Date: 2017-01-04
Type of information: Results
phase: 2
Announcement: results
Company: Isis Pharmaceuticals (USA)
Product: ISIS-GCGR Rx
Action
mechanism: antisense oligonucleotide. ISIS-GCGRRx is an antisense drug that targets the glucagon receptor, or GCGR, to reduce the effects of glucagon. 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. 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. Isis Pharmaceuticals has completed a Phase 1 study evaluating the safety of ISIS-GCGRRx in healthy volunteers. In this study, subjects tolerated ISIS-GCGRRx well with no clinically significant increases in lipids or blood pressure and with no hypoglycemic events. In addition, we observed an increase in total GLP-1, which was consistent with our preclinical observations.
Disease: type 2 diabetes
Therapeutic area: Metabolic diseases
Country:
Trial
details: This Phase 2 study of ISIS-GCGRRx was a double-blinded, randomized, placebo-controlled study in 75 patients with type 2 diabetes who had uncontrolled blood sugar despite treatment with stable metformin therapy. Patients received either 100 mg or 200 mg of ISIS-GCGRRx or placebo for 13 weeks added to their stable doses of metformin. In this study, the average incoming HbA1c level was 8.7 percent. After only 13 weeks of dosing, robust and sustained, dose-dependent, statistically significant mean reductions in HbA1c were achieved in patients treated at both doses. Additional measures of glucose control, including serum fructosamine and fasting plasma glucose levels were also significantly reduced in patients treated with ISIS-GCGRRx. The observed improvement in glucose control was in addition to those achieved with each patient's existing therapeutic regimen of metformin.
Latest
news: * On January 4, 2017, Ionis Pharmaceuticals announced positive data from a Phase 2 study of IONIS-GCGRRx in 79 patients with type 2 diabetes. In this study, patients with type 2 diabetes uncontrolled on stable, maximal metformin therapy treated with IONIS-GCGRRx achieved robust and sustained, statistically significant improvements in hemoglobin A1c (HbA1c) and other measures of glucose control after 26 weeks of treatment. Patients treated with 50 mg and 75 mg weekly doses achieved mean reductions in HbA1c of 0.7 percentage points (p ? 0.05) and 1.4 percentage points (p ? 0.001) from baseline, respectively, compared to a reduction of 0.1 percentage points for placebo-treated patients, in an intent to treat (ITT) analysis. A per protocol analysis showed additional improvements in HbA1c in both treatment groups compared to placebo. At baseline, mean HbA1c levels were approximately 8.8% for all cohorts. The primary goal of the Phase 2 study was to identify a dose that produced robust HbA1c reductions without triggering previously observed on-target liver enzyme elevations or other off-target side effects observed with small molecule inhibitors of GCGR, such as increases in LDL-cholesterol and blood pressure. This goal was achieved with the 50 mg dose cohort, in which there were no clinically meaningful (>3x upper limit of normal [ULN]) increases in liver enzymes observed. In the 75 mg cohort, three patients experienced alanine aminotransferase (ALT) elevations >3x ULN that resolved with dose reduction. In the study, IONIS-GCGRRx was generally safe and well tolerated. In both cohorts, there were no clinically meaningful changes in lipids, blood pressure, bodyweight, gastrointestinal symptoms or cases of hypoglycemia. There were no flu-like symptoms, abnormalities in renal function, or clinically meaningful platelet events observed. The majority of adverse events (AEs) reported were mild. The most common AE reported was a low incidence of injection site reactions (4.4% of injections). * On May 14, 2014, Isis Pharmaceuticals announced positive data from a Phase 2 study of ISIS-GCGRRx in patients with type 2 diabetes uncontrolled on stable metformin therapy. In this study, patients in the per protocol efficacy population treated with ISIS-GCGRRx achieved statistically significant reductions in measures of glucose control. The absolute mean reductions in hemoglobin A1c (HbA1c) were greater than 2 percentage points (p=0.001) and greater than 1 percentage points (p=0.001) in the 200 mg and 100 mg cohorts, respectively, compared to baseline after 13 weeks of treatment. Patients treated with ISIS-GCGRRx also experienced increased plasma GLP-1 levels. Isis will present additional detail from this study as a late-breaking abstract program at the American Diabetes Association 74th Scientific Sessions. ISIS-GCGRRx was generally well tolerated in the study. 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, no clinically meaningful changes in other laboratory values and no cases of symptomatic hypoglycemia. As has been observed with small molecule inhibitors of glucagon receptor, liver enzyme elevations that were not associated with elevated bilirubin or other indicators of liver damage were observed. These liver enzyme elevations are consistent with the pharmacology of glucagon receptor inhibition. ISIS-GCGRRx was not associated with increases in LDL-C, blood pressure or body weight gain (side effects associated with some small molecule inhibitors of glucagon receptor).
A substantial number of IONIS-GCGRRx-treated patients achieved HbA1c reductions of equal to or greater than 1 percentage point, including 42% of 50 mg-treated patients and 64% of 75 mg-treated patients, compared to 8% of the placebo-treated patients.
IONIS-GCGRRx-treated patients experienced a mean increase in total GLP-1 from baseline compared to a decline in placebo-treated patients.
