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Describes the 1991 Mini-Grant Winner Implements Project, a program designed to excite children about reading by creating special take-home book and play bags. Items included with the bags; Building a bridge between school, home and community; Positive responses the author has received.

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). Imeglimin absorption decreases when dose increases due to the saturation of the active uptake transport. Post absorption, imeglimin is rapidly and primarily distributed to organs and tissues, and has a half-life ranging from 9.03 to 20.2 h. Plasma protein binding of imeglimin is low, which explains the rapid distribution to the organs observed in all species. Imeglimin is excreted unchanged in urine, indicating a low extent of metabolism. Imeglimin is a substrate of multidrug and toxic compound extrusion (MATE) 2-K and a substrate and inhibitor of OCT1, OCT2, and MATE1. Clinical drug-drug interaction studies confirmed the absence of relevant clinical interaction with substrates or inhibitors of these transporters. Overall, the drug-drug interaction potential of imeglimin is low. Its pharmacokinetics profile has also been characterized in special populations, showing no influence of mild and moderate hepatic impairment but an impact of renal function on imeglimin renal clearance. Dosage adjustment is thus required in moderately and severely renally impaired patients. Imeglimin pharmacokinetics was shown to be insensitive to ethnicity and food intake and to have no effect on QTcF interval., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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. We tested the hypothesis that PXL065 would have similar efficacy but a better safety profile than Pio in patients with NASH., Methods: Patients (≥8% liver fat, NAFLD activity score [NAS] ≥4, F1-F3) received daily doses of PXL065 (7.5, 15, 22.5 mg) or placebo 1:1:1:1 for 36 weeks. The primary endpoint was relative % change in liver fat content (LFC) on MRI-proton density fat fraction; liver histology, non-invasive tests, safety-tolerability, and pharmacokinetics were also assessed., Results: One hundred and seventeen patients were evaluated. All PXL065 groups met the primary endpoint (-21 to -25% LFC, p = 0.008-0.02 vs. placebo); 40% (22.5 mg) achieved a ≥30% LFC reduction. Favorable trends in non-invasive tests including reductions in PIIINP (p = 0.02, 22.5 mg) and NAFLD fibrosis score (p = 0.04, 22.5 mg) were observed. On histology (n = 92), a ≥1 stage fibrosis improvement occurred in 40% (7.5 mg), 50% (15 mg, p = 0.06), and 35% (22.5 mg) vs. 17% for placebo; up to 50% of PXL065-treated patients achieved a ≥2 point NAS improvement without fibrosis worsening vs. 30% with placebo. Metabolic improvements included: HbA1c (-0.41% p = 0.003) and insulin sensitivity (HOMA-IR, p = 0.04; Adipo-IR, p = 0.002). Adiponectin increased (+114%, 22.5 mg, p <0.0001) vs. placebo. There was no dose-dependent effect on body weight or PXL065-related peripheral oedema signal. Overall, PXL065 was safe and well tolerated. Pharmacokinetics confirmed dose-proportional and higher steady state R- vs. S-Pio exposure., Impact and Implications: Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease., Conclusions: PXL065 is a novel molecule which retains an efficacy profile in NASH similar to Pio with reduced potential for PPARγ-driven side effects. A pivotal clinical trial is warranted to confirm the histological benefits reported herein., Impact and Implications: Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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. The primary endpoint was the effect of imeglimin vs placebo on changes from baseline to week 18 in glucose tolerance (glucose area under the curve [AUC]) during a 3 h-glucose tolerance test [OGTT]). Secondary endpoints included glycaemic control and calculated indices of insulin secretion and sensitivity., Results: A total of 59 subjects were randomized, 30 receiving imeglimin and 29 receiving placebo. The study met its primary endpoint. Least squares (LS) mean difference between treatment groups (imeglimin - placebo) for AUC glucose from baseline to week 18 was -429.6 mmol/L·min (p = .001). Two-hour post-dose fasting plasma glucose was significantly decreased with LS mean differences of -1.22 mmol/L (p = .022) and HbA1c was improved with LS mean differences of -0.62% (p = .013). The AUC 0-180min ratio C-peptide/glucose [LS mean differences of 0.041 nmol/mmol (p < .001)] and insulinogenic index were significantly increased by imeglimin treatment. The increase in insulin secretion was associated with an increase in beta-cell glucose sensitivity. Additionally, the insulin sensitivity indices derived from the OGTT Stumvoll (p = .001) and Matsuda (not significant) were improved in the imeglimin group vs placebo. Imeglimin was well tolerated with 26.7% of subjects presenting at least one treatment-emergent adverse event versus 58.6% of subjects in the placebo group., Conclusions: Results are consistent with a mode of action involving insulin secretion as well as improved insulin sensitivity and further support the potential for imeglimin to improve healthcare in T2D patients., (© 2022 Poxel SA. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

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., Methods: Two randomized placebo-controlled phase 1 clinical studies were conducted in Caucasian subjects after single (250-8000 mg) and multiple (250-2000 mg twice daily) ascending doses and in Japanese subjects after single (500-6000 mg) and multiple (500-2000 mg twice daily) ascending doses. Imeglimin plasma and urine concentrations were measured., Results: All imeglimin doses achieved maximal concentration between 1 and 3.5 h in Caucasians, and 1.5 and 3 h in Japanese subjects. The elimination half-lives (t 1/2 ) were dose-independent and means ranged between 9.03 and 20.2 h for Caucasians, and 4.45 and 12 h for Japanese subjects. Dose-normalized area under the plasma concentration-time curve decreased with dose in the 250-8000 mg and in the 500-6000 mg dose range in Caucasians and Japanese, respectively, suggesting a dose-dependent but less than dose-proportional effect in imeglimin exposure. Plasma accumulation was minimal following repeated dosing, and food did not affect the pharmacokinetics in either population. Exposures were generally similar between Caucasian and Japanese subjects with less than 20% difference, although there was a tendency for exposures in Japanese to be slightly higher. Imeglimin had an acceptable safety and tolerability profile, with dose-dependent mild gastrointestinal adverse events., Conclusion: Imeglimin was safe and well tolerated in these two phases 1 studies, with pharmacokinetics comparable between the two populations., Clinical Trial Registrations: EudraCT 2005-001946-18 and 2014-004679-21., (© 2022. The Author(s).)

X-linked adrenoleukodystrophy (ALD) is a severe orphan disease caused by mutations in the peroxisomal ABCD1 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. Methods : We investigated its effects in ALD patient-derived fibroblasts/lymphocytes and Abcd1 KO mouse glial cells. Readouts included VLCFA levels, mitochondrial function and mRNA levels of proinflammatory genes and compensatory transporters ( ABCD2-3 ). After PXL770 treatment in Abcd1 KO mice, we assessed VLCFA levels in tissues, sciatic nerve axonal morphology by electronic microscopy and locomotor function by open-field/balance-beam tests. Results : In patients' cells and Abcd1 KO glial cells, PXL770 substantially decreased C26:0 levels (by ∼90%), improved mitochondrial respiration, reduced expression of multiple inflammatory genes and induced expression of ABCD2-3 In Abcd1 KO mice, PXL770 treatment normalized VLCFA in plasma and significantly reduced elevated levels in brain (-25%) and spinal cord (-32%) versus untreated ( P < 0.001). Abnormal sciatic nerve axonal morphology was also improved along with amelioration of locomotor function. Conclusion : Direct AMPK activation exerts beneficial effects on several hallmarks of pathology in multiple ALD models in vitro and in vivo, supporting clinical development of PXL770 for this disease. Further studies would be needed to overcome limitations including small sample size for some parameters, lack of additional in vivo biomarkers and incomplete pharmacokinetic characterization. SIGNIFICANCE STATEMENT: Adrenoleukodystrophy is a rare and debilitating condition with no approved therapies, caused by accumulation of very long-chain fatty acids. AMPK is downregulated in the disease and has been implicated as a potential therapeutic target. PXL770 is a novel clinical stage direct AMPK activator. In these studies, we used PXL770 to achieve preclinical validation of direct AMPK activation for this disease - based on correction of key biochemical and functional readouts in vitro and in vivo, thus supporting clinical development., (Copyright © 2022 by The Author(s).)

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/1.73 m 2 were included in a population PK analysis. PK simulations were conducted using a population PK model, and the area under concentration-time curve (AUC) was extrapolated with power regression analysis to lower eGFR. The influence of eGFR, weight, and age on apparent clearance and of dose on relative bioavailability were quantified by population PK analysis. Simulations and extrapolation revealed that the recommended dosing regimen based on the AUC was 500 mg twice daily (b.i.d.) for patients with eGFR 15-45 ml/min/1.73 m 2 , and 500 mg with a longer dosing interval was suggested for those with eGFR less than 15. Simulations revealed that differences in plasma AUCs between Japanese and Western patients at the same dose were mainly driven by a difference in the eGFR and that the plasma AUC after 1000 and 1500 mg b.i.d. in Japanese and Western patients, respectively, was comparable in the phase IIb studies. These results indicate suitable dosages of imeglimin in the clinical setting of T2DM with renal impairment., (© 2021 Sumitomo Dainippon Pharma Co., Ltd and Poxel SA. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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., renal failure or major surgery). Imeglimin, a recently approved drug, is the first in a new class (novel mode of action) of T2D medicines. Although not a biguanide, Imeglimin shares a chemical moiety with Metformin and also modulates mitochondrial complex I activity, a potential mechanism for Metformin-mediated lactate accumulation. We interrogated the potential for Imeglimin to induce lacticacidosis in relevant animal models and further assessed differences in key mechanisms known for Metformin's effects. In a dog model of major surgery, Metformin or Imeglimin (30-1000 mg/kg) was acutely administered, only Metformin-induced lactate accumulation and pH decrease leading to lactic acidosis with fatality at the highest dose. Rats with gentamycin-induced renal insufficiency received Metformin or Imeglimin (50-100 mg/kg/h), only Metformin increased lactatemia and H + concentrations with mortality at higher doses. Plasma levels of Metformin and Imeglimin were similar in both models. Mice were chronically treated with Metformin or Imeglimin 200 mg/kg bid. Only Metformin produced hyperlactatemia after acute intraperitoneal glucose loading. Ex vivo measurements revealed higher mitochondrial complex I inhibition with Metformin versus slight effects with Imeglimin. Another mechanism implicated in Metformin's effects on lactate production was assessed: in isolated rat, liver mitochondria exposed to Imeglimin or Metformin, only Metformin (50-250 µM) inhibited the mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH). In liver samples from chronically treated mice, measured mGPDH activity was lower with Metformin versus Imeglimin. These data indicate that the risk of lactic acidosis with Imeglimin treatment may be lower than with Metformin and confirm that the underlying mechanisms of action are distinct, supporting its potential utility for patients with predisposing conditions., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

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. A novel small-molecule direct AMPK activator, PXL770, was used. Enzyme activity was measured with recombinant complexes. De novo lipogenesis (DNL) was quantitated in vivo and in mouse and human primary hepatocytes. Metabolic efficacy was assessed in ob/ob and high-fat diet-fed mice. Liver histology, biochemical measures, and immune cell profiling were assessed in diet-induced NASH mice. Direct effects on inflammation and fibrogenesis were assessed using primary mouse and human hepatic stellate cells, mouse adipose tissue explants, and human immune cells. PXL770 directly activated AMPK in vitro and reduced DNL in primary hepatocytes. In rodent models with metabolic syndrome, PXL770 improved glycemia, dyslipidemia, and insulin resistance. In mice with NASH, PXL770 reduced hepatic steatosis, ballooning, inflammation, and fibrogenesis. PXL770 exhibited direct inhibitory effects on pro-inflammatory cytokine production and activation of primary hepatic stellate cells. Conclusion: In rodent models, direct activation of AMPK is sufficient to produce improvements in all core components of NASH and to ameliorate related hyperglycemia, dyslipidemia, and systemic inflammation. Novel properties of direct AMPK activation were also unveiled: improved insulin resistance and direct suppression of inflammation and fibrogenesis. Given effects also documented in human cells (reduced DNL, suppression of inflammation and stellate cell activation), these studies support the potential for direct AMPK activation to effectively treat patients with NASH., (© 2021 Poxel SA. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

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 de novo lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL-both peak and AUC are reduced versus baseline-and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders., Competing Interests: C.C., D.E.M., F.M, J.D., P.G.-D., P.F., P.T., S.B., and S.H.-B. are employees of Poxel SA and have received stock options as a condition of employment. K.C. has served as a consultant for Allergan, Altimmune, Arrowhead, AstraZeneca, BMS, Boehringer Ingelheim, Coherus, Eli Lilly, Fractyl, Hanmi, Genentech, Gilead, Intercept, Janssen, Pfizer, Poxel, Prosciento, Madrigal, and Novo Nordisk. The study was funded and designed by the sponsor (Poxel SA) with the support of expert consultants in the NASH field. The corresponding author, all co-authors, and the sponsor had full responsibility for the decision to submit for publication. Patents WO2011080277A1 and WO2020099678A1, owned by Poxel SA, are related to this work., (© 2021 Poxel SA.)

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. Patients aged 18-75 years with liver fat content of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned (1:1:1:1), via an interactive web response system, to receive oral PXL770 250 mg once daily, 250 mg twice daily, or 500 mg once daily, or matched placebo. Patients were stratified according to type 2 diabetes status and study site. The primary endpoint was relative change in liver fat content from baseline compared with placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analysed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all as-randomised patients who received at least one dose of study treatment. Safety was analysed in the safety population, defined as all as-treated patients receiving at least one dose of the study treatment. The trial has been completed and the final results are reported. The trial is registered with ClinicalTrials.gov, NCT03763877., Findings: Between March 29, 2019, and March 13, 2020, 387 patients were screened, of whom 120 were included in the modified intention-to-treat and safety analyses (30 in the 250 mg once daily group, 30 in the 250 mg twice daily group, 29 in the 500 mg once daily group, and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was -1·1% in the placebo group, -1·0% in the 250 mg once daily group (mean difference versus placebo 0·1% [95% CI -15·4 to 15·7], p=0·99), -14·3% in the 250 mg twice daily group (-13·1% [-28·1 to 1·8], p=0·084), and -14·7% in the 500 mg once daily group (-13·5% [-28·5 to 1·4], p=0·076). At least one treatment-emergent adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-emergent adverse event was diarrhoea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group, and none in the placebo group). No life-threatening events or treatment-related deaths occurred., Interpretation: PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis., Funding: Poxel., Competing Interests: Declaration of interests KC reports grant and research support from Cirius, Echosens, Inventiva, Novartis, Novo Nordisk, Poxel, and Zydus, and is a consulting adviser for Allergan, Altimmune, Arrowhead, AstraZeneca, Bristol Myers Squibb (BMS), Boehringer Ingelheim, Coherus, Eli Lilly, Fractyl, Hanmi, Genentech, Gilead, Intercept, Janssen, Pfizer, Poxel, Prosciento, Madrigal, and Novo Nordisk. NA reports grant and research support from 89Bio, Akero, Axcella, BI, BMS, Celgene, Gilead, Galmed, Galectin, Genfit, Enanta, Enyo, Hanmi, Inventiva, Madrigal, Merck, NGM Bio, Novo Nordisk, Pfizer, Poxel, and Zydus; is a consulting adviser for 89Bio, Fibronostics, Gilead, Intercept, Pfizer, Terns, and Zydus; and reports educational fees from AbbVie, Alexion, CLDF, Gilead, Intercept, and Simply Speaking. SAH reports grant and research support from Akero, Axcella, Cirius, Civi Biopharma, Cymabay, Enyo, Galectin, Galmed, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Sagimet, and Viking; is a consulting adviser for 89 Bio, AgomAB, Akero, Alentis, Alimentiv, Altimmune, Arrowhead, Axcella, Boston Pharmaceuticals, B Riley FBR, Canfite, Chronwell, Civi Biopharma, Corcept, Cymabay, Echosens, Enyo, Fibronostics, Foresite Labs, Fortress, Galectin, Galmed, Genfit, Gilead, GNS Healthcare, Hepion, Hightide, Histoindex, Indalo, Inipharm, Intercept, Ionis, Kowa Research Institute, Madrigal, Medpace, Metacrine, Microba, NGM, Northsea, Novartis, Novo Nordisk, Nutrasource, PathAI, Piper Sandler & Co, Poxel, Prometic, Ridgeline, Sagimet, Sonic Incytes Medical, Terns, Theratechnologies, and Viking; and holds shares in Akero, Chronwell, Cirius, Galectin, Genfit, Hepion, Histoindex, Metacrine, NGM, Northsea, PathAI, and Sonic Incytes Medical. PF, DEM, SH-B, and SB are employees of and shareholders in Poxel. J-MG is a consulting adviser for Poxel. JD is a former employee of and shareholder in Poxel. VR reports grant and research support from Gilead and is a consulting adviser for Boehringer Ingelheim, Galmed, Genfit, Poxel, Intercept, Novo-Nordisk, Terns, Alexion, Alnylam, Theratechnologies, NGMBio, Sagimet, Prosciento, Inventiva, Hanmi, Covance, and 89 Bio. SJM declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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 (( R )-pioglitazone and ( S )-pioglitazone) that interconvert in vitro and in vivo . We aimed to characterize their individual pharmacology to develop a safer and potentially more potent drug for NASH. We stabilized the stereoisomers of pioglitazone with deuterium at the chiral center. Preclinical studies with deuterium-stabilized ( R )-pioglitazone (PXL065) and ( S )-pioglitazone demonstrated that ( R )-pioglitazone retains the efficacy of pioglitazone in NASH, including reduced hepatic triglycerides, free fatty acids, cholesterol, steatosis, inflammation, hepatocyte enlargement, and fibrosis. Although both stereoisomers inhibit the mitochondrial pyruvate carrier, PXL065 shows limited to no peroxisome proliferator-activated receptor gamma (PPARγ) activity, whereas ( S )-pioglitazone appears responsible for the PPARγ activity and associated weight gain. Nonetheless, in preclinical models, both stereoisomers reduce plasma glucose and hepatic fibrosis to the same extent as pioglitazone, suggesting that these benefits may also be mediated by altered mitochondrial metabolism. In a phase 1a clinical study, we demonstrated safety and tolerability of single 7.5-mg, 22.5-mg, and 30-mg doses of PXL065 as well as preferential exposure to the ( R )-stereoisomer in comparison to 45-mg pioglitazone. Conclusion : PXL065 at a dose lower than 22.5 mg is predicted to exhibit efficacy for NASH equal to, or greater than, 45-mg pioglitazone without the potentially detrimental weight gain and edema. The development of PXL065 for NASH represents a unique opportunity to leverage the therapeutic benefits of pioglitazone, while reducing or eliminating PPARγ-related side effects., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

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., Methods: An open-label, single-dose, parallel-group study was carried out in seven subjects with normal hepatic function and seven subjects with moderate hepatic impairment who received a single dose of imeglimin 1000 mg. Blood and urine samples were collected up to 48 h after imeglimin administration. Pharmacokinetics were determined using non-compartmental methods., Results: Imeglimin maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) in subjects with moderate hepatic impairment was 1.3-fold (90% confidence interval [CI] 1.05-1.60) and 1.5-fold (90% CI 1.19-1.82) higher than in subjects with normal hepatic function, but was not considered as clinically meaningful. Higher plasma exposure and amount of imeglimin renally excreted in moderate hepatic impaired subjects, associated with an unchanged elimination rate, suggests that this increase could be linked to a higher oral absorption and/or lower hepatic uptake in this population., Conclusions: Imeglimin was safe and well tolerated in all subjects., Clinical Trial Registration: EudraCT 2018-001950-83.

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. At a cellular and molecular level, Imeglimin's underlying mechanism may involve correction of mitochondrial dysfunction, a common underlying element of T2D pathogenesis. It has been observed to rebalance respiratory chain activity (partial inhibition of Complex I and correction of deficient Complex III activity), resulting in reduced reactive oxygen species formation (decreasing oxidative stress) and prevention of mitochondrial permeability transition pore opening (implicated in preventing cell death). In islets derived from diseased rodents with T2D, Imeglimin also enhances glucose-stimulated ATP generation and induces the synthesis of nicotinamide adenine dinucleotide (NAD + ) via the 'salvage pathway'. In addition to playing a key role as a mitochondrial co-factor, NAD + metabolites may contribute to the increase in GSIS (via enhanced Ca ++ mobilization). Imeglimin has also been shown to preserve β-cell mass in rodents with T2D. Overall, Imeglimin appears to target a key root cause of T2D: defective cellular energy metabolism. This potential mode of action is unique and has been shown to differ from that of other major therapeutic classes, including biguanides, sulphonylureas and glucagon-like peptide-1 receptor agonists., (© 2020 John Wiley & Sons Ltd.)

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. The underlying mechanism involves increases in the cellular nicotinamide adenine dinucleotide (NAD+) pool-potentially via the salvage pathway and induction of nicotinamide phosphoribosyltransferase (NAMPT) along with augmentation of glucose-induced ATP levels. Further, additional results suggest that NAD+ conversion to a second messenger, cyclic ADP ribose (cADPR), via ADP ribosyl cyclase/cADPR hydrolase (CD38) is required for imeglimin's effects in islets, thus representing a potential link between increased NAD+ and enhanced glucose-induced Ca2+ mobilization which-in turn-is known to drive insulin granule exocytosis. Collectively, these findings implicate a novel mode of action for imeglimin that explains its ability to effectively restore-β-cell function and provides for a new approach to treat patients suffering from Type 2 diabetes., Competing Interests: Authors S H-B, PF, SB and DM are employees and stockholders of Poxel SA, a research-based biotech company with no currently marketed products. Author MK is a salaried employee of Metabrain Research, a research-only company that is partnered with Poxel SA and participated in the conduct of experiments. These affiliations with commercial enterprises do not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation., Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined., Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (p E = 0.001; p S = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP ( p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP ( p = 0.007), but not in its subepithelial layers ( p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years., Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.

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., Methods: A phase 1 study was carried out in 16 subjects who received a single dose of 1500 mg imeglimin alone on day 1 followed by a 6-day treatment (day 5 to day 10) with cimetidine 400 mg twice daily. On day 8, a single dose of imeglimin was co-administered with cimetidine. Blood and urine samples were collected up to 72 h after each imeglimin administration. Pharmacokinetic parameters were determined using non-compartmental methods., Results: Imeglimin maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) were 1.3-fold [90% CI (1.12-1.62) and (1.10-1.46) for C max and AUC 0-last , respectively] higher when imeglimin was co-administered with cimetidine but this increase was not considered clinically relevant. This increase could be mainly explained by a reduction in renal elimination, mediated through the cimetidine inhibition of renal MATE1 transporter. Imeglimin taken alone or with cimetidine was safe and well tolerated in all subjects., Conclusions: No clinically significant drug-drug interaction exists between imeglimin and cimetidine, a reference inhibitor of MATE1, MATE2-K, OCT1 and OCT2 transporters., Clinical Trial Registration: EudraCT 2018-001103-36.

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 in vitro , we postulated that imeglimin could also exert longer term effects to prevent pancreatic β-cell death and preserve functional β-cell mass in vivo ., Methods: Zucker diabetic fatty (ZDF) male rats were treated by oral gavage with imeglimin at a standard dose of 150 mg/kg or vehicle, twice daily for five weeks. At treatment completion, oral glucose tolerance tests were performed in fasted animals before a thorough histomorphometry and immunohistochemical analysis was conducted on pancreas tissue slices to assess cellular composition and disease status., Results: Imeglimin treatment significantly improved glucose-stimulated insulin secretion (augmentation of the insulinogenic index) and improved glycaemia. Both basal insulinaemia and pancreatic insulin content were also increased by imeglimin. In ZDF control rats, islet structure was disordered with few β-cells; after imeglimin treatment, islets appeared healthier with more normal morphology in association with a significant increase in insulin-positive β-cells. The increase in β-cell mass was associated with a greater degree of β-cell proliferation in the presence of reduced apoptosis. Unexpectedly, a decrease in as a α-cell mass was also documented due to an apparent antiproliferative effect of imeglimin on this cell type., Conclusion: In male ZDF rats, chronic imeglimin treatment corrects a paramount component of type 2 diabetes progression: progressive loss of functional β-cell mass. In addition, imeglimin may also moderate a-cell turnover to further ameliorate hyperglycaemia. Cumulatively, these cellular effects suggest that imeglimin may provide for disease modifying effects to preserve functional β-cell mass., Competing Interests: This work was funded by Poxel SA as part of the development programme for imeglimin. SHB, DEM and SB are employees of Poxel and stockholders., (© 2020 Poxel SA. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

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. 12-Lead Holter ECGs were recorded from 1 h before dosing until at least 24 h after each dose. This study was performed at a single-center inpatient clinical pharmacology unit., Results: The upper bound of the two-sided 90% confidence interval for time-matched, placebo-subtracted, baseline-adjusted QTc intervals (ΔΔQTcF) did not exceed the regulatory threshold of 10 ms in any of the imeglimin dose groups. There were no QTcF values above 500 ms nor changes from pre-dose in QTcF above 60 ms in the imeglimin groups. Imeglimin did not exert a relevant effect on heart rate and PR or QRS intervals. Assay sensitivity was demonstrated by the effect of moxifloxacin 400 mg, with a lower bound two-sided 90% confidence interval for ΔΔQTcF of 10.6 ms., Conclusion: This thorough QT study demonstrated that therapeutic and supratherapeutic exposures of imeglimin did not induce a QT/QTc prolongation with a strong confidence as evidenced by the assay sensitivity., Trial Registration Number/date: NCT02924337/ October 5, 2016.

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. Pharmacokinetic parameters were determined from blood and urine; levels of all compounds were evaluated using liquid chromatography with tandem mass spectrometry., Results: Systemic exposure (AUC 0-τ area under the plasma concentration-time curve over a dosing interval and maximum concentration) to MET was 14% and 10% lower, respectively, when administered with IMEG. Approximately 40% of MET was excreted unchanged in urine, decreasing to 34% when given with IMEG. The 90% confidence intervals for AUC 0-τ and maximum concentration indicated no effect of co-administration on systemic exposure to MET. Mean AUC 0-τ and maximum concentration of SITA were similar with or without IMEG. Median times to maximum concentration were 0.7 and 1.0 h and mean elimination half-lives were 8.2 and 8.7 h with and without IMEG, respectively. Systemic exposure to IMEG was similar to previous phase I studies., Conclusions: Co-administration of IMEG with MET or SITA did not result in clinically relevant changes in systemic exposure to MET or SITA, although minor reductions in exposure (AUC 0-τ and maximum concentration) and renal elimination were noted when MET was given with IMEG vs placebo., Clinical Trial Registration: EudraCT2009-014520-40 (MET-IMEG DDI) and EudraCT2010-022926-34 (SITA-IMEG DDI).

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. Here, we show that imeglimin directly activates β-cell insulin secretion in awake rodents without affecting hepatic insulin sensitivity, body composition, or energy expenditure. These data identify a primary amplification rather than trigger the β-cell mechanism that explains the acute, antidiabetic activity of imeglimin., (Copyright © 2016 the American Physiological Society.)

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. Six-week imeglimin treatment significantly decreased glycemia, restored normal glucose tolerance, and improved insulin sensitivity without modifying organs, body weights, and food intake. This was associated with an increase in insulin-stimulated protein kinase B phosphorylation in the liver and muscle. In liver mitochondria, imeglimin redirects substrate flows in favor of complex II, as illustrated by increased respiration with succinate and by the restoration of respiration with glutamate/malate back to control levels. In addition, imeglimin inhibits complex I and restores complex III activities, suggesting an increase in fatty acid oxidation, which is supported by an increase in hepatic 3-hydroxyacetyl-CoA dehydrogenase activity and acylcarnitine profile and the reduction of liver steatosis. Imeglimin also reduces reactive oxygen species production and increases mitochondrial DNA. Finally, imeglimin effects on mitochondrial phospholipid composition could participate in the benefit of imeglimin on mitochondrial function. In conclusion, imeglimin normalizes glucose tolerance and insulin sensitivity by preserving mitochondrial function from oxidative stress and favoring lipid oxidation in liver of HFHSD mice., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

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. These cell-based BBB models are characterized by low paracellular permeation, well-developed tight junctions and functional efflux transporters. A study of twenty drugs shows similar compound ranking between rat and human models although with a 2-fold higher permeability in rat. cLogP < 5, PSA < 120 Å, MW < 450 were confirmed as essential for CNS drugs. An in vitro/in vivo correlation in rat (R² = 0.67; P = 2 × 10⁻⁴) was highlighted when in vitro permeability and efflux were considered together with plasma exposure and free fraction. The cell-based BBB model is suitable to optimize CNS-drug selection, to study interspecies differences and then to support human brain exposure prediction.

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. The best model to increase recovery of lipophilic compounds was determined as fasted state simulated intestinal fluid (FaSSIF) in the apical compartment and HBSS with 1% bovine serum albumin (BSA) in basolateral compartment. This model allows a correlation between absorption on Caco-2 cells and absorbed fraction in humans. For 35 compounds, only 2 outliers were observed in the Caco-2 assay using the FaSSIF model. These two outliers were the same outlier compounds as those observed with a classic Caco-2 method. Furthermore, a permeability assay of Pgp substrates evidenced efflux transport in both models and addition of a Pgp inhibitor suppressed Pgp efflux transport. FaSSIF in the apical compartment and HBSS with 1% BSA in the basolateral compartment is the model of choice to predict in vivo absorption for lipophilic acid drugs.

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. Several transporters were nevertheless quantitatively expressed at higher (MRP2, MRP3, MRP4, MRP5, MRP6, OATP-A, OATP-B, OCT1 and MCT1) or lower (BCRP) levels in Caco-2 cells comparatively to small intestine. Moreover, MDR1, MRP2, OATP-A and PEPT1 mRNA relative expression were found to differ in the two analyzed Caco-2 cell clones by at least a twofold factor, highlighting that some variations in transporter expression may occur in Caco-2 cells depending on cell origin, and therefore underlining the interest of carefully characterizing transporter levels in any Caco-2 cell clone before its use for drug transport assays.

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). The second, during which acyl glucuronides are incubated with human serum albumin (HSA), consists of assessing the reactivity of acyl glucuronides toward HSA. Both phases are performed successively in the same experiment. This model was validated using eight carboxylic drugs that were well known for their reactivity, their extent of covalent binding, and their immunological potential. These products were representative of the scale of reactivity. Each compound was incubated with HLM at 400 microM and metabolized into acyl glucuronide to different extents, ranging from 5.6% (tolmetin) to 89.4% (diclofenac). The first-order aglycone appearance rate constant and the extent of covalent binding to proteins were assayed during the incubation of acyl glucuronides formed with HSA for 24 h. Extensive isomerization phenomenon was observed for each acyl glucuronide between the two phases. An excellent correlation was observed (r(2), 0.94) between the extent of drug covalent binding to albumin and the aglycone appearance constant weighted by the percentage of isomerization. This correlation represents an in vitro reactivity scale, which will be helpful in drug discovery support programs to predict the covalent binding potential of new chemical entities. This screening model will also allow the comparison of acyl glucuronide reactivity for related structure compounds.

We developed an isocratic, selective, and very sensitive HPLC method for the determination of ketamine and its two main metabolites in plasma. The compounds were extracted from plasma by a liquid-liquid extraction with a dichloromethane:ethyl acetate mixture followed by an acidic back-extraction. Separation was achieved on a new stationary phase, Purospher RP-18 endcapped, with a mobile phase containing acetonitrile:0.03 mol/L phosphate buffer (23:77 by vol) adjusted to pH 7.2. Because of the high column efficiency and the significant improvement of peak symmetry, the quantification limit could be down to 5 micrograms/L for ketamine and norketamine (NK). The intraday and interday CVs ranged from 1.7% to 5.8% and 3.1% to 10.2% for all compounds respectively. The method is sensitive enough for monitoring ketamine, NK, and dehydroketamine in plasma during pharmacokinetic studies after an intravenous bolus of a low dose of ketamine.