Isis Pharmaceuticals, Inc. Form 10K - page 15

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We believe that physiciansmayuse ISIS-PTP1BRx in combinationwithmost of the other commonlyuseddiabetes drugs,
including insulin, GLP-1 agonists, andmore traditional drugs likemetformin, to treat patientswithdiabetes. The clinical development
plan for ISIS-PTP1BRx focuses on treatingdiabetic patientswho are inadequately controlledon insulin, helping themutilize insulin
more efficiently and treatingpatientswho are beginning to fail oral therapies, extending the time theyhave before becoming
dependent on insulin.
We are currently evaluating ISIS-PTP1BRx in aPhase 2 study inpatientswith type 2diabeteswho, despite takingmetformin
ormetformin plus sulfonylurea, have uncontrolledglucose levels.
ISIS-FGFR4 Rx — ISIS-FGFR4Rx is an antisense drug that specifically reduces the productionof fibroblast growth factor
receptor 4, or FGFR4, in the liver and fat tissues, which decreases the body’s ability to store fatwhile simultaneously increasing fat
burning and energy expenditure.Many anti-obesitydrugs 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 brainorCNS and therefore shouldnot produce any
CNS side effects.
Inpreclinical studies, antisense inhibitionof FGFR4 loweredbodyweightwhenwe administered it as a single agent and in
the presence or absence of a calorie-restricteddiet. Additionally, inhibitingFGFR4decreasedbodyweightwhenwe administered it in
combinationwith an appetite-suppressingdrug. In addition to reducingbodyweight, inhibitingFGFR4demonstrated an improvement
in insulin sensitivity. ISIS-FGFR4Rx is the first drug inourmetabolic franchise to treat obesity andutilizes technologywe in-licensed
fromVervaPharmaceuticals Ltd.
We plan to report data from thePhase 1 study in2014.
ISIS-DGAT2 Rx — ISIS-DGAT2Rx is an antisense drug that specifically reduces the productionof diacylglycerol
acyltransferase-2, orDGAT-2, a key component in the synthesis of triglycerides. By reducingDGAT2, ISIS-DGAT2Rx should reduce
liver fat inpatientswithnonalcoholic steatohepatitis, orNASH. TheNIH estimates that NASH affectsmore than20million people in
theUnitedStates and expects the number to increase as the rate of obesity rises. There are no effective therapies available for patients
withNASH and current treatments consist onlyof lifestyle changes. In addition, because clinicians associate increases in liver fat
with insulin resistance, ISIS-DGAT2Rx could alsobenefit patientswith type 2diabeteswho are insulin resistant.
We plan to complete preclinical evaluationof ISIS-DGAT2Rx in2014.
CancerFranchise
We are discovering anddeveloping antisense drugs to treat cancers both internally and throughour partnershipswith
AstraZeneca andOncoGenexTechnologies Inc. Cancer is an area of significant unmetmedical need and an area inwhich our
antisense technologyprovides uswithunique advantages indiscoveringnewdrugs. Cancer is an extremely complex disease that
involves a large number of targets. Withour technologywe can evaluate a verybroad anddiverse range of targets and identify their
involvement in different types of cancers. Using the informationwe gain early in researchon each of these targets, we canquickly
identifypromising targets for an anti-cancer drug. We select anti-cancer targets that provide amulti-faceted approach to treating
cancer.
Our cancer pipeline consists of anti-cancer antisense drugs that act uponbiological targets associatedwith cancer progression
and/or treatment resistance. In2012, we formed an anti-cancer alliancewithAstraZeneca that expands our anti-cancer efforts and
supports an aggressive andbroad clinical development plan for ISIS-STAT3Rx and ISIS-ARRx. AstraZeneca brings significant
experience that enables the identificationof novel genetic and epigenetic targets for cancer. CombiningAstraZeneca’s expertisewith
our drugdiscovery technology, we plan to expandour cancer franchisewith a number of promising new anti-cancer targets.
We believe the favorable tolerability and early evidence of clinical benefit of the anti-cancer drugs inour pipeline
demonstrate howuniquely suited our technology is to create novel cancer therapeutics. In addition, we believe our generation2.5
chemistry enhances the potency and effectiveness of our antisense drugs, and extends the applicabilityof our technology to cancers
that are difficult to treat. For instance, we presented positive interimPhase 1data onour first generation2.5drug, ISIS-STAT3Rx, in
patientswith advanced cancerwhodidnot adequately respond toprior chemotherapy treatment. In this interim analysis, we observed
clear responses in these patientswith an acceptable safety profile. Basedon these data, we andAstraZeneca are currently evaluating
ISIS-STAT3Rx in a clinical study in focusedpatient populationswith advanced cancer.