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Cancer

We are discovering and developing antisense drugs to treat cancers both internally and through our partnerships with AstraZeneca 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 with AstraZeneca that expands our anti-cancer efforts and supports an aggressive and broad clinical development plan for ISIS-STAT3Rx and ISIS-ARRx. AstraZeneca brings significant experience that enables the identification of novel genetic and epigenetic targets for cancer. Combining AstraZeneca’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, we presented positive interim Phase 1 data on our first generation 2.5 drug, ISIS-STAT3Rx, in patients with advanced cancer who did not adequately respond to prior chemotherapy treatment. In this interim analysis, we observed clear responses in these patients with an acceptable safety profile. Based on these data, we and AstraZeneca are currently evaluating ISIS-STAT3Rx in a clinical study in focused patient populations with advanced cancer.

Custirsen (OGX-011)

Custirsen, formerly OGX-011, now under license to Teva Pharmaceutical Industries Ltd., or Teva, is a second-generation antisense drug that targets clusterin, 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. In December 2009, OncoGenex licensed custirsen to Teva as part of a global license and collaboration agreement to develop and commercialize custirsen. Teva and OncoGenex are 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 FDA granted Fast Track Designation to custirsen for the treatment of metastatic prostate cancer in combination with docetaxel.

Teva and OncoGenex are collaborating on a global Phase 3 clinical program in patients with metastatic castrate resistant prostate cancer, or CRPC, and metastatic non-small cell lung cancer, or NSCLC. OncoGenex and Teva are evaluating custirsen in two Phase 3 clinical studies for first- and second-line chemotherapy in patients with metastatic CRPC. OncoGenex and Teva are also evaluating custirsen in a Phase 3 study as a second-line treatment in patients with NSCLC. Teva and OncoGenex have completed enrollment for the SYNERGY study as a first-line treatment in patients with CRPC. OncoGenex has stated that the FDA has agreed on the design of the SYNERGY trial, a Phase 3 study evaluating custirsen, via the special protocol assessment, or SPA, process. A SPA is an agreement between the FDA and the drug developer that the design and planned analysis of a study is sufficient to address objectives in support of a regulatory submission. Teva and OncoGenex expect to report results for the survival primary endpoint from the SYNERGY study in 2014.

OncoGenex and collaborating investigators evaluated custirsen in five Phase 2 studies in combination with various cancer therapies for prostate cancer, NSCLC, and breast cancer. OncoGenex reported results from a randomized Phase 2 study of custirsen in patients with advanced metastatic CRPC. In this study, OncoGenex reported a median overall survival of 23.8 months in patients treated with custirsen plus docetaxel compared to 16.9 months for patients treated with docetaxel alone. In addition, OncoGenex reported that the unadjusted hazard ratio, a measure used to determine the difference in survival between treatment groups, was 0.61, representing a 39 percent reduction in the rate of death for patients treated with custirsen. OncoGenex also reported that patients treated with custirsen in combination with docetaxel tolerated custirsen well.

OncoGenex has also evaluated custirsen in a Phase 1/2 combination study in patients with NSCLC. In January 2012, OncoGenex reported that one- and two-year survival rates were 54 percent and 30 percent, respectively, and 12 percent of patients were still alive at a median follow-up of 41 months. The median overall survival was 14.1 months and progression-free survival was 4.3 months.

ISIS-EIF4ERx

ISIS-EIF4ERx targets the gene that is responsible for producing the protein eukaryotic initiation factor-4e, or eIF-4E, which cells over-express in a variety of cancers, including prostate, lung, ovarian, liver, breast, head and neck, bladder, colon, thyroid and lymphoma. eIF-4E facilitates the synthesis of factors in the body that support the development, growth, progression and survival of cancer. In preclinical studies, we and collaborators demonstrated marked anti-cancer activity in a broad range of animal models of cancer and provided the first evidence in animals that tumor growth may be more susceptible to eIF-4E inhibition than growth of normal tissue. Targeting eIF-4E has been of great interest to the pharmaceutical industry and the oncology community. However, the pharmaceutical industry considers eIF-4E a difficult protein to target with traditional pharmaceutical approaches.

Eli Lilly and Company completed a Phase 1 study of ISIS-EIF4ERx in patients with cancer that showed that the subjects tolerated the drug well at doses up to 1,200 mg per week. Eli Lilly and Company has rights to license ISIS-EIF4ERx from us on predefined terms.

In 2010, we initiated a Phase 2 program of ISIS-EIF4ERx in patients with NSCLC and prostate cancer. The endpoints for both studies include progression-free survival, overall survival, response rates, time to progression and the reduction of a variety of biomarkers.

Apatorsen

Apatorsen, formerly OGX-427, is a second-generation antisense drug targeting heat shock protein 27, or Hsp27, which is a cell survival protein that cells over-produce in response to many cancer treatments, including hormone ablation therapy, chemotherapy and radiation therapy. Studies have shown that increased Hsp27 production is prevalent in many human cancers, including prostate, NSCLC, breast, ovarian, bladder, renal, pancreatic, multiple myeloma and liver cancers. Studies have also linked increased Hsp27 production to faster rates of cancer progression, treatment resistance and shorter survival duration.

OncoGenex is evaluating apatorsen in patients with cancer. In June 2010, OncoGenex reported results from a Phase 1 study of apatorsen in patients with a variety of cancers. In this study, patients treated with apatorsen as a single agent and in combination with docetaxel tolerated the drug well. In addition, apatorsen, when used as a single agent, demonstrated declines in circulating tumor cells at all doses and in all types of cancer OncoGenex evaluated. Apatorsen also demonstrated evidence of reduction in tumor markers defined as declines of prostate-specific antigen, or PSA, levels in prostate cancer and cancer-antigen-125 levels in ovarian cancer.

In February 2012, OncoGenex reported preliminary results from a Phase 1 study in patients with superficial bladder cancer. In this study, OncoGenex reported that treatment with apatorsen resulted in a trend towards decreased levels of Hsp27 and increased tumor cell death rates.

OncoGenex has initiated a broad Phase 2 program evaluating apatorsen in six Phase 2 studies in patients with cancer. In September 2012, OncoGenex reported preliminary results from a Phase 2 study in patients with CRPC. In this study, OncoGenex reported that treatment with apatorsen in combination with prednisone resulted in a higher number of patients without disease progression at 12 weeks and greater declines in prostate-specific antigen, or PSA, and circulating tumor cells compared to patients treated with prednisone alone. OncoGenex is also evaluating apatorsen in a Phase 2 study, referred to as Pacific, in combination with Zytiga and prednisone in patients with metastatic CRPC who have PSA progression.

OncoGenex has reported the initiation of several investigator-sponsored studies for apatorsen. The Spruce study is a Phase 2 investigator-sponsored study designed to evaluate progression-free survival benefit of apatorsen in combination with carboplatin/pemetrexed therapy in patients with previously untreated Stage IV non-squamous NSCLC. The Rainier study is a Phase 2 investigator-sponsored study designed to evaluate overall survival benefit of apatorsen in combination with Abraxane and gemcitabine therapy in patients with previously untreated metastatic pancreatic cancer.

In a Phase 2 study, referred to as Borealis-1, OncoGenex is evaluating overall survival benefit of apatorsen in combination with gemcitabine and cisplatin in patients with metastatic bladder cancer. OncoGenex is also evaluating apatorsen in a Phase 2 study, Borealis-2, in combination with docetaxel in patients with advanced or metastatic bladder cancer.

ISIS-STAT3Rx

ISIS-STAT3Rx is designed to treat cancer by inhibiting the production of 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 and multiple myeloma and promotes tumor cell growth and prevents cell death.

In 2012, we licensed ISIS-STAT3Rx to AstraZeneca as part of a broad alliance to discover and develop anti-cancer drugs. We are eligible to receive up to $75 million in milestone payments, including up to a $50 million milestone payment subject to meeting 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 new generation 2.5 chemistry. We believe the significant potency we observed in our preclinical studies with ISIS-STAT3Rx broadens the therapeutic opportunities for ISIS-STAT3Rx into many different types of cancer where STAT3 is implicated. Our initial focus is to evaluate ISIS-STAT3Rx in hematologic malignancies, such as lymphoma. Together with AstraZeneca, we have designed a development plan that could allow for a rapid path to the market in these patient populations. AstraZeneca has already initiated a Phase 1/2 study of ISIS-STAT3Rx in patients with advanced metastatic hepatocellular carcinoma, or HCC, a type of liver cancer, and will be evaluating additional therapeutic opportunities.

In preclinical studies, ISIS-STAT3Rx demonstrated antitumor activity in animal models of human cancer with an attractive safety profile. In 2012, we reported interim Phase 1 data in patients with cancer who did not adequately respond to prior chemotherapy treatment. In this study, we showed that ISIS-STAT3Rx treatment resulted in clear responses in patients with advanced cancer with an acceptable safety profile. Based on these data, we initiated a Phase 2 study in focused patient populations with advanced cancer.

ISIS-ARRx

ISIS-ARRx is an antisense drug designed to inhibit the production of the androgen receptor, or AR, for the treatment of patients with prostate cancer. Prostate cancer growth, proliferation and progression are all androgen-dependent, and AR function is involved in disease progression at all stages of prostate cancer. For patients diagnosed with metastatic prostate cancer, current treatments largely involve opposing the action of androgens by blocking the androgen receptor or removing circulating androgens. Although androgen deprivation therapy approaches are initially effective in delaying disease progression in patients with metastatic prostate cancer, over time the course of the disease will progress in many of these patients. Resistance to current therapies is frequent and can occur through a variety of mechanisms including the activation of AR signaling in tumor cells through the amplification, over expression and mutation of the AR gene. Because ISIS-ARRx can inhibit the production of all known forms of AR, including variants of the AR gene, we believe that this drug has the potential to be an effective treatment for all stages of prostate cancer, including prostate cancer patients who are resistant to current therapies.

ISIS-ARRx, also referred to as AZD5312 and previously referred to as ISIS-AZ1Rx, is part of our collaboration with AstraZeneca to discover and develop anti-cancer drugs. As ISIS-ARRx progresses in development, we are eligible to receive milestone payments as well as royalties on sales if ISIS-ARRx is successfully commercialized. ISIS-ARRx is the second drug in our cancer franchise to incorporate our new generation 2.5 chemistry.

In preclinical studies, ISIS-ARRx demonstrated antitumor activity in animal models of prostate cancer, including a model resistant to enzalutamide, a small molecule antagonist often used in patients with castration-resistant prostate cancer.

About Isis

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Our mission is to provide antisense drugs to patients with significant unmet medical needs.

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