Antisense Inhibition of Glucagon Receptor by IONIS-GCGRRx Improves Type 2 Diabetes Without Increase in Hepatic Glycogen Content in Patients With Type 2 Diabetes on Stable Metformin Therapy

Author:

Morgan Erin S.1,Tai Li-Jung1,Pham Nguyen C.1,Overman Julia K.1,Watts Lynnetta M.1,Smith Anne1,Jung Shiangtung W.1,Gajdošík Martin23,Krššák Martin23ORCID,Krebs Michael2ORCID,Geary Richard S.1,Baker Brenda F.1,Bhanot Sanjay1ORCID

Affiliation:

1. Ionis Pharmaceuticals, Inc., Carlsbad, CA

2. Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria

3. High Field MR Centre, Department of Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, Vienna, Austria

Abstract

OBJECTIVE To evaluate the safety and efficacy of IONIS-GCGRRx, a 2′-O-methoxyethyl antisense oligonucleotide targeting the glucagon receptor (GCGR), and the underlying mechanism of liver transaminase increases in patients with type 2 diabetes on stable metformin therapy. RESEARCH DESIGN AND METHODS In three phase 2, randomized, double-blind studies, patients with type 2 diabetes on metformin received weekly subcutaneous injections of IONIS-GCGRRx (50–200 mg) or placebo for 13 or 26 weeks. RESULTS Significant reductions in HbA1c were observed after IONIS-GCGRRx treatment versus placebo at week 14 (−2.0% 200 mg, −1.4% 100 mg, −0.3% placebo; P < 0.001) or week 27 (−1.6% 75 mg, −0.9% 50 mg, −0.2% placebo; P < 0.001). Dose-dependent increases in transaminases were observed with IONIS-GCGRRx, which were attenuated at lower doses and remained mostly within the normal reference range at the 50-mg dose. There were no other significant safety observations and no symptomatic hypoglycemia or clinically relevant changes in blood pressure, LDL cholesterol, or other vital signs. At week 14, IONIS-GCGRRx 100 mg did not significantly affect mean hepatic glycogen content compared with placebo (15.1 vs. −20.2 mmol/L, respectively; P = 0.093) but significantly increased hepatic lipid content (4.2 vs. −2.7%, respectively; P = 0.005) in the presence of transaminase increases. CONCLUSIONS IONIS-GCGRRx is a potent inhibitor of hepatic glucagon receptor expression with a potential to improve glycemic control at low weekly doses in combination with metformin. Significant reductions in HbA1c occurred across the full-dose range tested, with minimal transaminase elevations at lower doses. Furthermore, novel results suggest that despite inhibition of glycogenolysis after GCGR antagonism, IONIS-GCGRRx did not increase hepatic glycogen content.

Publisher

American Diabetes Association

Subject

Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine

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