Preclinical Studies Demonstrate Distinct Binding Site for Next-Generation Cardiac Myosin Inhibitor
SOUTH SAN FRANCISCO, CA, USA I February 20, 2020 I Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that preclinical data related to CK-3773274 (CK-274) were presented at the Biophysical Society 64th Annual Meeting in San Diego, CA elaborating on its mechanism of action and properties to modulate cardiac contractility in vitro and in vivo. CK-274 is a next-generation cardiac myosin inhibitor discovered by company scientists, in development for the potential treatment of hypertrophic cardiomyopathy (HCM).
“These data further characterize how CK-274 decreases cardiac contractility in vitro and in vivo, and provide evidence for a distinct and selective mechanistic binding site for CK-274 on cardiac myosin,” said Brad Morgan, Ph.D., Cytokinetics’ Senior Vice President, Research and Non-Clinical Development. “We are pleased to contribute these preclinical data supporting translation of cardiac myosin inhibition as a novel approach to the potential treatment of diseases associated with hypercontractility as we conduct REDWOOD-HCM, the Phase 2 clinical trial of CK-274 in patients with obstructive hypertrophic cardiomyopathy.”
Preclinical Research Data Presented at Biophysical Society Annual Meeting
Previous in vitro and in vivo studies have shown that CK-274 reduced cardiac contractility and reduced fractional shortening (a measure of cardiac function) in a dose and concentration dependent manner. New data presented at the Biophysical Society Annual Meeting demonstrate that CK-274 reduces cardiac myosin activity in vitro, and importantly it does not inhibit the actin-activated ATPase activity of smooth muscle myosin, supportive of its selectivity for cardiac myosin. Transient kinetic studies also show that CK-274 slows the rate of actin-activated phosphate release, without affecting ATP binding and hydrolysis, consistent with a mechanism that stabilizes myosin in weak actin-binding conformations. Additionally, the binding of CK-274 to cardiac myosin is shown to be mutually exclusive with the non-selective myosin inhibitor blebbistatin, thus suggesting they bind to the same or overlapping locations on cardiac myosin, but distinctly from one another given the differences in their selectivity for cardiac myosin. In contrast, the binding of blebbistatin and mavacamten, a cardiac myosin inhibitor, are not mutually exclusive, indicating CK-274 and mavacamten have distinct binding sites on cardiac myosin. These data characterize how CK-274 reduces cardiac contractility and demonstrate that cardiac myosin inhibition may address the underlying hypercontractility of the sarcomere in hypertrophic cardiomyopathies.
About CK-274
CK-274 is a novel, oral, small molecule cardiac myosin inhibitor that company scientists discovered independent of its collaborations. CK-274 arose from an extensive chemical optimization program conducted with careful attention to therapeutic index and pharmacokinetic properties that may translate into next-in-class potential in clinical development. CK-274 was designed to reduce the hypercontractility that is associated with hypertrophic cardiomyopathy (HCM). In preclinical models, CK-274 reduces myocardial contractility by binding directly to cardiac myosin at a distinct and selective allosteric binding site, thereby preventing myosin from entering a force producing state. CK-274 reduces the number of active actin-myosin cross bridges during each cardiac cycle and consequently reduces myocardial contractility. This mechanism of action may be therapeutically effective in conditions characterized by excessive hypercontractility, such as HCM.
In preclinical models of cardiac function, both in normal models of cardiac function and mouse models of HCM, CK-274 reduced cardiac contractility in a predictable dose and exposure dependent fashion. The preclinical pharmacokinetics of CK-274 were characterized, evaluated and optimized for potential ease-of-use in the clinical setting. A Phase 1 study demonstrated that CK-274 was safe and well tolerated in healthy participants. The pharmacokinetics of CK-274 were generally dose linear, and steady-state appeared evident within 14 days of dosing. Left ventricular ejection fraction decreased in an exposure dependent manner and the PK/PD relationship for CK-274 observed in humans was similar to that observed preclinically when adjusted for differences in protein binding. Specifically, the shallow exposure-response relationship observed preclinically appears to translate to humans and may enable flexible dose optimization in humans.
The overall development program will assess the potential of CK‑274 to improve exercise capacity and relieve symptoms in patients with hyperdynamic ventricular contraction due to HCM.
About Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder in which the heart muscle (myocardium) becomes abnormally thick (hypertrophied). The thickening of cardiac muscle leads to the inside of the left ventricle becoming smaller and stiffer, and thus the ventricle becomes less able to relax and fill with blood. In the majority of patients, thickening of the heart muscle in the left ventricular outflow tract obstructs the flow of blood out of the heart. This ultimately limits the heart’s pumping function, resulting in symptoms including chest pain, dizziness, shortness of breath, or fainting during physical activity. A subset of patients with HCM are at high risk of progressive disease which can lead to ventricular arrhythmias, atrial fibrillation, stroke, heart failure and sudden cardiac death. There are no current medical treatments that directly address the hypercontractility that underlies HCM.
About Cytokinetics
Cytokinetics is a late-stage biopharmaceutical company focused on discovering, developing and commercializing first-in-class muscle activators and next-in-class muscle inhibitors 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 impact muscle function and contractility. Cytokinetics is collaborating with Amgen Inc. (Amgen) to develop omecamtiv mecarbil, a novel cardiac muscle activator. Omecamtiv mecarbil is the subject of an international clinical trials program in patients with heart failure including GALACTIC-HF and METEORIC-HF. 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. Cytokinetics is collaborating with Astellas Pharma Inc. (Astellas) to develop reldesemtiv, a fast skeletal muscle troponin activator (FSTA). Astellas currently holds an exclusive worldwide license to develop and commercialize reldesemtiv. Licenses held by Amgen and Astellas are subject to specified co-development and co-commercialization rights of Cytokinetics. Cytokinetics is also developing CK-274, a novel cardiac myosin inhibitor that company scientists discovered independent of its collaborations, for the potential treatment of hypertrophic cardiomyopathies. Cytokinetics continues its over 20-year history of pioneering innovation in muscle biology and related pharmacology focused to diseases of muscle dysfunction and conditions of muscle weakness.
SOURCE: Cytokinetics
Post Views: 28
Preclinical Studies Demonstrate Distinct Binding Site for Next-Generation Cardiac Myosin Inhibitor
SOUTH SAN FRANCISCO, CA, USA I February 20, 2020 I Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that preclinical data related to CK-3773274 (CK-274) were presented at the Biophysical Society 64th Annual Meeting in San Diego, CA elaborating on its mechanism of action and properties to modulate cardiac contractility in vitro and in vivo. CK-274 is a next-generation cardiac myosin inhibitor discovered by company scientists, in development for the potential treatment of hypertrophic cardiomyopathy (HCM).
“These data further characterize how CK-274 decreases cardiac contractility in vitro and in vivo, and provide evidence for a distinct and selective mechanistic binding site for CK-274 on cardiac myosin,” said Brad Morgan, Ph.D., Cytokinetics’ Senior Vice President, Research and Non-Clinical Development. “We are pleased to contribute these preclinical data supporting translation of cardiac myosin inhibition as a novel approach to the potential treatment of diseases associated with hypercontractility as we conduct REDWOOD-HCM, the Phase 2 clinical trial of CK-274 in patients with obstructive hypertrophic cardiomyopathy.”
Preclinical Research Data Presented at Biophysical Society Annual Meeting
Previous in vitro and in vivo studies have shown that CK-274 reduced cardiac contractility and reduced fractional shortening (a measure of cardiac function) in a dose and concentration dependent manner. New data presented at the Biophysical Society Annual Meeting demonstrate that CK-274 reduces cardiac myosin activity in vitro, and importantly it does not inhibit the actin-activated ATPase activity of smooth muscle myosin, supportive of its selectivity for cardiac myosin. Transient kinetic studies also show that CK-274 slows the rate of actin-activated phosphate release, without affecting ATP binding and hydrolysis, consistent with a mechanism that stabilizes myosin in weak actin-binding conformations. Additionally, the binding of CK-274 to cardiac myosin is shown to be mutually exclusive with the non-selective myosin inhibitor blebbistatin, thus suggesting they bind to the same or overlapping locations on cardiac myosin, but distinctly from one another given the differences in their selectivity for cardiac myosin. In contrast, the binding of blebbistatin and mavacamten, a cardiac myosin inhibitor, are not mutually exclusive, indicating CK-274 and mavacamten have distinct binding sites on cardiac myosin. These data characterize how CK-274 reduces cardiac contractility and demonstrate that cardiac myosin inhibition may address the underlying hypercontractility of the sarcomere in hypertrophic cardiomyopathies.
About CK-274
CK-274 is a novel, oral, small molecule cardiac myosin inhibitor that company scientists discovered independent of its collaborations. CK-274 arose from an extensive chemical optimization program conducted with careful attention to therapeutic index and pharmacokinetic properties that may translate into next-in-class potential in clinical development. CK-274 was designed to reduce the hypercontractility that is associated with hypertrophic cardiomyopathy (HCM). In preclinical models, CK-274 reduces myocardial contractility by binding directly to cardiac myosin at a distinct and selective allosteric binding site, thereby preventing myosin from entering a force producing state. CK-274 reduces the number of active actin-myosin cross bridges during each cardiac cycle and consequently reduces myocardial contractility. This mechanism of action may be therapeutically effective in conditions characterized by excessive hypercontractility, such as HCM.
In preclinical models of cardiac function, both in normal models of cardiac function and mouse models of HCM, CK-274 reduced cardiac contractility in a predictable dose and exposure dependent fashion. The preclinical pharmacokinetics of CK-274 were characterized, evaluated and optimized for potential ease-of-use in the clinical setting. A Phase 1 study demonstrated that CK-274 was safe and well tolerated in healthy participants. The pharmacokinetics of CK-274 were generally dose linear, and steady-state appeared evident within 14 days of dosing. Left ventricular ejection fraction decreased in an exposure dependent manner and the PK/PD relationship for CK-274 observed in humans was similar to that observed preclinically when adjusted for differences in protein binding. Specifically, the shallow exposure-response relationship observed preclinically appears to translate to humans and may enable flexible dose optimization in humans.
The overall development program will assess the potential of CK‑274 to improve exercise capacity and relieve symptoms in patients with hyperdynamic ventricular contraction due to HCM.
About Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder in which the heart muscle (myocardium) becomes abnormally thick (hypertrophied). The thickening of cardiac muscle leads to the inside of the left ventricle becoming smaller and stiffer, and thus the ventricle becomes less able to relax and fill with blood. In the majority of patients, thickening of the heart muscle in the left ventricular outflow tract obstructs the flow of blood out of the heart. This ultimately limits the heart’s pumping function, resulting in symptoms including chest pain, dizziness, shortness of breath, or fainting during physical activity. A subset of patients with HCM are at high risk of progressive disease which can lead to ventricular arrhythmias, atrial fibrillation, stroke, heart failure and sudden cardiac death. There are no current medical treatments that directly address the hypercontractility that underlies HCM.
About Cytokinetics
Cytokinetics is a late-stage biopharmaceutical company focused on discovering, developing and commercializing first-in-class muscle activators and next-in-class muscle inhibitors 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 impact muscle function and contractility. Cytokinetics is collaborating with Amgen Inc. (Amgen) to develop omecamtiv mecarbil, a novel cardiac muscle activator. Omecamtiv mecarbil is the subject of an international clinical trials program in patients with heart failure including GALACTIC-HF and METEORIC-HF. 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. Cytokinetics is collaborating with Astellas Pharma Inc. (Astellas) to develop reldesemtiv, a fast skeletal muscle troponin activator (FSTA). Astellas currently holds an exclusive worldwide license to develop and commercialize reldesemtiv. Licenses held by Amgen and Astellas are subject to specified co-development and co-commercialization rights of Cytokinetics. Cytokinetics is also developing CK-274, a novel cardiac myosin inhibitor that company scientists discovered independent of its collaborations, for the potential treatment of hypertrophic cardiomyopathies. Cytokinetics continues its over 20-year history of pioneering innovation in muscle biology and related pharmacology focused to diseases of muscle dysfunction and conditions of muscle weakness.
SOURCE: Cytokinetics
Post Views: 28
