Product pipeline
atherogenics.com
AGI-1067
AGI-1067, our lead v-protectant product candidate, is a small
molecule that is orally dosed once per day. In pre-clinical testing,
AGI-1067 has shown the following three biological properties that
we believe will benefit patients with atherosclerosis:
AGI-1067 blocks expression of VCAM-1. We believe that
decreased VCAM-1 expression will diminish atherosclerosis
and restenosis.
AGI-1067 is a potent anti-oxidant.
AGI-1067 protects LDL cholesterol from converting into a
harmful inflammatory agent.
AGI-1067 lowers LDL cholesterol. LDL cholesterol lowering
reduces the risk of developing atherosclerosis
According to the American College of Cardiology, more than
seven million people in the United States have coronary artery
disease, including 1.5 million who have heart attacks every year. In
order to make a definitive diagnosis in patients with suspected
coronary artery disease, a specially trained cardiologist or
radiologist performs a diagnostic procedure called angiography in
which dye is injected through an intravenous catheter to image the
coronary arteries. Angiography can reveal coronary artery disease
that may require an invasive procedure. For more than one million
patients annually in North America, this invasive therapeutic
intervention takes the form of angioplasty. This procedure consists
of placing a balloon-tipped catheter into the coronary artery and
mechanically re-opening the blood vessel by expanding the
balloon under very high pressure. In addition, cardiologists may opt
to treat some of these coronary artery blockages by inserting a
small cylindrical mesh device, called a stent, to keep the blood
vessel open after the catheter is removed.
Angioplasty does not cure coronary artery disease, nor does it
treat the underlying chronic inflammation. In fact, angioplasty
induces an inflammatory response that contributes to its failure in
approximately 30% of patients who undergo the procedure. This
process of re-narrowing, or post-angioplasty restenosis, is a major
clinical problem that limits the effectiveness of the procedure.
Restenosis following balloon angioplasty occurs due to coronary
artery and endothelial cell damage. The development of stents and
the ongoing research and development activities with respect to
catheter improvement have not eradicated the problem of
restenosis, but have introduced the new problem of in-stent
restenosis which is particularly difficult to treat. In-stent restenosis
occurs when the cells that surround the stent proliferate and fill the
opening of the vessel.
Our initial development target is post-angioplasty restenosis.
More significantly, we believe that AGI-1067 may treat all areas of
the coronary artery susceptible to atherosclerosis in a way that
cannot be achieved with any existing therapy.
We have completed pre-clinical testing in multiple species to
establish the therapeutic properties of AGI-1067. Dosed orally,
AGI-1067 blocked VCAM-1 expression, prevented atherosclerosis
and showed potent anti-oxidant activity. In addition, AGI-1067
reduced LDL-cholesterol comparably to and in combination with
statins, which are widely used cholesterol lowering drugs.
Based upon our successful completion of pre-clinical testing, we
studied AGI-1067 in seven Phase I clinical trials in more than 150
men and women, including healthy volunteers and patients up to
the age of 85 to assess tolerability and potential for interaction with
other drugs. In addition, we have given AGI-1067 in combination
with other drug classes commonly used in patients with
atherosclerosis. In these clinical trials, six of which we conducted
under the Investigational New Drug Application for cholesterol
lowering, the subjects tolerated AGI-1067 well, with no dose or
use-limiting side effects. These positive results supported our
progress to Phase II clinical trials.
We are presently conducting a Phase II clinical trial in Canada to
assess the tolerability and efficacy of AGI-1067 as an agent to
prevent post-angioplasty restenosis. We opened our Canadian
Investigational New Drug Application in April 1999 for AGI-1067 as
an agent to prevent post-angioplasty restenosis. The Canadian
Antioxidant Restenosis Trial, called CART-1, is a multi-center,
randomized, double-blind, safety and efficacy dose-ranging study,
comparing AGI-1067 with placebo and an active control in patients
with established coronary artery disease who undergo elective
angioplasty. We plan to dose 315 patients for six weeks and follow
them for a total of six months. During angiography performed six
months after angioplasty, we will assess the efficacy of AGI-1067
by measuring directly the diameter of the opening of the treated
coronary artery. We enrolled the first patient in CART-1 on
September 2, 1999 and the trial is ongoing at four Canadian
centers of excellence in interventional cardiology. An independent
data and safety monitoring board reviews patient data periodically
to ensure the continued safety of enrolled patients.
We have formed a joint management committee with
Schering-Plough to oversee all aspects of development and
commercialization of AGI-1067. The committee consists of equal
numbers of AtheroGenics and Schering-Plough representatives.
Under direction of the joint management committee, we expect to
manage further clinical, pre-clinical and chemical development
work for AGI-1067.
AGI-Series for Respiratory Diseases
We are developing an intravenously-dosed, small molecule
v-protectant to treat exacerbations of cystic fibrosis. Based on
positive clinical trial results, we will evaluate our v-protectant for
the treatment of patients hospitalized with exacerbations of
asthma. For patients with chronic respiratory diseases, including
cystic fibrosis and asthma, an exacerbation is a sudden worsening
of the patient's breathing that usually requires hospitalization and
intensive therapy.
According to the Centers for Disease Control, asthma afflicts
more than 17 million adults and children in the United States. From
1980 to 1994, the prevalence of this disease increased by over
75%. Asthma morbidity and mortality continue to rise in spite of
massive public health efforts. In 1998, the combined direct and
indirect costs of asthma in the United States was $9.8 billion.
Current therapies that target the underlying disease include
corticosteroids and several classes of drugs that relieve symptoms
but are not effective for chronic inflammation. None of these drugs,
including inhaled corticosteroids, is particularly effective for treating
exacerbation of asthma which remains a major unmet medical
problem. We believe that v-protectants may reduce the
inflammation associated with the acute exacerbation of asthma
and may be useful in the treatment of up to 1.8 million patients
annually who develop acute exacerbations of asthma and seek
emergency room treatment in the United States.
Cystic fibrosis is a common hereditary disease among
Caucasians. According to the Cystic Fibrosis Foundation, there are
36,000 children and adults with cystic fibrosis in the United States.
Approximately 25% of patients with cystic fibrosis are hospitalized
at least once per year. Physicians treat exacerbations of cystic
fibrosis with antibiotics that treat the associated chronic bacterial
infection of the lungs. These antibiotics, however, do not address
the chronic inflammation that underlies cystic fibrosis. Physicians
no longer use corticosteroids routinely to treat exacerbations
because they compromise the patient's immune response to
bacterial infection. We believe that v-protectants can treat this
chronic inflammation without compromising the necessary immune
response to bacteria.
We have identified small molecule, v-protectant product
candidates from among five AGI-series of compounds for
intravenous administration to hospitalized patients with respiratory
diseases. We are evaluating these small molecules based on
development criteria such as potency, stability and ease of
formulation. We will use these criteria to choose a lead product
candidate for clinical development that targets one or more
respiratory disease indications. We plan to apply to the FDA for
fast track status for this product candidate as a treatment for
exacerbations of cystic fibrosis. We have observed a decrease in
lung inflammation in a pre-clinical model of asthma using a
compound discovered in this effort.
AGI-Series for Rheumatoid Arthritis
We are developing an orally-dosed, small molecule v-protectant
to treat patients with chronic rheumatoid arthritis who have not
responded to maximum current therapy. For patients with
rheumatoid arthritis, chronic therapy progresses from pain relievers
to increasingly toxic immunosuppressants, called disease
modifiers. Based on positive clinical trial results, we will evaluate
our v-protectant for the treatment of patients who are receiving
moderate disease modifying therapy.
Rheumatoid arthritis is a common auto-immune disease which
affects joints and arterial blood vessels. According to the Arthritis
Foundation, there are 2.1 million people with rheumatoid arthritis in
the United States. Rheumatoid arthritis and related diseases cost
the U.S. economy more than $65 billion annually in direct and
indirect costs. Approximately 70% of patients with rheumatoid
arthritis are young and middle-aged women. Physicians treat
rheumatoid arthritis with pain relievers including aspirin and other
non- steroidal anti-inflammatory drugs, and proceed in resistant
patients to treatment with low doses of corticosteroids and
immunosuppressants. The recent successful introduction of new
drugs, including Celebrex, Enbrel and Vioxx, has highlighted both
the market potential and the size and scope of the unmet medical
need of these patients. These drugs are partially effective but
either increase the risk of infection or do not address the chronic
vascular inflammation that marks rheumatoid arthritis.We believe
that v-protectants can treat the chronic inflammation of rheumatoid
arthritis including the direct inflammation of the arteries, without
increasing the patient's risk for infection.
We have identified small molecule, v-protectant product
candidates from among five AGI-series of compounds for oral
administration to rheumatoid arthritis patients who have not
responded to therapy. We are evaluating these small molecules
based on development criteria such as potency, stability and ease
of formulation.
AGI-Series for Post-Transplant Late and Chronic Solid
Organ Rejection
We are developing an orally-dosed, small molecule v-protectant
to treat late solid organ transplant rejection. Patients' immune
systems recognize transplanted organs as foreign and therefore
reject them. Physicians treat these patients with powerful
immuno-suppressants to block all immune and inflammatory
reactions that could cause acute solid organ rejection. These
therapies place patients at risk for life threatening infection. As the
body adapts to the transplanted organ, physicians modify therapy
gradually to reduce the likelihood of infection. During the first year,
approximately 25% of patients who receive solid organ transplants
develop a delayed sudden transplant rejection, which is called late
solid organ transplant rejection. We believe that v-protectants will
extend protection to the transplanted organ without increasing the
patient's risk for infection.
Those patients who do not reject the transplanted organ within
the first year remain at risk indefinitely to reject the transplanted
solid organ. This chronic inflammatory process is called chronic
solid organ transplant rejection. The vascular protection provided
by our product candidates may protect solid organs from rejection
beyond the first year without increasing the risk of infection. No
other solid organ anti-rejection drug in development has this
profile.
According to the American Society of Transplantation, there are
approximately 30,000 heart, kidney and liver transplant recipients
per year in the United States. Of these, 7,000 develop late
transplant rejection. There are 200,000 organ transplant recipients
in the United States who are at risk of chronic transplant rejection.
Chronic rejection is a major factor contributing to organ shortage.
We have identified small molecule, v-protectant product
candidates from among five AGI-series of compounds for oral
administration to patients who have received transplants. We are
evaluating these small molecules based on development criteria
such as potency, stability and ease of formulation. We will use
these criteria to choose a lead product candidate for clinical
development that targets late solid organ transplant rejection. We
plan to apply to the FDA for fast track status for this product
candidate as an adjunct to current transplant therapy, which
includes immunosuppressant and anti-inflammatory drugs. Based
on positive results, we will seek to expand the indication into
protection from chronic solid organ transplant rejection.
Diagnostic Assay Program
Based on our v-protectant technology platform, we have
designed a simple and proprietary blood test that measures a
circulating blood marker for atherosclerosis. We plan to conduct
tests on human blood samples to establish whether this new
marker, called Oxykine, is an accurate and useful diagnostic tool.
We believe Oxykine will allow physicians to determine whether a
patient has active and progressive atherosclerosis and whether the
disease is responding to medical therapy. There are currently no
diagnostic tools that meet this critical need in atherosclerosis
disease management. |
