Isis Publishes Data Demonstrating Antisense Targeting of ApoC-III Significantly Reduces ApoC-III and Triglycerides

      Isis Publishes Data Demonstrating Antisense Targeting of ApoC-III
               Significantly Reduces ApoC-III and Triglycerides

Research Shows Antisense Inhibition of ApoC-III and Triglycerides in Multiple
Species Including Humans

PR Newswire

CARLSBAD, Calif., April 1, 2013

CARLSBAD, Calif., April 1, 2013 /PRNewswire/ -- Isis Pharmaceuticals, Inc.
(NASDAQ: ISIS) announced today the publication of new data in the journal
Circulation Research [doi:10.1161/CIRCRESAHA.111.300367] demonstrating that
antisense targeting of apolipoprotein C-III (apoC-III) resulted in significant
reductions in apoC-III and triglycerides, each an independent risk factor for
cardiovascular disease.Hypertriglyceridemia is a serious medical condition
associated with premature coronary artery disease and an increased risk for
pancreatitis. Isis is developing its antisense apoC-III inhibitor,
ISIS-APOCIII[Rx], for the treatment of patients with severe
hypertriglyceridemia and plans to report top-line data in the middle of this
year.

"Patients with high triglycerides and high apoC-III levels are at significant
risk of developing cardiovascular disease, metabolic syndrome, diabetes and
pancreatitis.Despite currently available triglyceride-lowering agents, many
patients cannot reduce their triglycerides to acceptable levels. Because
apoC-III is a key regulator of triglyceride clearance from the blood and
itself is an independent risk factor for cardiovascular disease, lowering both
apoC-III and triglycerides could provide significant therapeutic benefit,"
said Richard Geary, Ph.D., senior vice president of development at Isis. "In
this paper, we report consistent activity of antisense inhibition of apoC-III
to lower both apoC-III and triglycerides in multiple rodent models of
dyslipidemia, in non-human primates and in man. These data support the
potential therapeutic benefit a selective apoC-III inhibitor could offer
patients with hypertriglyceridemia and elevated apoC-III. Following the
completion of the Phase 2 study, we plan to move rapidly into a Phase 3 study
in the most severe patients with triglyceride levels greater than 880 mg/dL
who are unable to reach acceptable triglyceride levels with currently
available treatments."

In the published data, treatment with an antisense compound targeting apoC-III
produced a variety of potential cardio-protective effects including
significant dose-dependent reductions of apoC-III and triglycerides in all
models and species, including man. In addition, treatment with an antisense
compound targeting apoC-III resulted in enhanced triglyceride clearance from
blood following a high-fat meal, reduction of VLDL particles and a slight
increase in HDL-C levels. In all models and in the Phase 1 study, antisense
inhibition of apoC-III was well tolerated. These data were consistent across
multiple preclinical models and species and in a Phase 1 study in healthy
volunteers demonstrating that Isis' antisense technology was able to produce
predictable and consistent responses among different animal models that
translate into corresponding activity in man. In the Phase 1 study, treatment
with ISIS-APOCIII[Rx] was well tolerated and produced rapid, dose-dependent
median reductions of up to 44 percent in plasma triglycerides and up to 78
percent in apoC-III protein, with two out of the three subjects in the highest
dose group achieving undetectable levels of apoC-III.

ABOUT ISIS-APOCIII[Rx
]ISIS-APOCIII[Rx] inhibits the production of apoC-III, a traditionally
'undruggable' target that inhibits the clearance of triglycerides from the
blood. People who do not produce apoC-III have lower levels of triglycerides
and lower instances of cardiovascular disease. ApoC-III is elevated in
patients with dyslipidemia, or an abnormal concentration of lipids in the
blood, and is frequently associated with multiple metabolic abnormalities,
such as insulin resistance and/or metabolic syndrome. In human population
studies, lower levels of apoC-III and triglycerides correlated with a lower
rate of cardiovascular events.

ABOUT HYPERTRIGLYCERIDEMIA
Hypertriglyceridemia can be caused by genetic defects, diet, obesity and
uncontrolled diabetes and can lead to serious health problems, including
cardiovascular disease and pancreatitis. Triglycerides are an important
measure of heart health and are routinely measured along with LDL-cholesterol
and HDL-cholesterol. Triglyceride levels of less than 150 mg/dL are
considered within a normal range, and the American Heart Association
recommends that a triglyceride level of less than 100 mg/dL is optimal.
Triglyceride levels of greater than 500 mg/dL are considered very high and
levels greater than 1,000 mg/dL are considered to be severely high. In these
patients, diet and exercise have limited therapeutic benefit. Patients with
severely high triglycerides are at a higher risk of developing pancreatitis, a
painful and sometimes fatal disease that requires hospitalization and close
monitoring. Based on prevalence data, Isis estimates there are greater than
200,000 patients with severely high triglycerides in the United States and
Europe despite currently available therapies.

ABOUT ISIS PHARMACEUTICALS, INC.
Isis is exploiting its leadership position in antisense technology to discover
and develop novel drugs for its product pipeline and for its partners. Isis'
broad pipeline consists of 28 drugs to treat a wide variety of diseases with
an emphasis on cardiovascular, metabolic, severe and rare diseases, and
cancer. Isis' partner, Genzyme, is commercializing Isis' lead product,
KYNAMRO™, in the United States for the treatment of patients with HoFH.
Genzyme is also pursuing marketing approval of KYNAMRO in other markets.
Isis' patents provide strong and extensive protection for its drugs and
technology. Additional information about Isis is available at
www.isispharm.com.

ISIS PHARMACEUTICALS' FORWARD-LOOKING STATEMENT
This press release includes forward-looking statements regarding the
discovery, development and potential for drugs for cardiovascular diseases,
and the development activities, therapeutic and commercial potential and
safety of ISIS-APOCIII[Rx]. Any statement describing Isis' goals,
expectations, financial or other projections, intentions or beliefs, including
the commercial potential of KYNAMRO, is a forward-looking statement and should
be considered an at-risk statement. 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 drugs. 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, 2012, which is on file with the SEC.
Copies of this and other documents are available from the Company.

In this press release, unless the context requires otherwise, "Isis,"
"Company," "we," "our," and "us" refers to Isis Pharmaceuticals and its
subsidiaries.

Isis Pharmaceuticals® is a registered trademark of Isis Pharmaceuticals, Inc.
KYNAMRO™ is a trademark of Genzyme Corporation.

SOURCE Isis Pharmaceuticals Inc.

Website: http://www.isispharm.com
Contact: D. Wade Walke, Ph.D., Executive Director, Corporate Communications
and Investor Relations, 760-603-2741, or Amy Blackley, Ph.D., Associate
Director, Corporate Communications, 760-603-2772
 
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