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 25 million people in the U.S., or 8 percent of the population, with type 2 diabetes constituting 90 percent to 95 percent of those cases.

Metabolic disease is a very large area of medical need and is another area in which we focus our drug discovery efforts. 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 are developing antisense drugs that doctors could add to existing therapies to treat diabetes and obesity. One hurdle for traditional drug development is the selective targeting of a disease-causing protein from closely related proteins. We design our antisense drugs to target the gene that is responsible for producing the disease-causing protein while avoiding unwanted activity associated with inhibiting a closely related protein. This design makes antisense drugs significantly more selective than many other therapeutic approaches. In addition, the liver and fat cells produce many of the most important therapeutic targets for metabolic disease. Our antisense drugs distribute to the liver and fat cells and inhibit the production of these key therapeutic targets. We plan to continue to discover and develop antisense drugs to treat metabolic disease and we are broadening our focus beyond type 2 diabetes. Our newest drug to enter development, ISIS-FGFR4_Rx, is an anti-obesity drug that inhibits the production of FGFR4 in fat cells and offers a new mechanism for weight control that may be complementary to appetite-suppressing therapies currently on the market.

• ISIS-PTP1B_Rx (Diabetes)
• ISIS-GCGR_Rx (Diabetes)
• ISIS-GCCR_Rx (Diabetes)
• ISIS-FGFR4_Rx (Obesity)
• ISIS-DGAT2_Rx (NASH)

ISIS-PTP1B_Rx

ISIS-PTP1B_Rx is an antisense drug that targets protein tyrosine phosphatase-1B, PTP-1B, for the treatment of type 2 diabetes. PTP-1B is a phosphatase that negatively regulates insulin receptor signaling and is responsible for turning off the activated insulin receptor. Reducing PTP-1B enhances insulin activity. Scientists have long recognized PTP-1B as an attractive target to treat 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. ISIS-PTP1B_Rx is designed to increase the body’s sensitivity to the natural hormone insulin, resulting in better glucose control for patients with type 2 diabetes. Because of its unique mechanism ISIS-PTP1B_Rx has the potential to contribute to the treatment of type 2 diabetes without causing weight gain or hypoglycemia. The reductions in LDL-C produced by PTP-1B inhibition should also provide an added benefit to patients.

Earlier Phase 2 studies of ISIS 113715 provided evidence of the therapeutic potential of inhibiting PTP-1B. In those studies, PTP-1B inhibition improved glucose control and reduced LDL-C in both newly diagnosed diabetic patients and in patients who were taking sulfonylureas. Those studies also showed that PTP-1B inhibition did not cause weight gain, another substantial advantage in the treatment of diabetic patients who are frequently obese and at high cardiovascular risk. The data from these studies support the development of ISIS-PTP1B_Rx and should allow a very rapid route to clinical proof-of-concept.

ISIS-PTP1B_Rx has the potential to be broadly useful in combination with most of the other commonly used drugs to treat patients with diabetes, including insulin, GLP-1 agonists, and more traditional drugs like metformin. The initial clinical development plan for ISIS-PTP1B_Rx will focus on treating diabetic patients who are inadequately controlled on insulin, helping them utilize insulin more efficiently; and patients who are beginning to fail oral therapies, extending the time they have before becoming dependent on insulin. We are evaluating ISIS-PTP1B_Rx in a Phase 1 study in healthy volunteers.

ISIS-GCGR_Rx

ISIS-GCGR_Rx is an antisense drug that targets the glucagon receptor (GCGR) to reduce the effects of glucagon, a hormone that causes excessive glucose production in the liver. 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 GCGR also increases the production of active glucagon-like peptide (GLP-1), a hormone that preserves pancreatic function and enhances insulin secretion. Therefore, 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, which were conducted in the most insulin-resistant models of type 2 diabetes, antisense reduction of GCGR produced robust glucose control, reduced levels of triglycerides and resulted in preservation of the pancreas without producing hypoglycemia. In these insulin-resistant models, antisense inhibition of GCGR had a significant effect in decreasing excessive liver glucagon action. In addition, it increased circulating GLP-1, thereby improving pancreatic function.

Given the dual-action mechanism of ISIS-GCGR_Rx, we believe that this drug could be used in diabetic patients with severe hyperglycemia who are not controlled with current treatments and who would benefit from a drug that significantly decreases glucose levels without producing hypoglycemia. We are currently evaluating ISIS-GCGR_Rx in a Phase 1 study in healthy volunteers.

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. Reduction of the GCCR action specifically in the liver and fat tissues is an attractive therapeutic approach, because it provide the desired effects on glucose and lipid control, without causing potential side effects associated with systemic GCCR inhibition.

In preclinical studies, we demonstrated reduction of GCCR specific to the liver and fat tissues, In addition, we have shown that antisense inhibition of GCCR produced robust lowering of blood glucose and lipid levels and a decrease in body fat in obese animals. Therefore ISIS-GCCR_Rx could be used in diabetic patients with moderate to severe hypoglycemia.

We are currently evaluating ISIS-GCCR_Rx in a Phase 1 study in healthy volunteers.

ISIS-FGFR4_Rx

ISIS-FGFR4_Rx is an antisense drug that specifically reduces the production of fibroblast growth factor receptor 4 (FGFR4) in the liver and fat tissues, which decreases the body’s ability to store fat while simultaneously increasing fat burning and energy expenditure. Because ISIS-FGFR4_Rx does not distribute to the brain or central nervous system (CNS), ISIS-FGFR4_Rx should not produce any CNS side effects, unlike many anti-obesity drugs that primarily work to suppress appetite by acting in the brain, commonly resulting in CNS side effects.

In preclinical studies, antisense inhibition of FGFR4 lowered body weight when administered as a single agent and in the presence or absence of a calorie-restricted diet. Additionally, inhibition of FGFR4 produced a decrease in body weight when administered in combination with an appetite-suppressing drug. In addition to the reduction in body weight, inhibiting FGFR4 demonstrated an improvement in insulin sensitivity. ISIS-FGFR4_Rx was safe and well tolerated in multiple species. ISIS-FGFR4_Rx is the first drug in our metabolic franchise to treat obesity and utilizes technology we in-licensed from Verva Pharmaceuticals.

We are currently evaluating ISIS-FGFR4_Rx in a Phase 1 study in healthy volunteers.

ISIS-DGAT2_Rx

ISIS-DGAT2_Rx specifically inhibits diacylglycerol acyltransferase-2, or DGAT-2, a key component in the synthesis of triglycerides. ISIS-DGAT2_Rx is designed to reduce liver fat in patients with nonalcoholic steatohepatitis (NASH), a common and often asymptomatic liver disease that can cause irreversible damage to the liver, and lead to liver cirrhosis and cancer. The incidence of NASH in the United States is estimated to be more than 20 million, and is expected to increase as the rate of obesity rises. There are no effective therapies available for patients with NASH and current treatments consist only of lifestyle changes. In addition, because increase in liver fat is strongly associated with insulin resistance, ISIS-DGAT2_Rx could also be beneficial for patients with type 2 diabetes who are insulin resistant.

We plan to conduct preclinical investigational new drug enabling studies on ISIS-DGAT2_Rx in 2012.