compound 18 / Genfit - LARVOL DELTA

Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis. (PubMed, J Med Chem) - "However, PPARα/δ dual agonist GFT-505 exhibited poor anti-NASH effects in a phase III clinical trial, probably due to its weak PPARα/δ agonistic activity and poor metabolic stability. H11, which had excellent PK properties and a good safety profile, showed potent in vivo anti-NASH effects in preclinical models. Together, H11 holds a great promise for treating NASH or other inflammatory and fibrotic diseases."

Journal • Fibrosis • Hepatology • Non-alcoholic Steatohepatitis • PPARA

Discovery of the first-in-class dual PPARδ/γ partial agonist for the treatment of metabolic syndrome. (PubMed, Eur J Med Chem) - "In this study, we identified a dual PPARδ/γ partial agonist 6 (ZLY06) based on the cyclization strategy of PPARα/δ dual agonist GFT505. In contrast, weight gain and hepatic steatosis were observed in Rosiglitazone, a widely used PPARγ full agonist. All of these results indicated that ZLY06 exhibits potential benefits on metabolic syndrome, while no adverse effects related to PPARγ full agonist."

Journal • Diabetes • Metabolic Disorders • PPARA • PPARG

Design, synthesis, and biological evaluation of a novel dual peroxisome proliferator-activated receptor alpha/delta agonist for the treatment of diabetic kidney disease through anti-inflammatory mechanisms. (PubMed, Eur J Med Chem) - "GFT505 is a dual PPAR-α/δ agonist, and the selectivity against PPAR-γ is still to be improved. Furthermore, compound 12 exhibited an evidently renoprotective effect on the DKD through inhibiting inflammatory process, which might at least partly via JNK/NF-κB pathways in vivo and in vitro. Overall, compound 12 hold therapeutic promise for DKD."

Journal • Diabetes • Diabetic Nephropathy • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease

Yellow loosestrife (Lysimachia vulgaris var. davurica) ameliorates liver fibrosis in db/db mice with methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis. (PubMed, BMC Complement Med Ther) - "Lipid accumulation and inflammatory responses in the liver were alleviated by feeding LV extract to NASH-induced mice. Moreover, the LV extract strongly prevented liver fibrosis by blocking TGFβ/Smad signaling. Hence, LV showed sufficient potency for use as a therapeutic agent against NASH."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • NFE2L2

The pharmacodynamic and differential gene expression analysis of PPAR α/δ agonist GFT505 in CDAHFD-induced NASH model. (PubMed, PLoS One) - "The down-regulated genes were enriched in cytokine-cytokine receptor interaction pathway and ECM-receptor interaction pathway, while the up-regulated genes were enriched in PPAR signaling pathway and fatty acid degradation pathway. This study provides clues and basis for further understanding on the mechanism of PPAR α/δ agonist on NASH."

Journal • PK/PD data • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Steatohepatitis • COL1A1 • COL1A2 • FABP4 • TIMP1

RESOLVE-IT: Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P3; N=2157; Terminated; Sponsor: Genfit; Active, not recruiting ➔ Terminated; Study did not meet the predefined primary surrogate efficacy endpoint, no safety issues identified

Clinical • Trial termination • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis

A Double-blind Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with Inadequate Response or Intolerance to Ursodeoxycholic Acid (clinicaltrialsregister.eu) - P3; N=150; Ongoing; Sponsor: GENFIT

Clinical • New P3 trial • Hepatology • Immunology • Primary Biliary Cholangitis • CRP • FGF19 • HP • PAI1 • TIMP1 • TNFA

Elafibranor, PK and Safety in Children and Adolescents 8 to 17 Years of Age With Non Alcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P2; N=10; Terminated; Sponsor: Genfit; N=20 ➔ 10; Trial completion date: Nov 2020 ➔ Jun 2020; Active, not recruiting ➔ Terminated; Trial primary completion date: Nov 2020 ➔ May 2020; Continuation of the trial cannot serve a scientific purpose, no safety concerns identified

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Hepatology • Non-alcoholic Steatohepatitis • APOA1 • APOB • HP • IL6 • TNFA

Study to Evaluate the Effect of Elafibranor on Hepatic Lipid Composition in Subjects With Nonalcoholic Fatty Liver (NAFL) (clinicaltrials.gov) - P2; N=17; Terminated; Sponsor: Genfit; Recruiting ➔ Terminated; Continuation of the trial cannot serve a scientific purpose

Clinical • Trial termination • Hepatology • Non-alcoholic Fatty Liver Disease

Study to Investigate the Potential Drug-Drug Interaction Between Elafibranor and Indomethacin (clinicaltrials.gov) - P1; N=26; Completed; Sponsor: Genfit; Recruiting ➔ Completed

Clinical • Trial completion

Elafibranor Pharmacokinetic Parameters in Renal Impaired Patients (clinicaltrials.gov) - P1; N=23; Completed; Sponsor: Genfit; Recruiting ➔ Completed

Clinical • Trial completion • Nephrology • Renal Disease

Elafibranor Pharmacokinetic Parameters in Elderly Healthy Volunteers (clinicaltrials.gov) - P1; N=21; Completed; Sponsor: Genfit; Recruiting ➔ Completed; N=30 ➔ 21

Clinical • Enrollment change • Trial completion • Dyslipidemia

RESOLVE-IT: Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P3; N=2000; Active, not recruiting; Sponsor: Genfit; Recruiting ➔ Active, not recruiting; Trial primary completion date: Dec 2021 ➔ Oct 2020

Clinical • Enrollment closed • Trial primary completion date • Fibrosis • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Elafibranor, PK and Safety in Children and Adolescents 8 to 17 Years of Age With Non Alcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P2; N=20; Active, not recruiting; Sponsor: Genfit; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • APOA1 • APOB • HP • IL6 • TNFA

Hepatoprotective effects of ZLY16, a dual peroxisome proliferator-activated receptor α/δ agonist, in rodent model of nonalcoholic steatohepatitis. (PubMed, Eur J Pharmacol) - "Moreover, ZLY16 offers more favorable effects in decreasing liver TC and TG accumulation, blocking liver fibrosis and inflammation than GFT505, the most advanced candidate of PPARα/δ agonist for the treatment of NASH. These results indicate that ZLY16 is a highly potent PPARα/δ agonist that provides great protection against NASH development, and may be useful for the treatment of NAFLD/NASH."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • IL6

[VIRTUAL] Aggravating Liver Lipid Accumulation and Fibrosis in Nonalcoholic Steatohepatitis Model of MS-NASH Mice by a Modified Amylin Diet (ADA 2020) - "The GAN diet fed MS-NASH mice can be a better NASH model for novel compound efficacy."

Preclinical • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • LEP

Design, synthesis, and biological evaluation of novel dual PPARα/δ agonists for the treatment of T2DM. (PubMed, Bioorg Chem) - "Moreover, oral glucose tolerance test exhibited that compound 6 exerts dose-dependent anti-diabetic effects in ob/ob mice and reveals similar potency to that of GFT505, the most advanced candidate in this field. These findings suggested that compound 6 is a promising candidate for further researches, and the extended chemical space might help us to explore better PPARα/δ agonist."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Combination drug therapy allows synergistic therapeutic dose reduction in NASH: a case study of elafibranor (GFT505) and an FXR agonist combination in a model of severe NASH (ILC 2017) - "In recent phase 2B studies, both elafibranor (ELA, PPARa/d agonist) and obeticholic acid (OCA; FXR agonist) have shown efficacy on NASH and fibrosis. The combination of ELA and OCA had synergistic antifibrotic effects in the CDAA/chol diet-induced NASH model. The therapeutic benefit was achieved at lower doses with the combination than with monotherapies. Our findings suggest that elafibranor/ OCA combination treatment would benefit a wider patient population and at lower therapeutic doses."

Combination therapy • Hepatocellular Cancer • Non-alcoholic Steatohepatitis

PPAR-alpha activation protects myocardium against ischemia/reperfusion injury in isolated rat heart (ESC 2012) - Presentation time: 20/05/2012 08:30 AM -12:30 PM; Selective activation of PPAR-alpha attenuated I/R injury & oxidative stress in left ventricle myocardium; Protective effects of WY were reversed by wortmannin indicating that activation of PI3K/Akt may be involved in protection against I/R injury in the rat heart conferred by PPAR-alpha agonists

Preclinical-animal • Dyslipidemia

Elafibranor Pharmacokinetic Parameters in Renal Impaired Patients (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Genfit; Trial completion date: Dec 2019 ➔ Apr 2020; Trial primary completion date: Dec 2019 ➔ Apr 2020

Clinical • Trial completion date • Trial primary completion date

Study to Investigate the Potential Drug-Drug Interaction Between Elafibranor and Indomethacin (clinicaltrials.gov) - P1; N=28; Recruiting; Sponsor: Genfit; Trial completion date: Dec 2019 ➔ May 2020; Trial primary completion date: Dec 2019 ➔ May 2020

Clinical • Trial completion date • Trial primary completion date

Elafibranor Pharmacokinetic Parameters in Elderly Healthy Volunteers (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: Genfit; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

Elafibranor Pharmacokinetic Parameters in Elderly Healthy Volunteers (clinicaltrials.gov) - P1; N=30; Not yet recruiting; Sponsor: Genfit

Clinical • New P1 trial

PHARMACOLOGICAL VALIDATION AND RNA-SEQ GENE EXPRESSION PROFILING OF TWO RODENT MODELS OF NASH, NEW MECHANISTIC INSIGHTS AND IMPLICATIONS (AASLD 2019) - "We tested efficacy of different NASH compounds in both models as determined by liver histopathology, and analyzed modulations of gene expression in model animal livers, and these in response to various compounds in both models by RNA-seq profiling. 1) We tested obeticholic acid (INT-747), elafibranor (GFT-505), selonsertib (GS-4997), cenicriviroc (TAK-652) and MGL-3196 in the HFD+CCl4 models. Our results revealed that these two models are mechanistically different. Either model could be pharmacologically validated with compounds of different MOAs. The demonstration of efficacy of these compounds could be mutually exclusive."

Study to Investigate the Potential Drug-Drug Interaction Between Elafibranor and Indomethacin (clinicaltrials.gov) - P1; N=28; Recruiting; Sponsor: Genfit; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open