Free fatty acid receptor agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II clinical development

ABSTRACT

Introduction: The alarming prevalence of type 2 diabetes mellitus (T2DM) stimulated the exploitation of new antidiabetic drugs with extended durability and enhanced safety. In this regard, the free fatty acid receptor 1 (FFA1) and FFA4 have emerged as attractive targets in the last decade. FFA1 has prominent advantages in promoting insulin and incretin secretion while FFA4 shows great potential in incretin secretion, insulin sensitization and anti-inflammatory effects.

Area covered: Herein, the authors focus specifically on FFA1 and FFA4 agonists in clinical trials and preclinical development. LY2922470, P11187 and SHR0534 are currently active in clinical trials while the CNX-011-67, SAR1, DS-1558 and BMS-986118 are in preclinical phase. The information for this review is retrieved from Integrity, Scifinder, Espacenet and clinicaltrials.gov databases.

Expert opinion: Current proof-of-concept in clinical trials suggests that FFA1 agonists have a significant improvement for T2DM without the risk of hypoglycemia. However, there are still several challenging problems including the mechanism of the receptor and the efficacy and safety of the ligands.

KEYWORDS:

• Free fatty acid
• FFA1
• GPR40
• GPR120
• GLP-1
• type 2 diabetes

Article highlights

• FFA1 and FFA4 agonists have unique mechanism of action with several significant advantages associated with low risk of hypoglycemia and weight gain.

• The most advanced FFA1 agonist TAK-875 revealed a very promising fasting plasma glucose and HbA_1c decrease in proof of concept clinical trials as well as in early phase III studies.

• TAK-875 was discontinued in phase III clinical trial because of liver toxicity and LY2881835 were halted for significant adverse effects, but whether the side effects are involved in the mechanism of action or the specifically chemical structure is unknown.

• Tremendous developments have been made in illuminating the mechanism and role of FFA1 and FFA4 in diabetes, but there are several challenging problems which are focused on the mechanism of receptor, efficacy and safety of ligands.

• Although the clinical developments of some FFA1 agonists have been discontinued, several FFA1 agonists (such as LY2922470, P11187 and SHR0534) are still under active clinical investigation.

• The new generation of FFA1 agonists (such as CNX-011-67, SAR1, DS-1558 and BMS-986118) being developed pre-clinically with unique chemical structure and optimized physicochemical property, although it is too early to foresee which one will be good enough for clinical development.

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Declaration of interests

The authors have received grants from the National Natural Science Foundation of China (Grants 81172932 and 81273376), the Natural Science Foundation of Jiangsu Province (Grant BK2012356), and the Fundamental Research Funds for the Central Universities, China Pharmaceutical University (Grant JKZD2013001). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.