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|Subject: PDLI Ularitide's Competition||Date: 9/16/2006 6:12 PM|
|Author: drPraveen||Number: 6 of 7|
Cytokinetics Announces Presentation of Phase I Clinical Trial Data for CK-1827452 During Recent and Late Breaking Trials Session at the 2006 Heart Failure Society of America Annual Meeting
Wednesday September 13, 12:42 pm ET
Novel Cardiac Myosin Activator Demonstrates Dose-Dependent Increases in Indices of Cardiac Function
Investor Luncheon and Teleconference Today to Discuss Clinical Results
SOUTH SAN FRANCISCO, Calif., Sept. 13 /PRNewswire-FirstCall/ -- Cytokinetics, Incorporated (Nasdaq: CYTK - News) announced positive data today from a first-in-humans Phase I clinical trial evaluating CK-1827452, a novel cardiac myosin activator, administered intravenously. Data from this double-blind, randomized, placebo-controlled, dose-escalation Phase I clinical trial of CK-1827452 were presented at a session entitled "Recent and Late Breaking Trials" at the 10th Annual Meeting of the Heart Failure Society of America in Seattle, Washington. The presentation was made by John R. Teerlink, M.D., F.A.C.C., F.A.H.A., F.E.S.C., Associate Professor of Medicine at the University of California, San Francisco, and Director of the Heart Failure Clinic, Veterans Affairs Medical Center, San Francisco. Dr. Teerlink was a Co-Principal Investigator and responsible for echocardiographic analysis for the Phase I clinical trial. This clinical trial was conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamic profile of a six-hour infusion of CK-1827452 in healthy volunteers.
In this Phase I clinical trial, the maximum tolerated dose (MTD) was determined to be 0.5 mg/kg/hr for the six-hour infusion in healthy volunteers. At this dose, the six-hour infusion of CK-1827452 produced a mean increase in left ventricular ejection fraction of 6.8 absolute percentage points as compared to placebo (p<0.0001). At the same dose, CK-1827452 also produced a mean increase in fractional shortening of 9.2 absolute percentage points versus placebo (p<0.0001). These increases in indices of left ventricular function were associated with an 84 milliseconds mean prolongation of systolic ejection time (p<.0.0001). These mean changes in ejection fraction, fractional shortening and ejection time were dose-proportional across the range of doses evaluated in this clinical trial. In addition, CK-1827452 exhibited linear, dose-proportional pharmacokinetics across the range of doses studied.
At the MTD of 0.5 mg/kg/hr for 6 hours and below, CK-1827452 was well-tolerated when compared to placebo. In addition, CK-1827452 was clinically well tolerated at 0.625 mg/kg/hr for six hours but too few volunteers received this dose to define it as the MTD. At the end of the six-hour infusion at the MTD, mean standing systolic blood pressure fell 13.0 mmHg (p<0.0001) and mean supine systolic blood pressure fell 7.4 mmHg (p<0.05) versus placebo. At doses up to and through the MTD, there were no dose-related changes versus placebo in the electrocardiographic PR, QT or corrected QT intervals. Up to and including the MTD, there was no dose-related increase in the overall incidence of adverse events.
At doses above the MTD that were not tolerated, the CK-1827452 infusions were terminated early due to symptoms of chest tightness, light-headedness, palpitations and feeling hot in both subjects treated at 1.0 mg/kg/hr and in one of two subjects treated at 0.75 mg/kg/hr. In these subjects, signs of intolerability included tachycardia (~150 bpm) and electrocardiographic changes. In one volunteer dosed at 1.0 mg/kg/hr, slight, transient increases in the cardiac-specific proteins troponin I & T were observed, but the cardiac-specific fraction of the enzyme creatine kinase remained normal. Subsequent electrocardiograms and echocardiograms returned to normal in this subject, and cardiac magnetic resonance imaging enhanced by gadolinium, a sensitive test for myocardial injury, detected no cardiac abnormality. These effects are believed to be related to an excess of the intended pharmacologic effect, resulting in excessive prolongation of the systolic ejection time, and resolved promptly with discontinuation of the infusions of CK-1827452.
"I was very pleased to share these data today with the heart failure treatment community. I believe these data are encouraging for heart failure patients currently underserved by available treatment options," stated Dr. John Teerlink. "These Phase I data support the further evaluation of CK-1827452 as a potential novel approach to address limitations of existing treatments for heart failure."
The Phase I clinical trial activity of CK-1827452 presented today is consistent with results from preclinical models that evaluated CK-1827452 in both normal dogs and dogs with heart failure. In these models, underlying the increases in cardiac function (as determined by dose-dependent increases in fractional shortening) were dose-related increases in the systolic ejection time, which have now also been observed in humans. In a preclinical study evaluating the effects of CK-1827452 in both normal dogs and dogs with heart failure (also presented at this meeting), CK-1827452, at the same dose, produced statistically significantly larger percent increases in stroke volume and cardiac output in dogs with heart failure compared to normal dogs (11% vs. 28% and 2% vs. 13%, respectively, p < 0.05). Furthermore, when administered to dogs with heart failure as a 0.25 mg/kg bolus followed by a 72-hour infusion at 0.25 mg/kg/hr, CK-1827452 increased fractional shortening (42%), stroke volume (45%) and cardiac output (32%) without increasing myocardial oxygen consumption.
"We are pleased with the results of this clinical trial. These data track closely with data from our preclinical testing of CK-1827452 and provide useful validation for the underlying therapeutic hypothesis for this novel form of inotropic therapy," stated Andrew A. Wolff, M.D., F.A.C.C., Cytokinetics' Senior Vice President of Clinical Research and Development and Chief Medical Officer. "We look forward to initiating a series of Phase II clinical trials to further evaluate the effects of CK-1827452 in various subpopulations of heart failure patients to inform potential registration studies."
In addition, Cytokinetics presented three posters relating to non-clinical data arising from its cardiovascular program. Two posters entitled, "In Vitro and In Vivo Characterization of CK-1827452, a Selective Cardiac Myosin Activator," presented by Kathleen A. Elias, Ph.D., Cytokinetics and "Activating Cardiac Myosin, a Novel Inotropic Mechanism to Improve Cardiac Function in Conscious Dogs with Congestive Heart Failure," presented by You-Tang Shen, M.D., Department of Cell Biology and Molecular Medicine and Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, provide supporting data on the preclinical profile of CK-1827452. The first poster contained data demonstrating that CK-1827452, consistent with its mechanism of action, increases contractility in myocytes without increasing calcium and significantly increases cardiac fractional shortening in normal rats, normal dogs and rats with heart failure. The second poster demonstrated that CK-1827452 increased stroke volume and left ventricular fractional shortening in normal dogs and increased cardiac output, stroke volume and left ventricular fractional shortening in dogs with heart failure. In association with the improvement of left ventricular systolic performance, left ventricular filling pressures, heart rate and total peripheral resistance decreased in the dogs with heart failure. In addition, a third poster entitled, "Cardiac Myosin Activator, CK-1316719, Increases Myofibril ATPase Activity and Myocyte Contractility in a Rat Model of Heart Failure," presented by Robert L. Anderson, Cytokinetics, provided data further validating the mechanism of another one of Cytokinetics' cardiac myosin activators.
"We are excited about the totality of both clinical and preclinical data presented this week at the Heart Failure Society of America," added James Sabry, M.D., Ph.D., Cytokinetics' CEO. "Our company is pleased to share these promising results with the scientific and medical communities further underscoring the value of our commitment to novel cytoskeletal drug discovery and development with potential benefit to patients in need."
Investor Luncheon and Presentation Today
Cytokinetics senior management will host an investor luncheon from 12:00 p.m. to 2:00 p.m. PT today in the Menzies Room at the Grand Hyatt Seattle, 721 Pine Street, Seattle, Washington to discuss the results of the Phase I clinical trial of CK-1827452. At the luncheon, a panel of speakers will discuss preclinical and Phase I clinical trial data with CK-1827452 and provide commentary on CK-1827452 and trends in the treatment of heart failure. The panel will include Fady Malik, M.D., Ph.D., F.A.C.C., Director of Cardiovascular Programs at Cytokinetics, Barry Massie, M.D., F.A.C.C., Professor of Medicine at the University of California, San Francisco and Chief of Cardiology at the Veterans Affairs Medical Center in San Francisco, John R. Teerlink, M.D., F.A.C.C., F.A.H.A., F.E.S.C., Associate Professor of Medicine at the University of California, San Francisco and the Director of the Heart Failure Clinic at the Veterans Affairs Medical Center, San Francisco, and Andrew A. Wolff, M.D., F.A.C.C., Senior Vice President of Clinical Research and Development and the Chief Medical Officer at Cytokinetics. The panel presentation and discussion will be simultaneously webcast beginning at 12:30 p.m. PT and can be accessed in the Investor Relations section of Cytokinetics' website at www.cytokinetics.com . The live audio of the forum is also accessible via telephone to investors, members of the news media and the general public by dialing either (866) 578-5771 (United States and Canada) or (617) 213-8055 (International) and typing in the passcode 82325202.
An archived replay of the webcast will be available via Cytokinetics' website until September 27, 2006. The replay will also be available via telephone from September 13, 2006 at 2:30 p.m. PT until September 27, 2006 by dialing (888) 286-8010 (United States and Canada) or (617) 801-6888 (International) and typing in the passcode 56551325.
Development Status of CK-1827452
A Phase I, first-in-humans clinical trial designed to evaluate CK-1827452, a novel, small-molecule, direct activator of cardiac myosin, was completed with an intravenous formulation in healthy volunteers. In this Phase I clinical trial, the maximum tolerated dose (MTD) was determined to be 0.5 mg/kg/hr for the six-hour infusion in healthy volunteers. At this dose, the six-hour infusion of CK-1827452 produced a statistically significant and clinically relevant increase in ejection fraction and fractional shortening, as measured from baseline to the end of the infusion, in comparison to placebo; these clinically relevant increases in cardiac function were associated with a statistically significant prolongation of systolic ejection time. At the MTD, CK-1827452 was well-tolerated when compared to placebo. Across the dosing levels evaluated in this clinical trial, infusions of CK-1827452 were characterized by linear, dose-proportional pharmacokinetics.
The clinical activity of CK-1827452 in the Phase I clinical trial was consistent with results from preclinical models which evaluated this drug candidate in both normal dogs and dogs with heart failure. In these preclinical models, underlying the increase in ejection fraction and fractional shortening was a dose-related increase in the systolic ejection time, which has now also been observed in humans. Data from a dog model of heart failure demonstrated that CK-1827452 increased cardiac contractility and cardiac output without increasing myocardial oxygen consumption. Preclinical studies have also demonstrated more pronounced effects of CK-1827452 on indices of cardiac function in dogs with heart failure compared to effects achieved in normal dogs.
Cytokinetics initiated a Phase I clinical trial to evaluate the pharmacokinetic profile of CK-1827452, when administered orally, in August of 2006 and expects that CK-1827452 will be entering an international Phase II clinical trials program in patients with heart failure in the second half of 2006. This program is planned to evaluate CK-1827452 in a diversity of patients including those with stable heart failure, inducible ischemia, impaired renal function and acute heart failure. This program is designed to test the safety and efficacy of CK-1827452, in both intravenous and oral formulations, for the potential treatment of heart failure across the continuum of care, both in the hospital and the outpatient settings.
Background on the Heart Failure Market
Heart failure is a widespread and debilitating syndrome affecting approximately five million people in the United States alone. The high and rapidly growing prevalence of heart failure translates into significant hospitalization rates and associated societal costs. The number of hospital discharges in the United States identified with a primary diagnosis of heart failure rose from 550,000 in 1989 to over 1 million in 2003. Heart failure is one of the most common primary discharge diagnoses identified in hospitalized patients over the age of 65 in the United States. The annual costs of heart failure in the United States are estimated to be $29.6 billion, including $19.3 billion for inpatient care. According to industry reports, the U.S. market for heart failure drugs was approximately $1.33 billion in 2004. Despite currently available therapies, readmission rates for patients over the age of 65 remain high at 30 to 40 percent within six months of hospital discharge and mortality rates exceed 50% over the five year period following a diagnosis of acute heart failure. The limited effectiveness of current therapies points to the need for next-generation therapeutics that may offer improved efficacy without increased adverse events.
Background on Cardiac Myosin Activators and Cardiac Contractility
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 contractility is driven by the cardiac sarcomere, a highly ordered cytoskeletal structure composed of cardiac myosin, actin and a set of regulatory proteins, and is the fundamental unit of muscle contraction in the heart. The sarcomere represents one of the most thoroughly characterized protein machines in human biology. Cytokinetics' cardiovascular program is focused towards the discovery and development of small molecule cardiac myosin activators in order to create next-generation treatments to manage acute and chronic heart failure. Cytokinetics' program is based on the hypothesis that activators of cardiac myosin may address certain mechanistic liabilities of existing positive inotropic agents by increasing cardiac contractility without increasing intracellular calcium, which may be associated with adverse clinical effects in heart failure patients. Current inotropic agents, such as beta-adrenergic receptor agonists or inhibitors of phosphodiesterase activity, increase cardiac cell contractility by increasing the concentration of intracellular calcium, which indirectly activates cardiac myosin; this effect on calcium levels, however, also has been linked to potentially life-threatening side effects. The inotropic mechanism of current drugs also increases the velocity of cardiac contractility and shortens systolic ejection time. In contrast, cardiac myosin activators have been shown to work in the absence of changes in intracellular calcium by a novel mechanism that directly stimulates the activity of the cardiac myosin motor protein. Cardiac myosin activators accelerate the rate-limiting step of the myosin enzymatic cycle and shift the enzymatic cycle in favor of the force producing state. This calcium-independent inotropic mechanism results not in an increase in the velocity of cardiac contraction, but instead, in a lengthening of the systolic ejection time, which results in increased cardiac contractility and cardiac output in a potentially more oxygen-efficient manner.
My Thoughts on the Results:
Basically the CYTK P1 IV results are very good and dose responsive. The fractional shortening and the improvement in ejection fraction seen are clinically significant. Safety profile appears to be good at 0.5mg/Kg dose.No QTc prolongation.The findings are similar to the ones seen in dog studies. It is definetely a competitor to PDLI's Ularitide. btw PDLI is looking to outlicense Ularitide in early 2007. But Heart failure is a big space of approx 5M and about half of these pts are expected to do well on drugs.
I am more interested in the CYTK 452 Oral version so they can start the acute decompensated heart failure pts on IV in the ER and send them home on oral.The serum half life is found to be 20 hrs which is favourable for an oral version. So have to see how the oral version goes.
As you know the MOA's are different and CYTK is a selective activator of the cardiac sarcomere by directly activating cardiac myosin whereas Ularitide is a recombinant form of the natriuretic peptide urodilantin. CYTK mechanism is very unique as it lengthens the duration of cardiac contraction(increases systolic ejection time) rather than the rate and doesn't increase the intracellular calcium which other inotropics do. There was no apparent desensitization seen on chronic dosing and the beneficial effects were sustained. Finally it comes to the improvement in patients mortality and morbidity which we will see later.
About PDLI's Ularitide:
cardiac natriuretic peptides:
Cardiac natriuretic peptides (including ANP, BNP, CNP and urodilatin) constitute a family of peptide hormones and neurotransmitters, sharing similar chemical structure (characterized by a cysteine bridge) and biological function. ANP and BNP are cardiac hormones because they are principally produced and secreted by cardiomyocytes. CNP is principally produced and secreted by endothelial cells, while urodilatin only by renal tubular cells. Natriuretic peptides share a direct diuretic, natriuretic and vasodilator effect and an inhibitory action on ventricular myocyte contraction as well as on remodeling, restenosis and other inflammatory processes of myocardium and smooth muscle cells. Cardiac natriuretic peptides share their biological action by means of specific receptors (NPR), which are present into the cell membranes of target tissues. Three different subtypes of NPRs have been so far identified in mammalian tissues. NPR-A and NPR-B are generally considered to mediate all known biological actions throughout the guanylate cyclase (GC) intracellular domain, while the third member of the natriuretic peptide receptor family, the NPR-C receptor, has not a GC domain. It is generally thought that the NPR-C is not linked to GC and so serves as a clearance receptor. Natriuretic peptides constitute a family sharing both endocrine. paracrine and autocrine actions and neurotransmitter and immuno-modulator functions. Therefore, it can be hypothesized that the cardiac natriuretic peptide system is closely related with other regulatory systems in a biological hierarchical networks.
Effects of the renal natriuretic peptide urodilatin (ularitide) in patients with decompensated chronic heart failure: a double-blind, placebo-controlled, ascending-dose trial.
• Mitrovic V,
• Luss H,
• Nitsche K,
• Forssmann K,
• Maronde E,
• Fricke K,
• Forssmann WG,
• Meyer M.
Kerckhoff-Klinik, Bad Nauheim, Germany.
BACKGROUND: Urodilatin (ularitide), a natriuretic peptide, is produced within the kidneys. The aim of this study was to define the role of 24-hour intravenous infusions of urodilatin in the treatment of decompensated chronic heart failure (DHF). METHODS: In this randomized, double-blind, ascending-dose safety study, 24 patients with DHF (cardiac index 1.91 +/- 0.34 L/min per square meter, pulmonary capillary wedge pressure 26 +/- 6 mm Hg, right atrial pressure 11 +/- 4 mm Hg) received urodilatin (7.5, 15, or 30 ng/(kg.min)) or placebo infusions over 24 hours. RESULTS: Compared with baseline, urodilatin decreased pulmonary capillary wedge pressure by 10 mm Hg in the 15 ng/(kg.min) group (P < .05) and by 15 mm Hg in the 30 ng/(kg.min) group (P < .05) at 6 hours. In the same dose groups, right atrial pressure decreased, and dyspnea as reported by patients tended to improve. At 24 hours, 15 and 30 ng/(kg.min) urodilatin infusions decreased N-terminal-pro-brain natriuretic peptide levels by 40% and 45%, respectively, compared with baseline. Between 1 to 12 hours, plasma cyclic guanosine monophosphate levels at 15 and 30 ng/(kg.min) urodilatin were significantly higher than both placebo and the respective baseline after infusion start (P < .05 and .01). Among the different groups, there was no obvious difference regarding total number of patients with adverse events and total number of adverse events. During infusion, 3 transient asymptomatic hypotensions occurred in the urodilatin groups. CONCLUSIONS: Our findings show that urodilatin may be a new agent for the therapy for DHF.
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