Isis Pharmaceuticals, Inc. Form 10K - page 22

with diabetes. The clinical development plan for ISIS-PTP1BRx focuses on treating diabetic patients who are
inadequately controlled on insulin, helping them utilize insulin more efficiently and treating patients who are
beginning to fail oral therapies, extending the time they have before becoming dependent on insulin.
ISIS-FGFR4Rx —ISIS-FGFR4Rx is an antisense drug we designed to target fibroblast growth factor
receptor 4, or FGFR4, in the liver and fat tissues. Reducing FGFR4 decreases the body’s ability to store fat
while simultaneously increasing fat burning and energy expenditure. Many anti-obesity drugs act in the brain to
suppress appetite, commonly resulting in central nervous system, or CNS, side effects. However, ISIS-FGFR4Rx
does not distribute to the brain or CNS and therefore should not produce any CNS side effects.
In preclinical studies, antisense inhibition of FGFR4 lowered body weight when we administered it as a
single agent and in the presence or absence of a calorie-restricted diet. Additionally, inhibiting FGFR4 decreased
body weight when we administered it in combination with an appetite-suppressing drug. In addition to reducing
body weight, inhibiting FGFR4 demonstrated an improvement in insulin sensitivity. ISIS-FGFR4Rx is the first
drug in our metabolic franchise to treat obesity and utilizes technology we in-licensed fromVerva
Pharmaceuticals Ltd.
We plan to initiate a Phase 2 study in obese patients in 2015.
Preclinical Development
The table below lists our preclinical drug in our metabolic franchise.
Drug Indication Partner
ISIS-DGAT2Rx NASH Isis owned
Cancer Franchise
We are discovering and developing antisense drugs to treat cancers both internally and through our
partnerships withAstraZeneca and OncoGenex Technologies Inc. Cancer is an area of significant unmet medical
need and an area in which our antisense technology provides us with unique advantages in discovering new
drugs. Cancer is an extremely complex disease that involves a large number of targets. With our technology we
can evaluate a very broad and diverse range of targets and identify their involvement in different types of
cancers. Using the information we gain early in research on each of these targets, we can quickly identify
promising targets for an anti-cancer drug. We select anti-cancer targets that provide a multi-faceted approach to
treating cancer.
Our cancer pipeline consists of anti-cancer antisense drugs that act upon biological targets associated with
cancer progression and/or treatment resistance. In 2012, we formed an anti-cancer alliance withAstraZeneca that
expands our anti-cancer efforts and supports an aggressive and broad clinical development plan for
ISIS-STAT3-2.5Rx and ISIS-AR-2.5Rx. AstraZeneca brings significant experience that enables the identification of
novel genetic and epigenetic targets for cancer. CombiningAstraZeneca’s expertise with our drug discovery
technology, we plan to expand our cancer franchise with a number of promising new anti-cancer targets.
We believe the favorable tolerability and early evidence of clinical benefit of the anti-cancer drugs in our
pipeline demonstrate how uniquely suited our technology is to create novel cancer therapeutics. In addition, we
believe our generation 2.5 chemistry enhances the potency and effectiveness of our antisense drugs, and extends
the applicability of our technology to cancers that are difficult to treat. For instance, data from a Phase 1/2
clinical study of ISIS-STAT3-2.5Rx showed evidence of antitumor activity in patients with cancer, including
advanced/metastatic hepatocellular carcinoma.
Custirsen —OncoGenex is developing Custirsen, formerly OGX-011, an antisense drug designed to target
clusterin. Clusterin is a secreted protein that acts as a cell-survival protein and is over-expressed in response to
anti-cancer agents. We and OncoGenex jointly discovered and conducted the initial development of custirsen.
OncoGenex is studying custirsen for use as an adjunct therapy to enhance the effectiveness of chemotherapy.
Custirsen has shown promising results in combination with currently available chemotherapies in several tumor
types. The FDAgranted Fast Track Designation to custirsen for the treatment of metastatic prostate cancer in
combination with docetaxel.
OncoGenex and collaborating investigators evaluated custirsen in five Phase 2 studies in combination with
various cancer therapies for prostate cancer, non-small cell lung cancer, or NSCLC, and breast cancer.
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