GSK256073 acutely regulates NEFA levels via HCA2 agonism but does not achieve durable glycaemic control in type 2 diabetes. A randomised trial

• Published in: European journal of pharmacology Vol. 755; pp. 95 - 101
• Main Authors: Dobbins, Robert, Byerly, Robert, Gaddy, Riley, Gao, Feng, Mahar, Kelly, Napolitano, Antonella, Ambery, Philip, Le Monnier de Gouville, Anne-Charlotte
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.05.2015
• Subjects: Aged; Blood Glucose - analysis; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Double-Blind Method; Fatty Acids, Nonesterified - blood; Female; Fructosamine - blood; Glycated Hemoglobin A - analysis; GSK 256073; HbA1c; Humans; Hydroxy-carboxylic acid receptor 2 (HCA2); Insulin - blood; Male; Middle Aged; Non Esterified Fatty Acid (NEFA); Receptors, G-Protein-Coupled - agonists; Receptors, Nicotinic; Treatment Outcome; Type 2 diabetes; Xanthines - administration & dosage; Xanthines - pharmacokinetics; Xanthines - pharmacology; Xanthines - therapeutic use; Type 2 diabetes; GSK 256073 (PubChem CID 46215799); Non Esterified Fatty Acid (NEFA); HbA1c; GSK 256073; Hydroxy-carboxylic acid receptor 2 (HCA2)
• DOI: 10.1016/j.ejphar.2015.03.005
• ISSN: 0014-2999

This study investigated safety and efficacy of GSK256073, an in vitro potent, selective GPR109A agonist, for treatment of subjects with type 2 diabetes mellitus (Type 2 DM) poorly controlled with metformin alone. Patients with Type 2 DM (n=94) were enroled into this randomised, double-blind (sponsor unblinded), placebo-controlled, parallel group trial. Participants received placebo for two weeks before being randomised (2:2:2:2:1:1) to receive doses of GSK256073 5mg twice-daily (BID), 10mg once-daily (QD), 25mg BID, 50mg QD or placebo BID or QD in addition to their current metformin treatment. The primary efficacy endpoint was change from baseline in glycosylated haemoglobin (HbA1c) at week 12. The safety profile of GSK256073 did not significantly differ from that of placebo. Decreases from baseline in HbA1c were observed in all treatment groups but were not statistically significant compared to placebo; at week 12 a maximum decrease of 0.30% from placebo was reached in the GSK256073 50mg QD group. On day 2, GSK256073 significantly decreased non-esterified fatty acid (NEFA) (0–12h) concentrations but pharmacological activity was lost (5mg BID, 10mg QD, 25mg BID) or reduced (50mg QD) at week 6. Drug exposure demonstrated 2-fold accumulation over 6 weeks. The primary efficacy objective of the study was not met. GSK256073 did not improve HbA1c concentrations at week 12. Despite sustained drug exposure, the ability of the HCA2 agonist to suppress plasma NEFA concentrations waned over time and targeted effects on glucose oxidation and insulin sensitivity subsided.