Efficacy and safety of fasiglifam (TAK‐875), a G protein‐coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double‐blind, placebo‐controlled, phase III trial

Abstract

AimTo assess the efficacy and safety of fasiglifam 25 and 50 mg in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise.MethodsThis phase III, double-blind, placebo-controlled, multicentre study included 192 patients randomized to once-daily treatment with fasiglifam 25 mg (n = 63) or 50 mg (n = 62) or placebo (n = 67) for 24 weeks. The primary efficacy endpoint was the change from baseline in glycated haemoglobin (HbA1c) at week 24.ResultsAt week 24, both fasiglifam groups had significantly reduced HbA1c levels compared with the placebo group (p < 0.0001). The least squares mean change from baseline in HbA1c was 0.16% with placebo, −0.57% with fasiglifam 25 mg and −0.83% with fasiglifam 50 mg. The percentage of patients who achieved an HbA1c target of <6.9% at week 24 was also significantly higher (p < 0.05) for fasiglifam 25 mg (30.2%) and 50 mg (54.8%) compared with placebo (13.8%). Fasiglifam significantly reduced fasting plasma glucose levels at all assessment points, starting from week 2. The incidence and types of treatment-emergent adverse events in each fasiglifam group were similar to those in the placebo group, and hypoglycaemia was reported in 1 patient receiving fasiglifam 50 mg. There were no clinically meaningful changes in body weight in any treatment group.ConclusionsFasiglifam significantly improved glycaemic control and was well tolerated, with a low risk of hypoglycaemia in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise; however, in a recent review of data from overall fasiglifam global clinical trials, concerns about liver safety arose and the clinical development of fasiglifam was terminated after this trial was completed.

Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

“…Indeed, the FFA1 agonist fasiglifam entered phase III clinical trials; although it was clearly able to regulate glycemia and to produce clinically relevant lowering of hemoglobin A1c levels in patients with type 2 diabetes Poitout, 2013, 2015;Kaku et al, 2015), it was withdrawn from further trials because of concerns of possible liver toxicity. Although FFA4 is expressed in the pancreas (Stone et al, 2014;Suckow et al, 2014), where it may play roles in the regulation of glucagon production (Suckow et al, 2014), it is also expressed in various enteroendocrine cells (Parker et al, 2009;Iwasaki et al, 2015;Liu et al, 2015), adipocytes (Oh et al, 2010(Oh et al, , 2014Liu et al, 2015) and macrophages (Oh et al, 2010(Oh et al, , 2014Im, 2015;Liu et al, 2015).…”

Fasiglifam/TAK-875, a Selective GPR40 Agonist, Improves Hyperglycemia in Rats Unresponsive to Sulfonylureas and Acts Additively with Sulfonylureas

“…Fasiglifam is the first GPR40 agonist to significantly improve glycemic control in patients with type 2 diabetes (Kaku et al, 2015). However, the clinical development of fasiglifam was terminated because of concerns about liver safety.…”

Novel agonists of free fatty acid receptor 1 (GPR40) based on 3-(1,3,4-thiadiazol-2-yl)propanoic acid scaffold

“…Currently, only one clinical investigation of a GPR40 agonist is underway, namely that of compound P11187 of undisclosed structure by Piramal 4 . However, the proof of principle of the new approach to treat T2DM was, in principle, established in the course of TAK-875 investigation 5 . Thus, current research effort worldwide 6 is aimed primarily at tackling the toxicity profile of GPR40 agonists.…”