title: GSK256073 acutely regulates NEFA levels via HCA2 agonism but does not achieve durable glycaemic control in type 2 diabetes. A randomised trial.
abstract: 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.
authors.affiliation: GlaxoSmithKline, Drug Discovery, Research Triangle Park, NC, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Dobbins
authors.affiliation: GlaxoSmithKline, Drug Discovery, Research Triangle Park, NC, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Byerly
authors.affiliation: GlaxoSmithKline, Drug Discovery, Research Triangle Park, NC, USA.
authors.forename: Riley
authors.initials: R
authors.lastname: Gaddy
authors.affiliation: GlaxoSmithKline, Quantitative Sciences, Upper Merion, PA, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: GlaxoSmithKline, Quantitative Sciences, Upper Merion, PA, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Mahar
authors.affiliation: GlaxoSmithKline, Immuno-Inflammation Therapeutic Area, Stevenage, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: Napolitano
authors.affiliation: Department of Endocrinology and Diabetes, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Ambery
authors.affiliation: GlaxoSmithKline, Drug Discovery, Laboratoire GSK, 27av du Quebec, 91951 les Ulis Cedex, France. Electronic address: anne-charlotte.m.degouville@gsk.com.
authors.forename: Anne-Charlotte
authors.initials: AC
authors.lastname: Le Monnier de Gouville
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D019270:Fructosamine / Q000097:blood; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D016896:Treatment Outcome; D014970:Xanthines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D019270:Fructosamine; D006442:Glycated Hemoglobin; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014970:Xanthines; C000604188:8-chloro-3-pentyl-1H-purine-2,6(3H,7H)-dione; C530636:HCAR2 protein, human; C517652:hemoglobin A1c protein, human
keywords: GSK 256073; GSK 256073 (PubChem CID 46215799); HbA1c; Hydroxy-carboxylic acid receptor 2 (HCA2); Non Esterified Fatty Acid (NEFA); Type 2 diabetes