Imeglimin: A Clinical Pharmacology Review.

Imeglimin (PXL008, EMD-387008, Twymeeg) is a first-in-class novel oral hypoglycemic agent, launched in Japan, for the treatment of type 2 diabetes mellitus. Its mechanism of action targets mitochondrial bioenergetics to ameliorate insulin resistance and to enhance β-cell function. This review summarizes the properties underlying the pharmacokinetic profile of imeglimin, a small cationic drug belonging to the tetrahydrotriazine chemical class, with a complex mechanism of absorption involving an active transport through organic cation transporters (OCTs).

Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1).

Background & Aims: Pioglitazone (Pio) is efficacious in NASH, but its utility is limited by PPARγ-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARγ activity but retains non-genomic activity.

Phase 2 trial with imeglimin in patients with Type 2 diabetes indicates effects on insulin secretion and sensitivity.

Introduction: The aim of the present study was to evaluate the effect of 18-week monotherapy with imeglimin on glucose tolerance and on insulin secretion/sensitivity in type 2 diabetic (T2D) patients.

Methods: The study was an 18-week, double-blind clinical trial in T2D subjects previously treated with stable metformin therapy and washed out for 4 weeks. Subjects were randomized 1:1 to receive a 1500 mg bid of imeglimin or placebo.

Pharmacokinetics of Imeglimin in Caucasian and Japanese Healthy Subjects.

Background: Imeglimin is a first-in-class novel oral antidiabetic marketed in Japan as TWYMEEG to treat type 2 diabetes mellitus. Its mode of action is distinct from all other anti-hyperglycemic classes.

Objective: To assess the pharmacokinetic and safety profile of imeglimin in Caucasian and Japanese healthy individuals.

Beneficial Effects of the Direct AMP-Kinase Activator PXL770 in In Vitro and In Vivo Models of X-Linked Adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a severe orphan disease caused by mutations in the peroxisomal transporter gene, leading to toxic accumulation of Very Long-Chain Fatty Acids (VLCFA - in particular C26:0) resulting in inflammation, mitochondrial dysfunction and demyelination. AMP-activated protein kinase (AMPK) is downregulated in ALD, and its activation is implicated as a therapeutic target. PXL770 is the first direct allosteric AMPK activator with established clinical efficacy and tolerability.

Reduced lactic acidosis risk with Imeglimin: Comparison with Metformin.

The global prevalence of type 2 diabetes (T2D) is expected to exceed 642 million people by 2040. Metformin is a widely used biguanide T2D therapy, associated with rare but serious events of lactic acidosis, in particular with predisposing conditions (e.g.

Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study.

AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting lipogenesis (DNL) and producing efficacy in preclinical models.

Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes.

Imeglimin is an orally administered first-in-class drug to treat type 2 diabetes mellitus (T2DM) and is mainly excreted unchanged by the kidneys. The present study aimed to define the pharmacokinetic (PK) characteristics of imeglimin using population PK analysis and to determine the optimal dosing regimen for Japanese patients with T2DM and chronic kidney disease (CKD). Imeglimin plasma concentrations in Japanese and Western healthy volunteers, and patients with T2DM, including patients with mild to severe CKD with an estimated glomerular filtration rate (eGFR) greater than 14 ml/min/1.

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study.

Background: AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD).

Methods: STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites.

Direct AMPK Activation Corrects NASH in Rodents Through Metabolic Effects and Direct Action on Inflammation and Fibrogenesis.

No approved therapies are available for nonalcoholic steatohepatitis (NASH). Adenosine monophosphate-activated protein kinase (AMPK) is a central regulator of cell metabolism; its activation has been suggested as a therapeutic approach to NASH. Here we aimed to fully characterize the potential for direct AMPK activation in preclinical models and to determine mechanisms that could contribute to efficacy for this disease.

Deuterium-Stabilized ()-Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPARγ Activity.

The antidiabetic drug pioglitazone is, to date, the most efficacious oral drug recommended off-label for the treatment of nondiabetic or diabetic patients with biopsy-proven nonalcoholic steatohepatitis (NASH). However, weight gain and edema side effects have limited its use for NASH. Pioglitazone is a mixture of two stereoisomers (()-pioglitazone and ()-pioglitazone) that interconvert and .

Imeglimin preserves islet β-cell mass in Type 2 diabetic ZDF rats.

Objectives: Type 2 diabetes (T2D) is driven by progressive dysfunction and loss of pancreatic β-cell mass. Imeglimin is a first-in-class novel drug candidate that improves glycaemia and glucose-stimulated insulin secretion in preclinical models and patients. Given evidence that imeglimin can attenuate β-cell dysfunction and protect β cells , we postulated that imeglimin could also exert longer term effects to prevent pancreatic β-cell death and preserve functional β-cell mass .

Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action.

Pancreatic islet β-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinical models and clinical trials in patients with Type 2 diabetes; however, the mechanism by which it restores β-cell function is unknown. Here, we show that imeglimin acutely and directly amplifies GSIS in islets isolated from rodents with Type 2 diabetes via a mode of action that is distinct from other known therapeutic approaches.

Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes.

Imeglimin is an investigational first-in-class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with evidence of statistically significant glucose lowering and a generally favourable safety and tolerability profile, including the lack of severe hypoglycaemia. Imeglimin's mechanism of action involves dual effects: (a) amplification of glucose-stimulated insulin secretion (GSIS) and preservation of β-cell mass; and (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signalling in both liver and skeletal muscle.

Pharmacokinetics of Imeglimin in Subjects with Moderate Hepatic Impairment.

Background: Imeglimin is a novel oral antidiabetic drug used to treat type 2 diabetes, targeting the mitochondrial bioenergetics. Imeglimin is mainly excreted unchanged by the kidneys and is a substrate of organic cation transporters, which are expressed in the kidney and the liver.

Objective: The aim of this study was to assess the effect of hepatic impairment on the pharmacokinetics of imeglimin.

In Vitro Investigation, Pharmacokinetics, and Disposition of Imeglimin, a Novel Oral Antidiabetic Drug, in Preclinical Species and Humans.

Imeglimin is a novel oral antidiabetic drug for treatment of type 2 diabetes that targets mitochondrial bioenergetics. Its pharmacokinetics absorption characteristics, metabolism, distribution, and elimination were assessed through several in vitro and in vivo experiments in both animals and humans. Its potential to induce drug-drug interactions was also extensively assessed.

Lack of Drug-Drug Interaction Between Cimetidine, a Renal Transporter Inhibitor, and Imeglimin, a Novel Oral Antidiabetic Drug, in Healthy Volunteers.

Unlabelled: BACKGROUND AND OBJECTIVE: Imeglimin is a novel oral antidiabetic drug to treat type 2 diabetes, targeting the mitochondrial bioenergetics. In vitro, imeglimin was shown to be a substrate of human multidrug and toxic extrusion transporters MATE1 and MATE2-K and organic cation transporters OCT1 and OCT2. The objective of the study was to assess the potential drug-drug interaction between imeglimin and cimetidine, a reference inhibitor of these transporters.

Absence of QTc prolongation in a thorough QT study with imeglimin, a first in class oral agent for type 2 diabetes mellitus.

Purpose: Imeglimin is the first in a new class of oral antidiabetic agents, the glimins, currently in development to improve glycemic control in patients with type 2 diabetes mellitus. A thorough QT study was conducted to establish electrophysiological effects of therapeutic and supratherapeutic doses of imeglimin on cardiac repolarization.

Methods: In this randomized, double-blind, four-period, placebo and active controlled crossover study, healthy subjects were administered a single dose of imeglimin 2250 mg, imeglimin 6000 mg, moxifloxacin 400 mg, and placebo.

Imeglimin Does Not Induce Clinically Relevant Pharmacokinetic Interactions When Combined with Either Metformin or Sitagliptin in Healthy Subjects.

Background And Objectives: Imeglimin (IMEG) is the first in a novel class of oral glucose-lowering agents with a unique mechanism of action targeting mitochondrial bioenergetics. We assessed whether repeated co-administration of IMEG and either metformin (MET) or sitagliptin (SITA) would influence the pharmacokinetics of either MET or SITA in healthy Caucasian men.

Methods: Healthy Caucasian men received either MET 850 mg twice daily with placebo (n = 16) or SITA 100 mg once daily with placebo (n = 16) on days 1-6, followed by MET 850 mg twice daily with IMEG 1500 mg twice daily or SITA 100 mg once daily with IMEG 1500 mg twice daily on days 7-12.

Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents.

Imeglimin is a promising new oral antihyperglycemic agent that has been studied in clinical trials as a possible monotherapy or add-on therapy to lower fasting plasma glucose and improve hemoglobin A1c (1-3, 9). Imeglimin was shown to improve both fasting and postprandial glycemia and to increase insulin secretion in response to glucose during a hyperglycemic clamp after 1-wk of treatment in type 2 diabetic patients. However, whether the β-cell stimulatory effect of imeglimin is solely or partially responsible for its effects on glycemia remains to be fully confirmed.

Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model.

Imeglimin is the first in a new class of oral glucose-lowering agents currently in phase 2b development. Although imeglimin improves insulin sensitivity in humans, the molecular mechanisms are unknown. This study used a model of 16-week high-fat, high-sucrose diet (HFHSD) mice to characterize its antidiabetic effects.

In vitro primary human and animal cell-based blood-brain barrier models as a screening tool in drug discovery.

Brain penetration is characterized by its extent and rate and is influenced by drug physicochemical properties, plasma exposure, plasma and brain protein binding and BBB permeability. This raises questions related to physiology, interspecies differences and in vitro/in vivo extrapolation. We herein discuss the use of in vitro human and animal BBB model as a tool to improve CNS compound selection.

Use of simulated intestinal fluid for Caco-2 permeability assay of lipophilic drugs.

The most commonly used method to assess intestinal permeability is the measurement of compound flux across a Caco-2 cells monolayer by using Hanks balanced salt solution (HBSS)-like buffers. Nevertheless, lipophilic acid drugs are poorly or not at all soluble in these types of buffers and their adsorption on the transwell plate is commonly observed. To reduce adsorption and increase solubility, permeability assays need to be developed in conditions other than classic conditions for lipophilic compounds.

Analysis of drug transporter expression in human intestinal Caco-2 cells by real-time PCR.

Expression of drug transporters corresponds to a crucial parameter in intestinal Caco-2 cells widely used for investigating drug absorption. In order to characterize it in an accurate, reproducible and comparative manner, we analyzed mRNA levels of 19 influx and efflux drug transporters through real-time quantitative polymerase chain reaction assays combined with the use of a total RNA reference standard. Profiles of transporter expression were found to be significantly correlated in two independent Caco-2 cell clones and in human small intestine, which may support the use of Caco-2 cells for investigating intestinal drug transport.

Development of an in vitro screening model for the biosynthesis of acyl glucuronide metabolites and the assessment of their reactivity toward human serum albumin.

An in vitro screening model was developed to determine the reactivity of acyl glucuronide metabolites from carboxylic drugs. This assay is composed of two phases. The first is a phase of biosynthesis of acyl glucuronides by human liver microsomes (HLM).