Cardiac Myosin Activator, CK-1827452, a Calcium-Independent Inotrope, Increases Left Ventricular Systolic Function by Increasing Ejection Time Rather than the Velocity of Contraction”. Circulation 114 (18 Suppl): 441.
- ^ Cleland JG, Teerlink JR, Senior R, Nifontov EM, Mc Murray JJ, Lang CC, Tsyrlin VA, Greenberg BH, Mayet J, Francis DP, Shaburishvili T, Monaghan M, Saltzberg M, Neyses L, Wasserman SM, Lee JH, Saikali KG, Clarke CP, Goldman JH, Wolff AA, Malik FI (Aug 2011). “The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial”. Lancet 378 (9792): 676–83. doi:10.1016/S0140-6736(11)61126-4. PMID 21856481.