Isis Announces Expedited Development Of ISIS-TTR Rx And Amendment To The Collaboration With GSK To Support Phase 2/3 Study

   Isis Announces Expedited Development Of ISIS-TTR Rx And Amendment To The
              Collaboration With GSK To Support Phase 2/3 Study

PR Newswire

CARLSBAD, Calif., Nov. 5, 2012

CARLSBAD, Calif., Nov. 5, 2012 /PRNewswire/ -- Isis Pharmaceuticals, Inc.
(NASDAQ: ISIS) announced today that Isis and GlaxoSmithKline (NYSE: GSK) have
agreed to amend the clinical development plan and financial terms relating to
ISIS-TTR[Rx] to reflect the accelerated development plan for the drug.
ISIS-TTR[Rx] is an antisense drug in development with GSK for the treatment of
TTR amyloidosis, a severe and rare genetic disease characterized by
progressive dysfunction of peripheral nerves and/or heart tissue. The revised
development plan anticipates initiation of a Phase 2/3, registration-directed,
clinical study later this year. ISIS-TTR[Rx] is one of several promising
drugs in Isis' pipeline that Isis expects will begin registration-directed
studies within the next several years.

"In our Phase 1 study, we demonstrated that ISIS-TTR[Rx] was generally well
tolerated and produced dose-dependent significant reductions in TTR protein
with several subjects reaching TTR protein levels that were below the limit of
assay detection," said Brett Monia, Ph.D., senior vice president, antisense
drug discovery at Isis. "We anticipate initiating the next clinical study
this year, which will evaluate the effects of ISIS-TTR[Rx] on neurological
dysfunction and on quality-of-life in patients with familial amyloid

Under the terms of the original collaboration agreement with GSK, which
includes five programs in addition to the TTR program, Isis is eligible to
receive on average up to $20 million in milestone payments per program, before
Phase 2 proof-of-concept, plus a licensing fee, additional post-licensing
milestone payments and double-digit royalties on sales from each product.
Isis has already received $10 million in milestone payments from GSK related
to the development of ISIS-TTR[Rx]. Under the amended terms of the agreement
Isis will receive a $2.5 million upfront payment and is eligible to earn a
$7.5 million milestone payment upon the initiation of the ISIS-TTR[Rx] Phase
2/3 study. Isis is also eligible to earn an additional $50 million in
pre-licensing milestone payments to support the ISIS-TTR[Rx] Phase 2/3 study.
In addition, GSK has increased the regulatory and sales milestones payable to
Isis should the product achieve registration and meet certain sales
thresholds. Isis will also receive double-digit royalties on sales of

"We have a robust pipeline of novel new drugs. Many of which, including
ISIS-TTR[Rx], could advance into registration studies in the next 12 to 18
months. Together with GSK, we have been able to rapidly advance the TTR
program from research to late-stage clinical development in just over two
years," said B. Lynne Parshall, J.D., chief operating officer and chief
financial officer at Isis. "Under the updated plan, Isis continues to manage
the clinical development of ISIS-TTR[Rx] while benefiting from GSK's
late-stage development and commercial expertise. We believe that ISIS-TTR[Rx]
could be a best-in-class medicine for patients who have limited therapeutic

Transthyretin amyloidosis is a genetic disease in which the patient inherits a
mutant gene that produces a misfolded form of transthyretin (TTR) protein,
which progressively accumulates in tissues, impairing their function. In
patients with transthyretin amyloidosis, both the mutant and normal forms of
TTR can build up as fibrils in tissues, including heart, peripheral nerves,
and the gastrointestinal tract. The presence of TTR aggregates interferes
with the normal functions of these tissues, and as the TTR protein aggregates
enlarge more tissue damage occurs and the disease worsens. There are two
common types of transthyretin amyloidosis, familial amyloid
polyneuropathy(FAP), which affects more than 10,000 patients worldwide, and
familial amyloid cardiomyopathy (FAC), which affects more than 40,000 patients
worldwide. Patients with FAP have TTR build up in peripheral nerve tissue
leading to the loss of nerve function and wasting. Patients with FAC have TTR
build up in the heart muscle and succumb to heart failure five to six years
after symptom onset. ISIS-TTR[Rx] is an investigational drug that is designed
to inhibit the production of all forms of TTR, and could offer an alternative
approach to treat all types of transthyretin-related amyloidosis.

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™, following regulatory approval. Isis' patents provide strong and
extensive protection for its drugs and technology. Additional information
about Isis is available at

This press release includes forward-looking statements regarding Isis'
collaboration with GlaxoSmithKline and the development, activity, therapeutic
potential and safety of ISIS-TTR[Rx]. 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

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

SOURCE Isis Pharmaceuticals, Inc.

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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