sorry, I think that I've posted this material before, but I want to post in above material from the CV Therapeutics 10-K.....
GPCR -- Directed Drug Discovery
In August, 1999, OSI purchased certain assets of Cadus Pharmaceuticals
Corporation. In this acquisition, OSI acquired Cadus' drug discovery programs
focused on G-protein coupled receptors or GPCRs. These receptors are one of the
most important families of targets for drug discovery in the pharmaceutical
industry. Approximately, forty percent of the currently marketed pharmaceutical
products target GPCRs. The acquired programs include Cadus' discovery program in
adenosine receptors, an important family of GPCR's. These programs will form the
core of OSI-owned and funded candidate development programs in the coming year.
The improved understanding of the physiology, pharmacology and molecular
biology of adenosine and adenosine receptors in recent years has provided a
solid foundation for active research and development in this field. Currently,
four adenosine receptor subtypes, A(1), A(2A), A(2B) and A(3), have been
characterized and R&D efforts have led to high quality proprietary lead
compounds for each.
Several adenosine receptor compounds are under development by OSI.
Promising adenosine A(1) and adenosine A(2B) receptor targeted compounds will
undergo evaluation as candidates for asthma, with the dual goals of identifying
an IND-track candidate against both targets and simultaneously assessing and
executing the best commercialization strategy. The A(1) compound is targeted for
the treatment of the bronchoconstriction associated with the acute phase of an
asthma attack while the A(2B) compound is directed toward blocking the
inflammatory components produced by mast cells and associated with the longer
term damage caused by the disease. OSI also has potent and selective A(2A)
targeted compounds that have potential for development as both anti-angiogenesis
agents and for the treatment of Parkinson's disease. Additionally, OSI has a
selective adenosine A(3) targeted compound that is undergoing extensive
evaluation in animal models for glaucoma. The targets of Parkinson's disease and
glaucoma are examples of programs outside OSI's disease area focus and may be
out-licensed or earlier partnered in the development process.
In addition, an A(1) targeted compound, CDS-096370, has potential for use
in the treatment of congestive heart failure and renal failure. This candidate
has been licensed to Solvay for advanced pre-clinical and clinical development.
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and, from the CV Therapeutics 10-K..........
CVT-510
In 1998, another drug candidate from our adenosine program, CVT-510,
began Phase I clinical trials. CVT-510 is intended for the potential
treatment of atrial arrhythmias. It is an adenosine A1 agonist which may
act selectively on the conduction system of the heart to slow electrical
impulses. CVT-510 may offer a new approach to rapid and sustained control
of emergent atrial arrhythmias by reducing heart rate without affecting
blood pressure.
POTENTIAL INDICATIONS
Atrial arrhythmias - including atrial fibrilation, atrial flutter and
atrial tachycardias - are involved in approximately 1.9 million primary and
secondary hospital diagnosis. In addition, they are a major complication of
heart attacks, heart failure and cardiac surgery. These arrhythmias are
rapid, often irregular heartbeats that spread from the atria through the AV
node to the ventricles, severely compromising heart function. Potentially
damaging consequences include low blood pressure and damage to the brain,
heart and other vital organs. Thus, these arrhythmias can be life-
threatening and are severe enough to require rapid treatment
Because of the severity of these conditions and the need to treat
patients quickly, intravenous therapies are typically used. Current medical
therapies aim to slow the heart to a normal rate but have significant
limitations in the acute care setting. Digitalis is effective in controlling
heart rate, but requires a long time to take effect. This can be dangerous
in patients with a failing heart. Calcium channel blockers, beta blockers
and adenosine act quickly but are themselves associated with hypotension and
depressed cardiac function. These drugs could potentially exacerbate the
condition of patients already experiencing cardiac dysfunction as a
complication of the arrhythmia.
Our broad understanding of the adenosine receptor system could offer a
new approach to this major medical problem. By selectively stimulating the
adenosine A1 receptor - which slows heart rate - without significantly
stimulating the adenosine A2 receptor - which lowers blood pressure -
CVT-510 may be able to intervene immediately in the arrhythmia process,
without unwanted cardiovascular effects. This could offer cardiac patients
and clinicians a therapeutic alternative. We were issued a composition of
matter patent in 1998 by the U.S. Patent and Trademark Office on a class of
compounds including CVT-510.
CLINICAL STATUS
An IND for CVT-510 was submitted in August 1998, and a Phase I clinical
study began in September 1998. This open-label dose-escalation safety study
is designed to measure the response of the cardiac conduction system to
CVT-510. We hope to gain some preliminary indication of the potential for
CVT-510 to treat the atrial arrhythmias. We plan to conclude the Phase I
study and begin a Phase II study with CVT-510 in 1999.
Our current estimate of the commencement of various clinical trials
included in this Report are forward-looking statements that involve risks
and uncertainties. The actual clinical trial dates could differ materially
from those anticipated in these forward-looking statements as a result of
certain factors, including the timing and results of earlier clinical trials
and the other factors set forth under "Risk Factors" and elsewhere in this
Report. There can be no assurance that CVT-510 will prove to be safe or
efficacious in humans or that CVT-510 will obtain FDA or other regulatory or
foreign marketing approval for any indication.
<PAGE>
ADENTRI (CVT-124)
Adentri is a potent and selective adenosine A1 receptor antagonist.
Preclinical studies and clinical trials indicate that Adentri may increase
sodium excretion. Thus, we believe that Adentri has the potential to be a
new therapy for treatment of edema due to CHF.
Adenosine is a naturally occurring hormone that modulates different
functions of the heart, brain, kidney and blood vessels. Its actions are
mediated in these organs by two classes of receptors, A1 and A2. They each
stimulate very different physiological effects that can be separately
targeted in drug development. Adenosine A1 receptors are located on the
proximal tubules of the kidney where they stimulate reabsorption of sodium
and hence of water. We believe that we were among the first to identify the
presence of these adenosine A1 receptors in the proximal tubule of the
kidney. In contrast to A1 receptors, adenosine A2 receptors stimulate the
dilation of blood vessels in the heart, muscles and kidney, thereby lowering
blood pressure.
Adentri was identified in our adenosine A1 receptor program. This
program is focused on the development of agents that are highly selective
for the adenosine A1 receptor and has produced both antagonists and agonists
to this class of receptors. We continue to explore additional applications
of the technology developed in the adenosine A1 receptor program.
We have focused on creating an adenosine A1 receptor antagonist specific
enough to avoid blocking the A2 receptor and thus avoiding unintended side
effects. This concept was developed based on our insight into the newly
discovered role of the A1 receptor on the proximal tubule cell of the kidney
and its potential importance in treatment of edema states, such as CHF,
which are characterized by excessive accumulation of sodium and water in the
body. |
