Metabolic disorders are chronic diseases that affect millions of people. There is still a significant need for new therapies for these patients. According to the Centers for Disease Control and Prevention, diabetes affects more than 29 million people in the United States, or nine percent of the population, with type 2 diabetes constituting 90 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 and development efforts. Our approach is to develop antisense drugs that doctors can add to existing therapies to treat diabetes. One hurdle for traditional drug development is that most traditional drugs cannot selectively target a disease-causing protein without also affecting closely related proteins, which often results in unwanted side effects. We design our antisense drugs to target the gene responsible for producing the disease-causing protein while avoiding unwanted effects on closely related proteins, thereby reducing the risk of side effects.
We have reported positive Phase 2 data from ISIS-GCGRRx and ISIS-PTP1BRx, the most advanced drugs in our metabolic franchise. These two drugs and our third drug, ISIS-GCCRRx, are designed to act upon targets in the liver or fat tissue through a distinct mechanism to improve insulin sensitivity, reduce glucose production, or affect other metabolic aspects of this complex disease.
ISIS-GCGRRx is an antisense drug that targets the glucagon receptor, or GCGR, to reduce the effects of glucagon. Glucagon is a hormone that opposes the action of insulin and stimulates the liver to produce glucose, particularly in type 2 diabetes. In patients with advanced diabetes, uncontrolled glucagon action leads to a significant increase in blood glucose levels. Therefore, attenuating glucagon action could have a significant glucose lowering effect in patients with severe diabetes. In addition, reducing GCGR produces more active glucagon-like peptide, or GLP-1, a hormone that preserves pancreatic function and enhances insulin secretion.
We are developing ISIS-GCGRRx to help provide better glucose control for patients with type 2 diabetes. In preclinical studies using the most insulin-resistant models of type 2 diabetes, antisense reduction of GCGR decreased excessive liver glucagon action, produced robust glucose control, reduced levels of triglycerides and helped preserve the pancreas without producing hypoglycemia. Although researchers have developed and evaluated small molecule inhibitors of GCGR and observed glucose-lowering effects, treatment with these small molecule inhibitors also produced side effects, including increases in lipids and blood pressure, limiting their potential use as drugs.
We have completed a Phase 1 study evaluating the safety of ISIS-GCGRRx in healthy volunteers. In this study ISIS-GCGRRx was generally well tolerated with no clinically significant increases in lipids or blood pressure and with no hypoglycemic events.
We have completed a Phase 2 placebo-controlled study evaluating ISIS-GCGRRx in patients with type 2 diabetes. In June 2014, we reported these data at the American Diabetes Association meeting. In this study, we showed that patients treated with ISIS-GCGRRx in addition to metformin achieved absolute mean reduction in hemoglobin A1c, or HbA1c, of up to 2.25 percentage points from baseline after only 13 weeks of treatment. Patients receiving placebo had a 0.25 percentage point reduction in HbA1c. In this study, more than half of the patients in the per protocol cohort achieved an HbA1c level of less than or equal to 7.0 percent. Patients treated with ISIS-GCGRRx in this study also achieved a mean reduction of up to 74.9 µmol/L in fructosamine. In addition, in these patients a mean increase in total GLP-1 of up to 19.97 pmol/L was observed.
In this study ISIS-GCGRRx was generally well tolerated. The most common adverse event was infrequent injection site reactions, which were predominantly mild and typically resolved rapidly. There were no flu-like symptoms, no abnormalities in renal function and no cases of symptomatic hypoglycemia. ISIS-GCGRRx was not associated with clinically meaningful increases in LDL-C, triglycerides, blood pressure or body weight gain (side effects associated with some small molecule inhibitors of glucagon receptor). As has been observed with small molecule inhibitors of glucagon receptor and consistent with the pharmacology of glucagon receptor inhibition, liver enzyme elevations that were neither associated with elevated bilirubin nor other indicators of liver damage were observed. Liver enzyme elevations were much less frequent and lower in the 100 mg dose cohort compared to the 200 mg dose cohort and declined after dosing discontinued. There were no clinically meaningful changes in other laboratory values.
. Given the unique mechanism of action and good tolerability observed, we believe that doctors could use ISIS-GCGRRx in diabetic patients with severe hyperglycemia who are not controlled with current treatments and who could benefit from a drug that significantly decreases glucose levels and preserves pancreatic function.
ISIS-GCCRRx is an antisense drug that targets glucocorticoid receptor, or GCCR. Glucocorticoid hormones effect a variety of processes throughout the body, including promoting liver glucose production and fat storage. Scientists associate excessive GCCR activity in the liver and fat with obesity, insulin resistance and glucose intolerance. Although scientists have long recognized inhibiting GCCR as an attractive strategy for improving glycemic and lipid control in patients with type 2 diabetes, the side effects associated with systemic GCCR inhibition have challenged traditional drug developers. Antisense inhibitors of GCCR take advantage of the unique tissue distribution of oligonucleotides that allows the antisense drugs to inhibit glucocortocoid action primarily in liver and fat tissue. Notably, antisense drugs delivered systemically do not reduce GCCR expression in the central nervous system or adrenal glands, which could lead to systemic side effects. Reducing GCCR specifically in the liver and fat tissues is an attractive therapeutic approach because it lowers glucose and lipids, without causing potential side effects associated with systemic GCCR inhibition.
In preclinical studies, we showed that we can reduce GCCR specifically in the liver and fat tissues. In addition, we have shown that antisense inhibition of GCCR produced robust lowering of blood glucose, lipid levels and decreased body fat in obese animals. We have completed a Phase 1 study evaluating the safety of ISIS-GCCRRx in healthy volunteers. In this study, subjects tolerated ISIS-GCCRRx well, and we observed reductions of GCCR specifically in the liver and fat tissues, consistent with our preclinical observations.
We believe that doctors could use ISIS-GCCRRx in diabetic patients with moderate to severe hyperglycemia who are also obese or have high levels of cholesterol and triglycerides. We also believe that there are other attractive therapeutic opportunities for doctors to use ISIS-GCCRRx in patients with diseases in which there is glucocorticoid excess, such as Cushing’s Syndrome, and other diseases where a selective GCCR inhibitor could be beneficial.
For more information on ISIS-GCCRRx and Cushing’s Syndrome, please click here.
ISIS-PTP1BRx is an antisense drug that targets protein tyrosine phosphatase-1B, or PTP-1B, to treat 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. We designed ISIS-PTP1BRx 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-PTP1BRx may help treat patients with type 2 diabetes without causing weight gain or hypoglycemia, also known as low blood sugar. The reductions in LDL-C produced by inhibiting PTP-1B should also provide an added benefit to patients.
We have completed a Phase 1 study evaluating the safety of ISIS-PTP1BRx in healthy volunteers. In this study, subjects tolerated ISIS-PTP1BRx well. We also observed encouraging data in measures of insulin sensitivity and in a biomarker associated with weight loss. These Phase 1 data are consistent with our findings from our Phase 2 ISIS 113715 studies and support our preclinical observations of increased potency with ISIS-PTP1BRx compared to ISIS 113715.
We reported top-line data from a Phase 2 study of ISIS-PTP1BRx in patients with type 2 diabetes with or without sulfonylurea therapy. In this study, patients treated with ISIS-PTP1BRx achieved statistically significant reductions in body weight and HbA1c. In patients treated with ISIS-PTP1BRx, a mean reduction in HbA1c of 0.7 percentage points from baseline was achieved at 36 weeks, compared to a mean reduction of 0.2 percentage points for placebo-treated patients (p=0.03). Patients treated with ISIS-PTP1BRx also experienced a statistically significant mean reduction in body weight from baseline at 36 weeks (p=0.01). Patients received 200 mg of ISIS-PTP1BRx or placebo for 26 weeks added to their stable doses of their background therapies. In this study, the average incoming HbA1c level was 8.6 percent and the average BMI was 34 kg/m2. Patients in this study were not required to conform to any type of restrictive or weight-loss diet beyond the standard dietary restrictions they adhered to upon entry into the study. In this study ISIS-PTP1B Rx was generally well tolerated. The most common adverse event was infrequent injection site reactions, which were predominantly mild and resolved rapidly.
We believe that physicians may use ISIS-PTP1BRx in combination with most of the other commonly used diabetes drugs, including insulin, GLP-1 agonists, and more traditional drugs like metformin, to treat patients with diabetes. The clinical development plan for ISIS-PTP1BRx focuses on treating diabetic patients who are inadequately controlled on insulin, helping them utilize insulin more efficiently and treating patients who are beginning to fail oral therapies, extending the time they have before becoming dependent on insulin.
ISIS-FGFR4Rx is an antisense drug that specifically reduces the production of fibroblast growth factor receptor 4, or FGFR4, in the liver and fat tissues, which decreases the body’s ability to store fat while simultaneously increasing fat burning and energy expenditure. Many anti-obesity drugs act in the brain to suppress appetite, commonly resulting in central nervous system, or CNS, side effects. However, ISIS-FGFR4Rx does not distribute to the brain or CNS and therefore should not produce any CNS side effects.
In preclinical studies, antisense inhibition of FGFR4 lowered body weight when we administered it as a single agent and in the presence or absence of a calorie-restricted diet. Additionally, inhibiting FGFR4 decreased body weight when we administered it in combination with an appetite-suppressing drug. In addition to reducing body weight, inhibiting FGFR4 demonstrated an improvement in insulin sensitivity. ISIS-FGFR4Rx is the first drug in our metabolic franchise to treat obesity and utilizes technology we in-licensed from Verva Pharmaceuticals Ltd.
ISIS-DGAT2Rx is an antisense drug that specifically reduces the production of diacylglycerol acyltransferase-2, or DGAT-2, a key component in the synthesis of triglycerides. By reducing DGAT2, ISIS-DGAT2Rx should reduce liver fat in patients with nonalcoholic steatohepatitis, or NASH. The NIH estimates that NASH affects more than 20 million people in the United States and expects the number 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 clinicians associate increases in liver fat with insulin resistance, ISIS-DGAT2Rx could also benefit patients with type 2 diabetes who are insulin resistant.