V-PROTECTANT TECHNOLOGY
We have developed a proprietary drug discovery
technology platform for the treatment of chronic
inflammatory diseases. This platform is based on the work
of our scientific co-founders R. Wayne Alexander, M.D.,
Ph.D., and Russell M. Medford, M.D., Ph.D. In 1993 Drs.
Alexander and Medford discovered a novel mechanism
within arterial blood vessel walls through which the
excessive accumulation of leukocytes could be controlled
without affecting the body's ability to fight infection. This
platform is called vascular protectant, or v-protectant
technology. V-protectant technology exploits the
observation that the endothelial cells that line the interior
wall of the blood vessel play an active role in recruiting
leukocytes from the blood to the site of chronic
inflammation. V-protectants are therapeutic small
molecules that block a class of signals, called oxidant
signals, that are generated within endothelial cells. These
oxidant signals activate genes that produce inflammatory
proteins. The protein products of these selected genes,
including VCAM-1, attract leukocytes to the site of chronic
inflammation. We believe that an excess number of
VCAM-1molecules on the surface of cells is a disease
state. By blocking this specific type of inflammation, we
believe that AGI-1067 and other v-protectants will not
undermine the body's ability to protect itself against
infection.
INFLAMMATORY DISEASES
Inflammation is a normal response of the body to protect
tissues from infection, injury or disease. The inflammatory
response begins with the production and release of
chemical agents by cells in the infected, injured or
diseased tissue. These agents cause redness, swelling,
pain, heat and loss of function. Inflamed tissues generate
additional signals that recruit leukocytes to the site of
inflammation. Leukocytes destroy any infective or injurious
agent, and remove cellular debris from damaged tissue.
This inflammatory response usually promotes healing but,
if uncontrolled, may become harmful.
The inflammatory response can be either acute or
chronic. Acute inflammation lasts at most only a few days.
The treatment of acute inflammation, where therapy
includes the administration of aspirin and other
non-steroidal anti-inflammatory agents, provides relief of
pain and fever for patients. In contrast, chronic
inflammation lasts weeks, months or even indefinitely and
causes tissue damage. In chronic inflammation, the
inflammation becomes the problem rather than the solution
to infection, injury or disease. Chronically inflamed tissues
continue to generate signals that attract leukocytes from
the bloodstream. When leukocytes migrate from the
bloodstream into the tissue they amplify the inflammatory
response. This chronic inflammatory response can break
down healthy tissue in a misdirected attempt at repair and
healing. Diseases characterized by chronic inflammation
include, among others:
Atherosclerosis, including coronary artery disease;
Asthma;
Cystic fibrosis;
Rheumatoid arthritis; and
Solid organ transplant rejection.
Atherosclerosis is a common disease that results from
inflammation and the buildup of plaque in arterial blood
vessel walls. Plaque consists of inflammatory cells,
cholesterol and cellular debris. Atherosclerosis, depending
on the location of the artery it affects, may result in heart
attack, stroke or amputation. There are no medications
available for physicians to treat directly the underlying
chronic inflammation of atherosclerosis.
Atherosclerosis of the blood vessels of the heart is
called coronary artery disease. Treatment for coronary
artery disease often progresses to therapeutic procedures
including angioplasty or bypass surgery to re-establish an
effective blood supply to the heart. Angioplasty corrects the
blockage by the inflation of a balloon delivered by catheter,
with or without the placement of a stent, at the site of the
obstructing plaque. After angioplasty, the artery opened by
the procedure often re-narrows. Inflammation plays an
important role in this re-narrowing called restenosis. There
is no medical treatment for restenosis.
Asthma is a common chronic inflammatory disease of
the bronchial tubes, which are the airways in the lungs.
Asthma is marked by episodic airway attacks that are
caused by many stresses, including allergy, cold air, ozone
or exercise. Asthma therapy has concentrated on the use
of inhaled corticosteroids to reduce chronic inflammation
and bronchodilators to provide symptomatic relief.
Asthmatic patients, however, continue to experience
flare-ups, or exacerbations, that are not prevented or
treated by these medicines.
Cystic fibrosis is an inherited disease that presents in
childhood with blocked glands of various organs, including
the lungs, intestines and pancreas. This chronic blockage
leads to chronic inflammation and recurrent lung infections.
Patients with cystic fibrosis develop chronic lung
inflammation that may suddenly flare with severe
consequences. Current treatment only attempts to control
infection, primarily with antibiotics.
There is a wide variety of other chronic inflammatory
diseases, including rheumatoid arthritis and solid organ
transplant rejection. Physicians regularly use
anti-inflammatory agents, such as aspirin, other
non-steroidal anti-inflammatory drugs and corticosteroids,
alone or in combination with immuno-suppressants, to treat
these diseases.
However, these diseases may suddenly flare due to
either the tissue inflammation that underlies them or
bacteria that take advantage of the suppressed immune
response induced by present therapies. Treatments for the
underlying disease have major side effects and are not
completely effective for these inflammatory exacerbations.
For example, systemic corticosteroids cause major side
effects including high blood pressure, adult-onset diabetes,
cataracts, brittle bones and increased risk of infection.
Many physicians are only now becoming aware of the
key role of chronic inflammation in diverse diseases such
as atherosclerosis and asthma for which existing
anti-inflammatory treatments are incomplete and limited in
use. As more physicians recognize that a wide range of
chronic diseases are inflammatory in nature, we believe
that these physicians will require safer and more effective
anti-inflammatory treatments. We believe that one of these
therapeutic approaches will be the administration of drugs
designed to block the migration of leukocytes through
blood vessel walls into inflamed tissues. |
