Abstracts - Orals, Featured Poster Presentations, and Posters
SUN 807-838-Diabetes - Diagnosis, Complications & Outcomes
Expo Halls ABC (Moscone Center)
Poster Board SUN-836
We have previously reported that antisense reduction of hepatic glucagon receptor expression normalized blood glucose levels in rodent T2DM models and produced pharmacological activity in monkeys (Diabetes 2006; 55 (suppl 1): 1399-P). In the current double-blind, placebo–controlled dose escalation study, we evaluated the safety, tolerability and PD of ISIS-GCGRRx after administration at multiple dose levels (50, 100, 200 and 300 mg). Subjects received 6 doses of the study drug at each dose level over a 4-week period (3 doses during the first week on days 1, 3, 5 and once weekly for an additional 3 weeks). ISIS-GCGRRX treatment was well tolerated and did not cause clinically significant changes in vital signs, triglycerides, total cholesterol, LDL-cholesterol, BP, hepatic or renal function as compared to placebo treated subjects. Also, no hypoglycemia was observed during the treatment period. In addition to demonstrating an acceptable safety profile, ISIS-GCGRRX increased total and active GLP-1 levels in treated subjects. Total GLP-1 levels increased significantly in all dosing groups starting on Day 15 and continued to increase until Day 36, two weeks post-treatment. By Day 36, mean change from baseline in total GLP-1 levels in the 200 mg and 300 dosing groups was 38 ±51 pg/mL (*p=0.0012) and 34 ±15 pg/mL (*p=0.0012) as compared to the placebo treated subjects (0.29 ± 5 pg/mL). Increases in active GLP-1 levels were also observed in all dosing groups as compared to placebo treatment; mean percent change from baseline for the 200 mg and 300 mg dosing groups on Day 36 were 86% and 94% respectively as compared to placebo (11%). Taken together, the data support further development of ISIS-GCGRRX for T2DM patients who are severely diabetic and uncontrolled with existing therapies.
Disclosure: EM: Management Position, Isis Pharmaceuticals. LW: Clinical Researcher, Isis Pharmaceuticals, Inc.. RG: Management Position, Isis Pharmaceuticals. Nothing to Disclose: CB, SX, MM
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