Metabolic Disease

We are pursuing the discovery and development of antisense drugs for metabolic diseases such as diabetes and obesity. These chronic diseases affect millions of people and there continues to be a significant need for new therapies for these patients. According to the Centers for Disease Control and Prevention, diabetes affects more than 20 million people in the U.S., or 7 percent of the population, with type 2 diabetes constituting 90 percent to 95 percent of those cases.

We now have four drugs in our pipeline to treat type 2 diabetes, each of which acts upon targets in the liver, fat tissue, or the kidney through distinct mechanisms to improve insulin sensitivity, reduce glucose production, or affect other metabolic aspects of this complex disease. We plan to continue to discover and develop antisense drugs to treat metabolic disease and we are broadening our focus beyond type 2 diabetes. For example, we are expanding our research focus to obesity. At the 2009 American Diabetes Association annual conference we presented new preclinical data on eight research programs with novel targets that could offer new mechanisms to treat metabolic disease, including obesity. Among the data presented, we demonstrated that antisense drugs can significantly lower blood glucose and produce robust insulin-sensitization. We also reported that antisense drugs are able to reduce fat mass and body weight in animals by modulating genes in peripheral tissues such as the liver and fat without having any effects in the central nervous system, validating our anti-obesity therapeutic strategy. We feel that treating obesity is an area where antisense drugs can have an impact and, as a result, we are actively evaluating many exciting obesity targets.

• ISIS 113715 (Diabetes)
• ISIS-GCGR_Rx (Diabetes)
• ISIS-GCCR_Rx (Diabetes)
• ISIS-SGLT2_Rx (Diabetes)

ISIS 113715

ISIS 113715 is an antisense drug that targets 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 provides us with 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.

In October 2009, we reported positive top-line Phase 2 data for ISIS 113715 in patients with type 2 diabetes who had uncontrolled blood sugar despite treatment with stable doses of sulfonylurea. The study showed consistent and statistically significant reductions in multiple short and intermediate measures of glucose control. In addition to lowering blood glucose, ISIS 113715 caused statistically significant and clinically meaningful reductions in LDL cholesterol. Furthermore, consistent with the preclinical data with ISIS 113715, a tendency toward weight loss was observed even in this short-term study without strict dietary control. The effect of ISIS 113715 on weight was preceded by a statistically significant increase in circulating adiponectin, a hormone that increases with weight loss. ISIS 113715 demonstrated a favorable safety profile with no exacerbation of sulfonylurea-induced hypoglycemia or other clinically significant adverse effects.

ISIS-GCGR_Rx

ISIS-GCGR_Rx is an antisense drug that targets GCGR. 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 recently reported Phase 1 data in which ISIS-GCGR_Rx produced a significant improvement in glucagon-induced blood glucose levels and was well tolerated. In this study, normal volunteers were administered a glucagon infusion that caused an increase in blood glucose levels. Subjects treated with ISIS-GCGR_Rx showed a dose-dependent decrease in blood glucose levels and at a dose of 400 mg/week of ISIS-GCGR_Rx demonstrated statistically significant decreases in blood glucose following the glucagon infusion (p<0.0001).

ISIS-GCGR_Rx was developed with Ortho-McNeil-Janssen Pharmaceuticals, Inc., or OMJP, as part of a collaboration. During our research collaboration with OMJP, we identified more potent antisense inhibitors to GCGR. A more potent drug should enhance the therapeutic profile of the GCGR program and provide much greater commercial value. This collaboration has ended and we have regained the rights to the glucagon receptor program. We will continue to pursue this target and plan to move a more potent inhibitor forward in development.

ISIS-GCCR_Rx

ISIS-GCCR_Rx 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 scientists have long recognized inhibiting GCCR as an attractive strategy for developing 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 CNS, or adrenal glands, which could 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. We were developing our GCCR program as part of our collaboration with OMJP. OMJP has returned the program to us, and we will be moving this program forward in development.

ISIS-SGLT2_Rx

ISIS-SGLT2_Rx is an antisense drug that targets 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-SGLT2_Rx is also unique due to its 12 nucleotide length rather than the more typical 18 to 21 nucleotide sequences that comprise our other drugs. 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-SGLT2_Rx could be a potent, highly active drug that will provide significant therapeutic benefits.

We are evaluating ISIS-SGLT2_Rx 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.