OR17-2 ISIS-GCCRRX, a Novel Glucocorticoid (GC) Receptor Antisense Drug Reduces Cholesterol and Triglycerides and Attenuates Dexamethasone Induced Hepatic Insulin Resistance without Systemic GC Antagonism in Normal Subjects

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR17-Diabetes: New Diagnostic & Treatment Modalities
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:30 AM
Room 307 (Moscone Center)
Erin Morgan*1, Claudette Bethune1, Richard Larouche2, Shuting Xia1 and Richard Geary3
1Isis Pharmaceuticals Inc., Carlsbad, CA, 2PharmaNet/i3, 3Isis Pharmaceuticals Inc., Carlsbad
Reduction of excessive GC action has been reported to alleviate hyperglycemia in rodents and humans. However, systemic GC inhibition results in adrenal insufficiency and stimulation of the HPA axis. We previously demonstrated that liver selective glucocorticoid receptor (CR) antagonism with antisense drugs improved hyperglycemia and hyperlipidemia in preclinical models without systemic GC antagonism (Diabetes 2005;54:1846-53). The current randomized double-blind, placebo-controlled, Phase 1 study in normal subjects evaluated the safety, tolerability, and PD of multiple (MD) subcutaneous ISIS-GCCRRx injections at 60, 120, 210 and 420 mg/wk. A dexamethasone (DEXA) challenge (8 mg for 2 days) was administered in the 420 mg MD cohort before and after 6 weeks of treatment. DEXA induced hepatic insulin resistance and compensatory hyperinsulinemia as well as increased HOMA-IR.  ISIS-GCCRRx attenuated DEXA induced hepatic insulin resistance as reflected by a 10% and 11% reduction in mean fasting insulin levels and HOMA IR, respectively. DEXA induced lymphopenia was not affected with GCCRRx treatment indicating no systemic CR antagonism. Even in subjects with high-normal cholesterol (mean baseline cholesterol 202 mg/dL and triglycerides 126 mg/dL), reductions in mean total cholesterol (8.4 mg/dL), triglycerides (17%), VLDL (19%) and ApoCIII (16%) were observed. No clinically significant changes in blood pressure (including no orthostatic hypotension), hepatic, renal and standard safety assessments were reported. Importantly, no hypoglycemia or evidence of HPA axis stimulation (no ACTH increases) was observed. In conclusion, this study demonstrated that liver specific CR antagonism with ISIS-GCCRRx was well tolerated, improved lipid profiles, and attenuated DEXA induced hepatic changes without affecting the HPA axis, supporting further evaluation in patients with T2DM.

Disclosure: EM: Management Position, Isis Pharmaceutical. CB: Clinical Researcher, Isis Pharmaceuticals, Inc.. RG: Management Position, Isis Pharmaceuticals. Nothing to Disclose: RL, SX

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm