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 onmetformin 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.
RCT Entities:
OBJECTIVE: To evaluate the safety and efficacy of IONIS-GCGRRx, a 2'-O-methoxyethyl antisenseoligonucleotide 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.
Authors: Janet M Sasso; Barbara J B Ambrose; Rumiana Tenchov; Ruchira S Datta; Matthew T Basel; Robert K DeLong; Qiongqiong Angela Zhou Journal: J Med Chem Date: 2022-05-09 Impact factor: 8.039
Authors: Ryan A Lafferty; Laura M McShane; Zara J Franklin; Peter R Flatt; Finbarr P M O'Harte; Nigel Irwin Journal: J Endocrinol Date: 2022-09-14 Impact factor: 4.669