Isis Pharmaceuticals Reports Positive Phase 1 Data On Three Drugs In Development To Treat Metabolic Disorders

     Isis Pharmaceuticals Reports Positive Phase 1 Data On Three Drugs In
                   Development To Treat Metabolic Disorders

Conference Call and Slide Presentation December 7th, 12:00 p.m. EST at
www.isispharm.com

PR Newswire

CARLSBAD, Calif., Dec. 7, 2012

CARLSBAD, Calif., Dec. 7, 2012 /PRNewswire/ --Isis Pharmaceuticals, Inc.
(NASDAQ: ISIS) announced today positive results from Phase 1 studies of three
drugs, ISIS-PTP1B[Rx], ISIS-GCGR[Rx] and ISIS-GCCR[Rx], in development to
treat metabolic disorders, including type 2 diabetes. In all three Phase 1
studies, the drugs were safe and well tolerated with early encouraging data
that supports the unique mechanism of each drug. All three drugs are part of
Isis' metabolic franchise and are designed to act through distinct mechanisms
to improve insulin sensitivity and/or reduce glucose production.

"Our goal is to develop safe, effective drugs with unique mechanisms of action
that can provide significant therapeutic benefit for patients with metabolic
disorders, including type 2 diabetes. This year we have moved closer to this
goal with the completion of our initial clinical studies on three promising
drugs from our metabolic franchise. These drugs are uniquely positioned to
fill the critical voids in diabetes therapy," said Stanley T. Crooke, M.D.,
Ph.D., chief executive officer at Isis. "While these drugs may be beneficial
as single agents, our goal is to develop them as adjuncts to existing diabetes
therapies. We believe that each drug has the potential to address a distinct
and significant commercial market in patients with type 2 diabetes."

ISIS-PTP1B[Rx]
ISIS-PTP1B[Rx] targets protein tyrosine phosphatase-1B (PTP-1B) and is
designed to increase the body's sensitivity to insulin, resulting in better
glucose control for patients with type 2 diabetes. Because of its unique
mechanism, ISIS-PTP1B[Rx] has the potential to help patients achieve glucose
control without weight gain or hypoglycemia. In the Phase 1 study of
ISIS-PTP1B[Rx ]in obese healthy volunteers, Isis observed encouraging data in
measures of insulin sensitivity and in a biomarker associated with weight
loss. Previous clinical experience with the PTP-1B inhibitor ISIS 113715
demonstrated that PTP-1B inhibition improved glucose control and reduced
LDL-cholesterol without causing weight gain. "These new ISIS-PTP1B[Rx] data
are consistent with our findings from the earlier Phase 2 studies of ISIS
113715. It is also important to note that ISIS-PTP1B[Rx] is a significantly
more potent PTP-1B inhibitor than our earlier inhibitor, ISIS 113715, and, as
such, we expect more robust effects in clinical trials," said Sanjay Bhanot,
M.D., Ph.D., vice president, clinical development and translational medicine
at Isis. "We believe that ISIS-PTP1B[Rx] has the potential to be broadly
useful in combination with most of the other commonly used drugs to treat
patients with diabetes, including insulin, glucagon-like peptide (GLP-1)
agonists, and more traditional drugs like metformin."

ISIS-GCGR[Rx]
ISIS-GCGR[Rx] targets the glucagon receptor (GCGR) and is designed to reduce
the effects of glucagon, a hormone that causes increased glucose production in
the liver. In patients with advanced diabetes, uncontrolled glucagon action
leads to a significant increase in blood glucose levels. Therefore,
attenuating glucagon action could have a significant glucose lowering effect
in patients with severe diabetes. "Although small molecule inhibitors of GCGR
have demonstrated glucose-lowering effects in diabetic patients, they also
have produced limiting side effects, including increases in lipids and blood
pressure. In contrast, in our Phase 1 study ISIS-GCGR[Rx] displayed a good
safety profile with no clinically significant increases in blood pressure or
lipids and with no hypoglycemia. In addition, we observed an increase in
active GLP-1, a hormone that preserves pancreatic function and enhances
insulin secretion, that confirmed the activity we observed in our preclinical
studies," continued Dr. Bhanot. "Given the unique mechanism of action and
potentially favorable safety profile observed in the Phase 1 study, we believe
that ISIS-GCGR[Rx] could be valuable for diabetic patients with severe
hyperglycemia who are not controlled with current treatments by not only
controlling glucose, but also preserving pancreatic function, which would
enhance endogenous insulin activity."

ISIS-GCCR[Rx]
ISIS-GCCR[Rx] targets the glucocorticoid receptor (GCCR) and is designed to
reduce the effects of glucocorticoids, hormones that promote liver glucose
production and fat storage in the liver and fat tissues. Because excessive
GCCR activity in the liver and fat is associated with obesity, insulin
resistance and glucose intolerance, ISIS-GCCR[Rx] has the potential to improve
glycemic and lipid control in patients with type 2 diabetes. "Reduction of
GCCR in tissues other than the liver and fat, such as the brain, can result in
many unwanted and potentially toxic side effects, as has been reported with
small molecule inhibitors of GCCR. Because ISIS-GCCR[Rx] reduces GCCR
activity only in liver and fat tissues, we avoid these unwanted side effects.
In preclinical studies, we demonstrated that antisense reduction of GCCR was
limited to the liver and fat tissues and produced robust lowering of glucose
and lipid levels. Results from our ISIS-GCCR[Rx] Phase 1 study were
consistent with the liver- and fat-specific activity we observed in our
preclinical studies, and also provided early encouraging data on the drug's
therapeutic activity," concluded Dr. Bhanot. "Given the mechanism of action,
we believe that ISIS-GCCR[Rx] could be particularly useful for diabetic
patients with moderate to severe hyperglycemia who are also obese or have high
levels of cholesterol and triglycerides."

CONFERENCE CALL
At 12:00 p.m. Eastern Standard Time today, December 7^th, Isis will conduct a
live webcast and slide presentation. Interested parties may listen to the
call by dialing 866-362-4831 and refer to the passcode "ISIS 2012" or access
the webcast with or without audio at www.isispharm.com. A webcast replay will
be available for a limited time at the same address.

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 25 drugs to treat a wide variety of diseases with
an emphasis on cardiovascular, metabolic, severe and rare diseases, and
cancer. Isis' partner, Genzyme, plans to commercialize Isis' lead product,
KYNAMRO™, in the United States and Europe following regulatory approval.
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
development, activity, therapeutic potential and safety of the drugs in Isis'
metabolic pipeline. Any statement describing Isis' goals, expectations,
financial or other projections, intentions or beliefs, including the planned
commercialization 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, 2011 and its most recent quarterly report
on Form 10-Q, which are on file with the SEC. Copies of these 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, +1-760-603-2741, or Amy Blackley, Ph.D., Associate
Director, Corporate Communications, +1-760-603-2772
 
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