Cardiovascular Research

We are continuing to build our cardiovascular disease franchise by evaluating additional potential drug targets that influence the onset and progression of cardiovascular disease. We intend to expand our cardiovascular franchise with additional drugs to treat various aspects of cardiovascular disease through complimentary mechanisms. In addition, we continue to add to our scientific understanding of our drugs and disease targets, including the biological processes that are linked to our disease targets and the impact of our drugs on these processes. For instance, PCSK9 is a promising target for lowering cholesterol. It has been shown that humans with genetic mutations leading to increased levels of PCSK9 have severe high cholesterol. Additional research may enable us to continue to identify other novel disease intervention targets that can lead to the development of potent and highly effective drugs to treat cardiovascular disease. (return to top)

Mipomersen (ISIS 301012) — Mipomersen is a second-generation antisense drug that reduces the production of apoB-100, a protein critical to the synthesis and transport of "bad" cholesterol.  On January 7, 2008, Isis announced the licensing of mipomersen to Genzyme as the preferred partner to continue development, commercialize and market the drug.  Mipomersen is currently in Phase 3 studies for patients with familial hypercholesterolemia (FH), a disease which creates an increased risk of premature cardiovascular disease (CVD) and CVD-related death.  In phase 2 studies, mipomersen, a weekly injectable therapeutic, was observed to reduce cholesterol and other atherogenic lipids beyond reductions achieved with standard lipid-lowering drugs, enabling more patients to achieve LDL-C targets.

The initial indication sought for mipomersen will be for patients with homozygous FH, and enrollment in a phase 3 trial in this patient population is expected to be completed by the end of this year.  Data are expected to be available in mid-2009 and a U.S. filing for this indication is anticipated during the second half of 2010.

In August 2008, Genzyme and Isis initiated a second Phase 3 study of mipomersen in patients with heterozygous FH and coronary artery diseas.  The study will evaluate the safety and efficacy of mipomersen and is a randomized, double-blind, placebo-controlled study taking place at approximately 30 sites in the U.S. and Canada, with an anticipated total enrollment of around 100 patients.  Patients on a stable dose of other lipid-lowering agents are being randomized 2:1 to receive a 200 mg dose of mipomersen or placebo weekly for 26 weeks.  The primary endpoint will be percent reduction in LDL cholesterol, and data are expected to be available in 2010.  The trial will add to the body of clinical data on mipomersen and the overall product profile.

Later in 2008, Genzyme and Isis plan to begin three additional trials evaluating mipomersen's safety and efficacy in reducing LDL cholesterol in high-risk patients during the second half of 2008.  These trials will include: one for apheresis-eligible patients, and two for high-risk, high cholesterol patients.  All three have anticipated trial designs that include a 2:1 randomization ratio of a 200 mg dose of mipomersen or placebo weekly for 26 weeks.

These trials will continue to build the body of clinical evidence around mipomersen's value in managing very high risk patients.  Data from the trials will also inform the design of the morbidity and mortality outcome study for potential expansion of mipomersen's label to include a broader group of at-risk, high cholesterol patients on maximally tolerated, currently available therapies.

Following the finalization in June of the mipomersen license and collaboration agreement between Genzyme and Isis, the mipomersen IND and all regulatory authority has been transferred to Genzyme.  Now that this transition has taken place, the companies are looking forward to Genzyme beginning discussions with the FDA and regulatory authorities in Europe, where the development path for mipomersen may differ from that in the U.S. (return to top)

ISIS 353512—ISIS 353512 is an antisense drug that targets C-reactive protein (CRP).  For many years, CRP has been used as a clinical biomarker of diseases with an inflammatory component, such as cardiovascular disease, Crohn’s disease, rheumatoid arthritis and end-stage renal disease.  Elevated levels of CRP have been linked to coronary artery disease and a growing body of evidence from clinical trials implicates CRP in cardiovascular disease progression.  Although CRP’s active participation in these diseases remains to be determined, several lines of evidence support a causal role of CRP in disease, suggesting that it may be therapeutically beneficial to decrease CRP levels in patients who are at risk for coronary events.  In addition, elevated CRP levels have been associated with a worsening of overall outcome in conditions such as end-stage renal disease, suggesting that lowering CRP in these patients would be beneficial.  In preclinical studies, ISIS 353512 produced dramatic suppression of liver and serum CRP levels.

ISIS 353512 is currently in a Phase 1 study in a blinded, randomized, placebo-controlled, dose-escalation study designed to assess the safety and pharmacokinetic profile of ISIS 353512 as well as to assess the initial effects of the drug on baseline CRP levels in healthy volunteers.  In addition, Isis is designing a broad Phase 2 program to investigate multiple indications for ISIS 353512. (return to top)

BMS-PCSK9—BMS PCSK9 is a development candidate that targets proprotein convertase subtilisin kexin 9 (PCSK9), a member of a large family of proteases, helps regulate the amount of LDL-cholesterol in the bloodstream through its interactions with the LDL-receptor.  Genetic studies in humans have demonstrated that elevation in PCSK9 concentrations can lead to severely high concentrations of LDL-cholesterol, whereas low PCSK9 concentrations are associated with low LDL-cholesterol concentrations.

In May 2007, BMS entered into a collaboration with Isis to identify antisense drugs that target PCSK9, BMS PCSK9 is the first development candidate identified from the collaboration and could offer a new and complementary mechanism to current lipid-lowering therapies for the prevention and treatment of cardiovascular disease. (return to top)

ISIS 113715—ISIS 113715 is our second generation antisense inhibitor of protein tyrosine phosphatase 1b, or PTP-1b, for the treatment of type 2 diabetes. PTP-1b is responsible for turning off the activated insulin receptor. As a result, by reducing levels of PTP-1b, ISIS 113715 enhances the activity of insulin. We plan to initially develop ISIS 113715 as an adjunct to insulin therapy. ISIS 113715 presents the opportunity to develop a first-in-class drug with a novel mechanism of action and an insulin signal enhancer with anti-obesity and lipid lowering potential.

PTP-1b has long been recognized as an attractive target for treatment of diabetes, but due to structural similarities among closely related proteins, pharmaceutical companies have had difficulty identifying small molecule drugs with sufficient specificity to be safe. Our antisense technology allows us to design very specific drugs that inhibit PTP-1b and that do not inhibit other protein family members, making it possible to reduce PTP-1b activity without effecting other closely related proteins that would likely lead to unwanted side effects.

ISIS 113715 is currently in Phase 2 development for the treatment of type 2 diabetes. In humans and preclinical studies, ISIS 113715 has demonstrated reductions in blood glucose without causing low blood sugar, weight gain or nausea. As part of our Phase 2 program, we are conducting a combination study of ISIS 113715 in patients with type 2 diabetes. Because our initial registration plan for ISIS 113715 is as an adjunct to insulin therapy, we are evaluating it in combination with sulfonylureas. Sulfonylureas, which are commonly prescribed oral antidiabetic drugs, increase insulin secretion in the body and therefore they offer the best approximation of a combination with insulin therapy in the milder disease setting appropriate for this first combination experience with ISIS 113715. We plan to report results of this Phase 2 study during 2008. (return to top)

ISIS 325568—ISIS 325568 is an antisense drug that targets glucagon receptor, or GCGR. Our GCGR program was licensed to OMI as part of a metabolic disease collaboration we established in 2007. Glucagon is a hormone that opposes the action of insulin and stimulates the liver to produce glucose. In type 2 diabetes, unopposed action of glucagon can lead to increased blood glucose levels. Reducing the expression of GCGR using antisense inhibitors, and thereby reducing excessive liver glucose production, should lower blood glucose and help control type 2 diabetes.

In preclinical studies, ISIS 325568 led to improved glucose control and reduced levels of blood triglycerides without producing hypoglycemia. While this is justification enough to pursue GCGR as a therapeutic target, the additional activity of ISIS 325568 in increasing circulating glucagon-like peptide, or GLP-1, makes it an even more attractive drug for development. GLP-1 is a hormone that helps to preserve pancreatic function, enhancing insulin secretion.

ISIS 325568 is currently being evaluated in a Phase 1 study designed to assess activity, including its effect on liver glucose production, as well as safety and the characteristics of ISIS 325568 that determine its effectiveness as a drug. The initiation of this trial marked the completion of our first milestone with OMI in our metabolic disease collaboration, and we believe that, in addition to safety, this trial will provide the opportunity to demonstrate proof-of-concept in humans. Working with OMI, we expect to complete this Isis initiated phase 1 safety study of ISIS 325568 within the next year, and we expect OMI will initiate a phase 2 study on ISIS 325568.(return to top)

ISIS 377131—ISIS 377131 is an antisense drug that targets the glucocorticoid receptor, or GCCR. Glucocorticoid hormones have a variety of effects throughout the body, including promoting liver glucose production and fat storage. Although inhibition of GCCR has long been recognized as an attractive strategy for development of therapeutics for Type 2 diabetes, the side effects associated with systemic GCCR inhibition have challenged development of traditional drugs. Antisense inhibitors of GCCR take advantage of the unique tissue distribution of oligonucleotides that allows the antisense drugs to antagonize glucocortocoid action primarily in liver and fat tissue. Notably, antisense drugs do not reduce GCCR expression in the central nervous system or adrenal glands—inhibition of GCCR expression in these two organs can lead to systemic side effects. In preclinical studies, Isis has shown that ISIS 377131 has a broad therapeutic profile that includes reduction of blood glucose levels, a dramatic and favorable effect on lipid levels including cholesterol and triglycerides, and a reduction in body fat. (return to top)

ISIS 388626—ISIS 388626 is our latest metabolic disease drug to enter our development pipeline for the treatment of diabetes. ISIS 388626 is a generation 2.2 antisense drug that targets the sodium dependent glucose transporter type 2 (SGLT2) to increase blood sugar excretion thereby reducing blood sugar levels. Because SGLT2 is responsible for glucose re-absorption in the kidney, blocking that action promotes glucose excretion and lowers blood sugar.

In preclinical studies, ISIS 388626 and other antisense inhibitors of SGLT2, effectively reduced target mRNA levels in several animal species, increased urinary glucose excretion and consequently lowered blood glucose levels and HbA1c (in hyperglycemic animals) without causing dangerously low levels of blood sugar known as hypoglycemia.  These data are consistent with expectations based on human subjects who have mutations in the SGLT2 gene and have increased urine glucose levels but are otherwise asymptomatic.  ISIS 388626 effectively and specifically inhibits the production of SGLT2 in the kidney tissue, without having any effect on a related gene product, SGLT1.  In addition to being Isis’ first antisense drug for a kidney target, ISIS 388626 is also unique due to its 12 nucleotide length rather than the more typical 18 – 21 nucleotide sequences that comprise Isis’ other drugs.  This attribute simplifies manufacturing and has the potential to substantially reduce related expenses.  The short sequence may also contribute to ISIS 388626’s unusually high potency; it is among the most potent antisense drugs that Isis has evaluated in preclinical models. We anticipate initiating IND-enabling studies for ISIS 388626 in 2008. (return to top)

CancerPortfolio

We are pursuing the discovery and development of antisense drugs to treat cancers through our partnerships with OncoGenex and Lilly. Our current portfolio consists of four antisense drugs that act upon biological targets associated with cancer progression and/or treatment resistance. We believe that our second generation antisense drugs have properties that make them attractive therapies for cancer. (return to top)

OGX‑011—OGX-011 is a second generation antisense inhibitor of clusterin, a secreted protein that acts as a cell-survival protein and is over-expressed in response to anti-cancer agents, like chemotherapy, hormone ablation and radiation therapy.  OGX-011 was jointly discovered by Isis and OncoGenex and is being developed by OncoGenex.  OncoGenex recently reported preliminary Phase 2 data of OGX-011 in patients with hormone refractory prostate cancer at the 2008 Annual Meeting of the American Society of Clinical Oncology (ASCO).  Investigators found that, in this patient population, OGX-011 continues to show better than expected survival results when compared to publish results.  In August 2008, OGX-011 was granted Fast Track Designation from the U.S. Food and Drug Administration as a treatment in combination with docetaxel for progressive metastatic prostate cancer.  OGX-011 is currently being evaluated in five Phase 2 clinical studies in prostate, lung and breast cancer. (return to top)

OGX‑427—OGX‑427 is the second anti-cancer drug in our collaboration with OncoGenex and is a second generation antisense inhibitor targeting heat shock protein 27, or Hsp27. Hsp27 is a cell survival protein that is over-produced in response to many cancer treatments, including hormone ablation therapy, chemotherapy and radiation therapy. Increased Hsp27 production is observed in many human cancers, including prostate, NSCLC, breast, ovarian, bladder, renal, pancreatic, multiple myeloma and liver cancers. Increased Hsp27 production is linked to faster rates of cancer progression, treatment resistance and shorter survival duration. In single agent preclinical studies, OGX-427 demonstrated significant anti-tumor activity at low concentrations. In addition, when combined with chemotherapy, in preclinical prostate cancer studies, OGX-427 was able to significantly enhance the anti-tumor activity of the widely used chemotherapy drug, paclitaxel. OncoGenex is currently conducting a Phase 1 clinical study of OGX-427 in patients with breast, ovarian, bladder, prostate or lung cancer. OncoGenex expects to initiate Phase 2 clinical studies of OGX‑427 in 2008. (return to top)

ATL/TV1102—Now under license to Teva Pharmaceuticals, ATL/TV1102 is an antisense inhibitor of CD49d, which is a subunit of Very Late Antigen-4, or VLA-4. Studies in animal models have demonstrated that inhibition of VLA-4 has a positive effect on a number of inflammatory diseases, including multiple sclerosis. In December 2001, we licensed ATL/TV1102to ATL. Based on the results of a dose-escalating Phase 1 study of TV-1102 that showed that 6 mg/kg/week of TV-1102 appeared well tolerated, ATL initiated a Phase 2 clinical trial of TV-1102 in patients with multiple sclerosis.

In 2008, ATL licensed TV-1102 to Teva and most recently, Teva and ATL reported Phase 2a results showing that ATL/TV1102 significantly reduced disease activity in patients with RRMS.  Based on these encouraging results, Teva intends to conduct additional preclinical and clinical research on ATL/TV1102. (return to top)

AIR645 (ISIS 369645)—We have licensed AIR645, formerly ISIS 369645, to newly formed Altair, a venture capital funded biotechnology company that was created to focus on the discovery, development and commercialization of our antisense drugs to treat respiratory conditions. AIR645 is an inhaled second generation antisense inhibitor of the alpha subunit of the interleukin 4 receptor, IL-4R‑alpha that inhibits IL‑4 and IL‑13 signaling. IL‑4 and IL‑13 are two important cytokines in asthma, which regulate inflammation, mucus overproduction and airway hyper‑responsiveness. In preclinical studies, we have shown that a mouse‑optimized antisense inhibitor of IL-4R‑alpha potently reduced target messenger RNA, or mRNA, and protein levels, and had pharmacologic activity in mouse models of asthma that included reducing lung cytokine production, inflammation, and airway hyper‑ responsiveness. In addition, these studies showed that, when delivered by inhalation, AIR645 rapidly distributed to the airways and achieved therapeutic drug concentrations in multiple cell types with little systemic exposure. Altair initiated Phase 1 evaluation of AIR645 in 2008. (return to top)

ISIS 333611—ISIS 333611 is our first drug to enter development for the treatment of an inherited, aggressive form of ALS, which is also known as Lou Gehrig’s disease. ISIS 333611 was granted Orphan Drug designation by the FDA for the treatment of ALS. The drug is administered directly into the central nervous system by a small pump that infuses drug into the cerebral spinal fluid. This type of administration is called intrathecal infusion.

In animal models, researchers have demonstrated that ISIS 333611, when delivered into the cerebral spinal fluid, inhibits Cu/Zn superoxide dismutase, or SOD1, a molecule that is associated with an inherited, aggressive form of ALS. In July 2006, researchers reported in the Journal of Clinical Investigation that treatment with ISIS 333611 prolongs life in rats that show many features of ALS. By delivering ISIS 333611 directly to the fluid that circulates within the central nervous system, investigators were able to lower production of the mutant protein in neurons and surrounding cells. The ALS Association and the Muscular Dystrophy Association are providing funding for IND-enabling studies of ISIS 333611. (return to top)