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-STAT3-2.5Rx and ISIS-AR-2.5Rx. 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, 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 (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.

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. OncoGenex reported results from a randomized Phase 2 study of custirsen in patients with advanced metastatic castrate resistant prostate cancer, or 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.

OncoGenex is conducting a global Phase 3 clinical program in patients with CRPC and metastatic NSCLC. OncoGenex reported results from the Phase 3 SYNERGY study evaluating custirsen as a first-line treatment in patients with CRPC. OncoGenex reported that treatment with custirsen did not meet the primary endpoint of statistically significant improvement in overall survival compared to first-line therapy alone (median survival 23.4 months vs. 22.2 months, respectively.) OncoGenex is continuing development of custirsen and has completed enrollment in the Phase 3 AFFINITY study in patients with CRPC. OncoGenex is also evaluating custirsen in a Phase 3 clinical study, ESPIRIT, as a second-line treatment in patients with NSCLC.


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. OncoGenex has also reported 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 seven 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 evaluating apatorsen in a Phase 2 study, referred to as Borealis-1, in patients with metastatic bladder cancer in combination with first-line gemcitabine and cisplatin. In December 2014, OncoGenex reported top-line data from this study showing that treatment at the 600 mg dose correlated with a 14 percent reduction in risk of death and a 17 percent reduction in progressive disease and death. OncoGenex reported that less benefit was observed in the 1000 mg cohort due to increased adverse events leading to a higher rate of discontinuation of both apatorsen and chemotherapy.

OncoGenex is also evaluating apatorsen in these five Phase 2 studies:

  • Borealis-2 is a study in patients with advanced or metastatic bladder cancer in combination with docetaxel. OncoGenex began enrolling in this study in April 2013.
  • Pacific is an investigator-sponsored study in combination with Zytiga and prednisone in patients with metastatic CRPC who have PSA progression. Enrollment is estimated to be 80 patients and began in December 2012.
  • Spruce is an investigator-sponsored study in combination with carboplatin/pemetrexed therapy in patients with previously untreated Stage IV non-squamous NSCLC. Enrollment is estimated to be 155 patients and began in August 2013.
  • Cedar is an investigator-sponsored study in combination with carboplatin/gemcitabine therapy in patients with previously untreated advanced Non-squamous lung cancer. Enrollment is estimated to be 140 patients and began in August 2014.
  • Rainier is an investigator-sponsored study in combination with ABRAXANE and gemcitabine therapy in patients with previously untreated metastatic pancreatic cancer. Enrollment is estimated to be 130 patients and began in August 2013.


ISIS-STAT3-2.5Rx, also called AZD9150 and formerly 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.

ISIS-STAT3-2.5Rx 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-STAT3-2.5Rx broadens the therapeutic opportunities for ISIS-STAT3Rx into many different types of cancer where STAT3 is implicated.

In preclinical studies, ISIS-STAT3-2.5Rx 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-STAT3-2.5Rx 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-AR-2.5Rx, also called AZD5312 and formerly ISIS-AZ1Rx and 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-AR-2.5Rx 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.

In preclinical studies, ISIS-AR-2.5Rx 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. In November 2014 at the European Cancer Symposium, AstraZeneca presented preclinical results of ISIS-AR-2.5Rx showing ISIS-AR-2.5Rx can substantially reduce levels of all forms of the androgen receptor, including splice variants that have been implicated in promoting androgen resistance in prostate cancer. Moreover, evidence was presented demonstrating that ISIS-AR-2.5Rx is effective in prostate cancer models that display resistance to current standard of care prostate cancer treatments.

ISIS-AR-2.5Rx is part of our collaboration with AstraZeneca to discover and develop anti-cancer drugs. AstraZeneca is currently evaluating ISIS-AR-2.5Rx in a Phase 1/2 study in patients with AR-related cancers and plans to report data from this study in 2015.

About Isis

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Mission & Values

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

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