Isis Pharmaceuticals, Inc. Form 10K - page 17

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InFebruary2012, OncoGenex reportedpreliminary results from a Phase 1 study inpatientswith superficial bladder cancer.
In this study,OncoGenex reported that treatmentwith apatorsen resulted in a trend towards decreased levels ofHsp27 and increased
tumor cell death rates.
OncoGenexhas initiated a broadPhase 2program evaluating apatorsen in sixPhase 2 studies inpatientswith cancer. In
September 2012, OncoGenex reportedpreliminary results from aPhase 2 study inpatientswithCRPC. In this study, OncoGenex
reported that treatmentwith apatorsen in combinationwithprednisone resulted in a higher number of patientswithout disease
progression at 12weeks andgreater declines inprostate-specific antigen, or PSA, and circulating tumor cells compared to patients
treatedwithprednisone alone. OncoGenex is also evaluating apatorsen in a Phase 2 study, referred to as Pacific, in combinationwith
Zytiga andprednisone inpatientswithmetastaticCRPCwhohavePSAprogression.
OncoGenexhas reported the initiationof several investigator-sponsored studies for apatorsen. TheSpruce study is aPhase 2
investigator-sponsored studydesigned to evaluate progression-free survival benefit of apatorsen in combinationwith
carboplatin/pemetrexed therapy inpatientswith previouslyuntreatedStage IVnon-squamousNSCLC. TheRainier study is aPhase 2
investigator-sponsored studydesigned to evaluate overall survival benefit of apatorsen in combinationwithAbraxane andgemcitabine
therapy inpatientswithpreviouslyuntreatedmetastatic pancreatic cancer.
In a Phase 2 study, referred to asBorealis-1, OncoGenex is evaluatingoverall survival benefit of apatorsen in combination
withgemcitabine and cisplatin inpatientswithmetastatic bladder cancer. OncoGenex is also evaluating apatorsen in aPhase 2 study,
Borealis-2, in combinationwithdocetaxel inpatientswith advancedormetastatic bladder cancer. OncoGenex expects to report data
from theBorealis-1 study in the secondhalf of 2014.
ISIS-STAT3Rx —We designed ISIS-STAT3Rx to treat cancer by inhibiting the productionof a gene critical for tumor cell
growth and survival. Signal transducer and activator of transcription 3, or STAT3, is over-active in a variety of cancers, including
brain, lung, breast, bone, liver andmultiplemyeloma andpromotes tumor cell growth andprevents cell death.
In2012, we licensed ISIS-STAT3Rx toAstraZeneca as part of a broad alliance todiscover anddevelop anti-cancer drugs. We
are eligible to receive up to$75million inmilestone payments, includingup to a $50millionmilestone payment subject tomeeting
pre-agreed efficacy and safety criteria in the ongoing ISIS-STAT3Rx study. We are also eligible to receive double-digit royalties on
sales of ISIS-STAT3Rx.
ISIS-STAT3Rx is our first drug to incorporate our newgeneration2.5 chemistry. We believe the significant potencywe
observed inour preclinical studieswith ISIS-STAT3Rx broadens the therapeutic opportunities for ISIS-STAT3Rx intomanydifferent
types of cancerwhereSTAT3 is implicated. Our initial focus is to evaluate ISIS-STAT3Rx in hematologicmalignancies, such as
lymphoma. TogetherwithAstraZeneca, we have designed a development plan that could allow for a rapid path to themarket in these
patient populations. AstraZeneca has already initiated a Phase 1/2 studyof ISIS-STAT3Rx inpatientswith advancedmetastatic
hepatocellular carcinoma, orHCC, a type of liver cancer, andwill be evaluating additional therapeutic opportunities.
Inpreclinical studies, ISIS-STAT3Rx demonstrated antitumor activity in animalmodels of human cancerwith an attractive
safetyprofile. In2012, we reported interimPhase 1data inpatientswith cancerwhodidnot adequately respond toprior
chemotherapy treatment. In this study,we showed that ISIS-STAT3Rx treatment resulted in clear responses inpatientswith advanced
cancerwith an acceptable safety profile. Basedon these data, we initiated a Phase 2 study in focused patient populationswith
advanced cancer. We plan to report data from this Phase 2 study at a future scientificmeeting.
ISIS-ARRx — ISIS-ARRx is an antisense drugdesigned to inhibit the production of the androgen receptor, orAR, for the
treatment of patientswithprostate cancer. Prostate cancer growth, proliferation andprogression are all androgen-dependent, andAR
function is involved indisease progression at all stages of prostate cancer. For patients diagnosedwithmetastatic prostate cancer,
current treatments largely involve opposing the actionof androgens byblocking the androgen receptor or removing circulating
androgens. Although androgendeprivation therapy approaches are initially effective indelaying disease progression inpatientswith
metastatic prostate cancer, over time the course of the diseasewill progress inmanyof these patients. Resistance to current therapies
is frequent and canoccur through a varietyofmechanisms including the activationofAR signaling in tumor cells through the
amplification, over expression andmutation of theARgene. Because ISIS-ARRx can inhibit the productionof all known forms ofAR,
includingvariants of theARgene, we believe that this drughas the potential to be an effective treatment for all stages of prostate
cancer, including prostate cancer patientswho are resistant to current therapies.
ISIS-ARRx, also referred to asAZD5312 andpreviously referred to as ISIS-AZ1Rx, is part of our collaborationwith
AstraZeneca todiscover and develop anti-cancer drugs. As ISIS-ARRx progresses indevelopment, we are eligible to receivemilestone
payments aswell as royalties on sales if ISIS-ARRx is successfully commercialized. ISIS-AR Rx is the seconddrug inour cancer
franchise to incorporate our newgeneration2.5 chemistry.