ISIS 301012 Reduces Atherosclerotic Plaques In Animal Models

Isis
Pharmaceuticals, Inc. (Nasdaq: ISIS) today announced results of a study
showing that ISIS 301012 reduced atherosclerotic plaques, apoB-100, and
circulating inflammatory cytokines in an animal model of atherosclerosis.
These data support a growing body of evidence demonstrating that ISIS
301012 has the potential to treat patients with coronary artery disease.
Isis recently reported in a Phase 2 trial that ISIS 301012 produced rapid,
dose-dependent and prolonged reductions of its target, apoB-100, with
concomitant reductions in low density lipoprotein (LDL or "bad"
cholesterol), very low density lipoprotein (VLDL), total cholesterol and
triglyceride levels in patients with high cholesterol. ISIS 301012 is a
second-generation antisense drug that inhibits the expression of apoB-100,
a protein critical to the formation and transport of the "bad" cholesterol
particles involved in heart disease -- LDL and VLDL. Rosanne Crooke, Ph.D.,
Director of Cardiovascular Research of Isis Pharmaceuticals, presented
these data at the Arteriosclerosis, Thrombosis and Vascular Biology (ATVB)
meeting in Denver, Colorado.


ISIS 301012 was administered to mice that were bred to contain no LDL
receptor. These transgenic mice also expressed human apoB-100. In this
transgenic model, mice develop extensive atherosclerotic plaques. A 14-week
treatment with ISIS 301012 produced a dose-dependent reduction in apoB-100
levels, with concomitant decreases in aortic plaque volume. At 50 mg/kg/wk,
ISIS 301012 treatment reduced the levels of apoB-100 by 69% (p







ABOUT ISIS 301012


ISIS 301012 is a second-generation antisense drug that inhibits
apoB-100, a protein critical to the synthesis and transport of the "bad"
cholesterol involved in heart disease -- low density lipoprotein
cholesterol (LDL) and very low density lipoprotein (VLDL). Lowering
cholesterol and triglyceride levels is a key component in the prevention
and management of cardiovascular disease.


Development plans for ISIS 301012 include the rapid development of the
drug for patients with familial hypercholesterolemia (FH), a genetic
disorder that causes extremely high cholesterol levels and results in the
early onset of heart disease. ISIS 301012 has the potential for an
accelerated pathway to commercialization because of the unmet medical need
in this desperate patient population. Additional trials have been designed
to address the larger commercial market represented by the traditional
population of patients with high cholesterol who are still not reaching
their targeted cholesterol levels.


In September 2005, Isis initiated the Phase 2 development program of
ISIS 301012. Phase 2 trials of ISIS 301012 are being conducted in patients
with high cholesterol. Isis is continuing its Phase 2 single-agent trial
using higher dosing (300 and 400 mg/wk) of ISIS 301012 in patients with
high cholesterol. Isis is also conducting a Phase 2 trial of ISIS 301012 in
combination with statin therapy in patients with high cholesterol. Isis is
also conducting Phase 2 studies of ISIS 301012 in FH.


Isis recently reported initial data from the low-dose cohorts of a
Phase 2 clinical trial of ISIS 301012 as a single-agent in patients with
high cholesterol. ISIS 301012 produced rapid, dose-dependent and prolonged
reductions of its target, apoB-100, with concomitant reductions in LDL,
VLDL, total cholesterol and triglyceride levels in patients with high
cholesterol. In Phase 1 trials, ISIS 301012 produced rapid, dose-dependent
and prolonged reductions of its target, apoB-100, with concomitant
reductions in LDL, VLDL, total cholesterol and triglycerides in normal
subjects with elevated cholesterol. In a drug-drug interaction study, ISIS
301012 did not interact with simvastatin or ezetimibe, currently available
lipid lowering drugs with which ISIS 301012 may be dosed in combination.
Additionally, the drug has been well tolerated.


ABOUT CHOLESTEROL AND CARDIOVASCULAR DISEASE


According to the American Heart Association, an estimated 107 million
American adults have total blood cholesterol values of 200 mg/dL and
higher, and of these about 38 million American adults have levels of 240 or
above. In adults, total cholesterol levels of 240 mg/dL or higher are
considered "high risk". Levels from 200 to 239 mg/dL are considered
"borderline-high risk". Low-density lipoprotein, or LDL, known as the "bad"
cholesterol, can clog arteries, increasing the risk of heart attack and
stroke.


According to the World Health Organization (WHO), heart disease and
stroke kill 17 million people a year, which is almost one-third of all
deaths globally. By 2020, the WHO projects that heart disease and stroke
will become the leading cause of both death and disability worldwide, with
the number of fatalities projected to increase to over 20 million a year
and by 2030 to over 24 million a year.


Familial hypercholesterolemia is a dominantly inherited genetic
condition that results in markedly elevated LDL (low-density lipoprotein)
cholesterol levels beginning at birth, and resulting in heart attacks at an
early age. Affected people have consistently high levels of low-density
lipoprotein, which leads to premature atherosclerosis of the coronary
arteries.


ABOUT ISIS' SYMPHONY GENISIS COLLABORATION


In April 2006, Isis entered into a collaboration with Symphony Capital
Partners, L.P. and a group of co-investors to form Symphony GenIsis, Inc.,
capitalized with $75 million, to fund the development of Isis'
cholesterol-lowering drug, ISIS 301012, and two novel drugs from Isis'
metabolic disease program. Isis licensed to Symphony GenIsis the
intellectual property for its apoB-100, glucagon receptor and
glucocorticoid receptor programs. The financing will support Isis'
development of ISIS 301012 through the completion of
registration-supporting clinical studies in patients with familial
hypercholesterolemia and the completion of Phase 2b clinical trials in
patients with high cholesterol. The financing will also support Isis'
development of two novel diabetes drugs through initial proof of concept in
human clinical trials. In addition to providing the financial support to
move these drugs forward aggressively, the transaction allows Isis to
continue to control and manage the development of ISIS 301012 and two other
potentially valuable drugs through key development milestones.


ABOUT ISIS PHARMACEUTICALS, INC.


Isis is exploiting its expertise in RNA to discover and develop novel
drugs for its product pipeline and for its partners. The Company has
successfully commercialized the world's first antisense drug and has 15
drugs in development. Isis' drug development programs are aimed at treating
cardiovascular, metabolic and inflammatory diseases. Isis' partners are
focused in disease areas such as inflammatory, ocular, viral and
neurodegenerative diseases, and cancer. In its Ibis division, Isis is
developing and commercializing the IBIS biosensor system, a revolutionary
system to identify infectious organisms. As an innovator in RNA-based drug
discovery and development, Isis is the owner or exclusive licensee of
approximately 1,500 issued patents worldwide. Additional information about
Isis is available at isispharm


.
This press release includes forward-looking statements regarding the
development, therapeutic potential and safety profile of ISIS 301012 for
the treatment of high cholesterol and cardiovascular disease. Any statement
describing Isis' goals, expectations, intentions or beliefs is a
forward-looking statement and should be considered an at-risk statement,
including those statements that are described as Isis' goals. Such
statements are subject to certain risks and uncertainties, particularly
those inherent in the process of discovering, developing and
commercializing drugs that are safe and effective for use as human
therapeutics, and in the endeavor of building a business around such
products. Isis' forward-looking statements also involve assumptions that,
if they never materialize or prove correct, could cause its results to
differ materially from those expressed or implied by such forward-looking
statements. Although Isis' forward-looking statements reflect the good
faith judgment of its management, these statements are based only on facts
and factors currently known by Isis. As a result, you are cautioned not to
rely on these forward-looking statements. These and other risks concerning
Isis' programs are described in additional detail in Isis' annual report on
Form 10-K for the year ended December 31, 2005, which is on file with the
U.S. Securities and Exchange Commission (SEC) and available from the
Company.


Isis Pharmaceuticals, Inc.

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