Reduction of Hepatic Glucagon Receptor Expression with an Antisense Drug (ISIS-GCGRRX) Increases Total and Active GLP-1 Levels without Affecting Cholesterol or BP in Normal Subjects

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 807-838-Diabetes - Diagnosis, Complications & Outcomes
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-836
Erin Morgan*1, Claudette Bethune1, Lynnetta Watts1, Shuting Xia1, Michael McDonnell2 and Richard Geary3
1Isis Pharmaceuticals Inc., Carlsbad, CA, 2Inc Research Early Stage, Toronto, ON, Canada, 3Isis Pharmaceuticals Inc., Carlsbad
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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