Cardiovascular Research

Cardiovascular disease is the leading cause of death in the United States. A common cause of cardiovascular disease is atherosclerosis, or hardening of the arteries, that occurs when cholesterol and inflammatory cells accumulate in blood vessels. Researchers have shown a strong correlation between high cholesterol levels and subsequent cardiovascular diseases. Lowering cholesterol is a key component in preventing and managing cardiovascular disease. Another independent risk factor for cardiovascular disease is high levels of C-reactive protein, or CRP, which clinicians associate with significantly worse outcomes in patients with cardiovascular disease.

We build our cardiovascular disease franchise by evaluating potential drug targets that influence the onset and progression of cardiovascular disease, and we intend to expand our franchise with additional drugs to treat various aspects of cardiovascular disease through complimentary mechanisms. For instance, studies have shown that humans with increased levels of Factor XI are at an increased risk for blood clots forming in their veins, heart attacks and potential strokes.  Clotting factors, including Factor XI, are areas of active research for us and could lead to the development of potent and highly effective drugs to treat disease.  Using antisense compounds we inhibited all of the clotting factors that are made in the liver, and we are evaluating each clotting factor as a potential antisense drug target.  In November 2008, we presented a cardiovascular review during the annual meeting of the American Heart Association in which we provided additional detail on our Factor XI program and other late-stage research programs. (return to top)

Mipomersen—Mipomersen is a first-in-class apo-B synthesis inhibitor currently in Phase 3 development.  It is intended to reduce LDL-cholesterol, or LDL-C, by preventing the formation of atherogenic lipoproteins.  We plan to develop mipomersen for patients who cannot adequately control their cholesterol levels with current therapies and who need new treatment options. Lowering high cholesterol represents a large market opportunity, in which patients still need new treatment options. The current recommendations from the National Cholesterol Education Program’s Adult Treatment Panel III are for LDL-C goals of less than 100 mg/dL for very high-risk patients and less than 130 mg/dL for moderately high-risk patients. The very high-risk population in the United States is about 1.5 to 2 million patients, who are either compliant on both statins and ezetimibe or who are highly statin intolerant.

Mipomersen’s mechanism of action is to reduce the production of apolipoprotein B-100, or apoB-100, which is the protein that carries certain forms of cholesterol and triglyceride particles in the bloodstream. ApoB-100 can carry cholesterol in the bloodstream in a variety of forms, high-density lipoprotein or HDL being the good form, and LDL-C, and very low-density lipoprotein or VLDL being the bad or atherogenic forms directly involved in heart disease. ApoB-100 is found in both bad types of cholesterol particles and is a target that the pharmaceutical industry has long recognized as an attractive point of intervention.  In multiple preclinical models, antisense inhibitors targeted to apolipoprotein B, or apoB, demonstrate reductions in atherosclerotic plaques.  Our preclinical data show that apoB inhibition itself is anti-inflammatory, providing an additional potential mechanism by which patients might achieve cardiovascular benefit.

In June 2008 we licensed mipomersen to Genzyme as part of a strategic transaction that included licensing fees, milestone payments and a mipomersen profit sharing arrangement, which will enable us to continue to benefit from mipomersen’s success.  It is a late-stage product in our pipeline and an important potential growth-driver for us.

In Phase 2 studies, mipomersen, a weekly injectable therapeutic, was observed to reduce LDL-C beyond reductions achieved with standard lipid-lowering drugs, enabling more patients to achieve LDL-C targets.  It was also observed to reduce triglycerides, lipoprotein (a), or Lp(a), and serum apoB, all generally accepted risk factors for cardiovascular disease.  We believe that mipomersen may be of benefit for patients who cannot control their cholesterol with current therapies.

The initial filing for mipomersen will be for patients with homozygous familial hypercholesterolemia, or homozygous FH, a genetic disorder that causes extremely high cholesterol levels and results in the early onset of heart disease.  The Food and Drug Administration, or FDA, granted mipomersen Orphan Drug designation for treating patients with homozygous FH, a very rare, especially severe form of the disease.  Orphan Drug designation encourages and facilitates development of drugs for rare diseases, offering provisions such as reimbursement of certain development costs and market exclusivity upon approval.  We are currently conducting a fully enrolled Phase 3 trial for this population, which we intend to use to support the first U.S. filing for the indication targeted in the second half of 2010.

During the past year, we enhanced our understanding of the mipomersen safety profile with long-term dosing data from our open-label extension study that showed no new safety concerns and increased our safety database in duration and patient numbers.  We also identified another patient population with severe high cholesterol, which has similar risk of cardiovascular events as the homozygous FH population and we feel represents an attractive market opportunity, with an estimated 6 thousand patients in the United States.  Together with Genzyme, we initiated four additional mipomersen studies, including three Phase 3 studies in heterozygous familial hypercholesterolemia, or heterozygous FH, patients, high-risk high-cholesterol patients and severe high-cholesterol patients.  We also initiated a Phase 2 study in high-risk, high-cholesterol patients who are intolerant to statins.

These trials will provide additional data on mipomersen in high-risk patient populations and expand our experience with new patient populations, including patients with severe high cholesterol, statin intolerant patients and patients with type 2 diabetes. These studies will substantially increase the size of the database of patients treated with mipomersen, maximizing the profile and potential for the drug. We and Genzyme expect the data to help inform the design of a clinical outcomes study of mipomersen, potentially increasing the probability of success of that trial.   The outcomes study may also support the eventual potential expansion of mipomersen’s label to include a broader group of at-risk, high-cholesterol patients. (return to top)

ISIS-CRPRx—ISIS-CRPRx is a generation 2.2 antisense drug that inhibits CRP, a protein produced in the liver.  CRP levels increase dramatically during inflammatory disorders, and excessive amounts of CRP have been linked to coronary artery disease. Furthermore, a growing body of evidence from clinical trials implicates CRP in cardiovascular disease progression.  These results suggest that it may be therapeutically beneficial to significantly decrease CRP levels in patients who are at risk for coronary events.  In addition, clinicians have associated elevated CRP levels with a worsening of overall outcomes in conditions such as end-stage renal disease, suggesting that lowering CRP could help these patients.  CRP elevation is also evident in many other major inflammatory diseases such as Crohn’s disease and rheumatoid arthritis.

In preclinical studies, we observed dramatic suppression of liver and serum CRP levels with our antisense inhibitor of CRP. ISIS-CRPRx is currently in a Phase 1 blinded, randomized, placebo-controlled, dose-escalation study designed to assess the safety and pharmacokinetic profile of our drug in addition to the initial effects of our drug on baseline CRP levels in healthy volunteers. (return to top)

BMS-PCSK9Rx—BMS-PCSK9Rx is an antisense drug that targets proprotein convertase subtilisin/kexin type 9, or PCSK9, a member of a large family of proteins.  PCSK9 is an important protein involved in the metabolism of cholesterol.  Its role is to break down the cell surface receptor that captures LDL particles.  Therefore, inhibiting PCSK9 increases the number of receptors available to remove LDL-C from the bloodstream.  Genetic studies in humans have demonstrated that elevated PCSK9 can lead to severely high levels of LDL-C, whereas low PCSK9 is associated with low LDL-C levels.  These observations suggest that it may be therapeutically beneficial to decrease PCSK9 levels in patients who are at risk for cardiovascular disease.

In May 2007, Bristol-Myers Squibb entered into a collaboration with us to identify antisense drugs that target PCSK9.  In 2008, we achieved the first milestone in this collaboration with the selection BMS-PCSK9Rx as a development candidate.  BMS-PCSK9Rx could offer a new and complementary mechanism to current lipid-lowering therapies for the prevention and treatment of cardiovascular diseases. (return to top)

ISIS 113715—ISIS 113715 is our 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.

Scientists have long recognized PTP-1B 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 affecting 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 Phase 2 data on ISIS 113715 during 2009. (return to top)

OMJP-GCGR—We licensed our glucagon receptor, or GCGR, program to Ortho-McNeil-Janssen Pharmaceuticals, Inc. (OMJP) 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, we observed improved glucose control and reduced levels of blood triglycerides without producing hypoglycemia following treatment with an antisense inhibitor of GCGR. While this is justification enough to pursue GCGR as a therapeutic target, the additional activity of our GCGR drug in increasing circulating glucagon-like peptide, or GLP-1, makes GCGR an even more attractive therapeutic target for development. GLP-1 is a hormone that helps to preserve pancreatic function, enhancing insulin secretion.

We and our partner, OMJP, completed a Phase 1 study on OMJP-GCGRRx that we designed to assess activity and safety in healthy volunteers. (return to top)

OMJP-GCCR—We licensed our glucocorticoid receptor, or GCCR, program to Ortho-McNeil-Janssen Pharmaceuticals, Inc. (OMJP) as part of a metabolic disease collaboration we established in 2007.  Glucocorticoid hormones have a variety of effects throughout the body, including promoting liver glucose production and fat storage.  Although scientists have long recognized the inhibition of GCCR as an attractive strategy for development of therapeutics for type 2 diabetes, the side effects associated with systemic GCCR inhibition have challenged developers 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.  Inhibiting GCCR expression in these two organs can lead to systemic side effects.

In preclinical studies, we have shown that antisense inhibition of GCCR reduced levels of blood glucose, demonstrated a dramatic and favorable effect on lipid levels including cholesterol and triglycerides, and reduced body fat.  These observations suggest that an antisense drug that inhibits GCCR could have a broad therapeutic profile. (return to top)

ISIS-SGLT2Rx—ISIS-SGLT2Rx is a generation 2.2 antisense drug targeting sodium—glucose co-transporter type 2, or SGLT2, which is the major transporter for blood sugar re-absorption in the kidney.  By specifically blocking the production of SGLT2 in the kidney tissue, we can promote blood sugar excretion and reduce blood sugar levels, without having any effect on a related gene product, SGLT1.

In addition to being our first antisense drug directed at a target in the kidney, ISIS-SGLT2Rx is also unique due to its 12 nucleotide length rather than the more typical 18 to 21 nucleotide sequences that comprise our other drugs.  This attribute simplifies manufacturing and has the potential to substantially reduce related expenses.  It is among the most potent antisense drugs that we have evaluated in preclinical models. In preclinical studies, inhibition of SGLT2 was very potent in reducing blood glucose levels and hemoglobin, or HbA1c, which is a measure of long-term glucose control, without causing low blood sugar, called 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.  Therefore, we believe that ISIS-SGLT2Rx could be a potent, highly active drug that will provide significant therapeutic benefits.

We are evaluating ISIS-SGLT2Rx in a Phase 1 study designed to assess the safety and activity of the drug in healthy volunteers by measuring the effect on glucose excretion in urine. (return to top)

Cancer Portfolio

We are pursuing the discovery and development of antisense drugs to treat cancers internally and 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.  We and OncoGenex jointly discovered and conducted the initial development of OGX-011.  OncoGenex is now developing OGX-011 on its own.

OncoGenex recently reported positive survival results from a Phase 2 study of OGX-011 in combination with docetaxel and prednisone compared to docetaxel and prednisone alone for first-line treatment of metastatic castrate resistant prostate cancer. The National Cancer Institute of Canada, Clinical Trials Group conducted the trial and analyzed the data, which showed a median survival of 27.5 months compared to docetaxel and prednisone alone of 16.9 months in 82 patients with metastatic or locally recurring prostate cancer refractory to hormone therapy.  The current results were based on study data with a median follow-up of approximately 30 months for both the OGX-011 and control arms.  Results currently indicate that patients in the OGX-011 arm have a death rate of approximately 40% lower than patients in the control arm.  The current 10.6 month median overall survival advantage observed in the OGX-011 group represents an increase over the median survival observed in the control group. As a basis for comparison, the FDA approved docetaxel based on a survival advantage of approximately 2.4 months over mitoxantrone.

Previous results regarding the primary endpoint analysis, PSA response, for this trial were presented at the American Society of Clinical Oncology 2007 annual meeting. In a Phase 2 study evaluating OGX-011 in combination with second-line chemotherapy for metastatic castrate resistant prostate cancer, OGX-011 showed better than expected survival results in combination with second-line chemotherapy, reduction in levels of serum clusterin, durable reductions in pain, and a decline in prostate specific antigen, or PSA, a protein that is often elevated in patients with prostate cancer.

In August 2008, the FDA granted OGX-011 Fast Track Designation as a treatment in combination with docetaxel for progressive metastatic prostate cancer.  The FDA also agreed upon the design of a Phase 3 registration trial of OGX-011 with overall survival as the primary endpoint in patients with castrate resistant prostate cancer, through the Special Protocol Assessment process.  In October 2008, the FDA confirmed the appropriateness of durable pain palliation as a primary endpoint for a second Phase 3 trial design for the product market approval for OGX-011 as a treatment for castrate resistant prostate cancer.

OncoGenex is also evaluating OGX-011 in an ongoing Phase 1/2 combination study in patients with non-small cell lung cancer, or NSCLC.  In February 2009, OncoGenex reported data showing that after two years, 30% of patients who had received OGX-011 with first-line chemotherapy were still alive.  Previously, OncoGenex reported a mature median survival of 14.1 months and a one-year survival rate of 54%.

OncoGenex is currently evaluating OGX-011 in multiple 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. Studies have linked increased Hsp27 production 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 drugs, such as docetaxel. OncoGenex is currently conducting a Phase 1 clinical study of OGX-427 in patients with breast, ovarian, bladder, prostate, lung cancer or NSCLC who have failed potentially curative treatments or for which a curative treatment does not exist. (return to top)

Neurodegenerative Disease

We are pursuing the discovery and development of antisense drugs for neurodegenerative diseases in which there is a large unmet need for new treatment options.  We have initiated several programs to develop drugs to treat severe neurodegenerative diseases, and have funded three of these programs through grants. Our most advanced of the programs, ISIS-SOD1Rx to treat amyotrophic lateral sclerosis, or ALS, also known as Lou Gehrig’s disease, is currently in preclinical toxicology studies. In addition, as part of our alliance with Genzyme, we have a preferred partner relationship for the development and commercialization of antisense drugs for neurodegenerative and certain rare diseases. (return to top)

ISIS-SOD1Rx—ISIS-SOD1Rx is our first drug to enter development that targets superoxide dismutase, or SOD1, a molecule associated with an inherited, aggressive form of ALS. The FDA granted ISIS-SOD1Rx Orphan Drug designation for the treatment of ALS. A small pump administers the drug directly into the central nervous system infusing the drug into the cerebral spinal fluid.  Clinicians call this type of administration intrathecal infusion.

Researchers reported in the Journal of Clinical Investigation that treatment with ISIS-SOD1Rx prolonged life in rats that showed many symptoms of ALS. By delivering our drug 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 investigational new drug-enabling, or IND-enabling, studies for ISIS-SOD1Rx.  Additionally, as part of our alliance with Genzyme, Genzyme has the first right of refusal to license ISIS-SOD1Rx from us. (return to top)

Inflammatory Disease

The broad applicability of our antisense technology allows us to create promising drugs in a variety of disease areas, many of which are underserved with current treatment options.  For instance, our partners Antisense Therapeutics Limited and Teva recently presented encouraging Phase 2 data on ATL/TV 1102 showing that ATL/TV 1102 significantly reduced disease activity in patients with MS.  This data demonstrates the effectiveness of our antisense technology and represents promise for patients with MS. (return to top)

ATL/TV1102—Now under license to Teva, 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 inhibiting VLA-4 positively affects a number of inflammatory diseases, including MS.

We licensed ATL/TV1102 to Antisense Therapeutics Limited (ATL) in December 2001 and, in February 2008, ATL licensed ATL/TV1102 to Teva, which has responsibility for continued development of ATL/TV1102. In 2008, Teva and ATL reported Phase 2a results of ATL/TV1102 showing significantly reduced disease activity in patients with relapsing remitting MS, for which we earned a milestone payment. (return to top)

AIR645—We have licensed AIR645 to Altair, a venture capital funded biotechnology company focused 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, or IL-4R-alpha, which inhibits interleukin 4, or IL-4, and interleukin 13, or 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 showed that inhibiting IL-4R-alpha with an antisense compound potently reduced target RNA and protein levels.  Inhibiting IL-4R also demonstrated 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 is currently completing a Phase 1 study on AIR645 in normal volunteers and a Phase 1b study in asthmatic patients. (return to top)

Other Diseases

We have been successful in developing novel drugs and licensing them to highly focused satellite companies that have the specific expertise and resources to continue developing these drugs.  Together with our partners we continue to advance new drugs into development and move antisense drugs into clinical studies that are outside of our core therapeutic areas. (return to top)

In 2008, iCo provided interim results of an ongoing Phase 1 study of iCo-007 in patients with diffuse diabetic macular edema. (return to top)