Elafibranor, an Agonist of the Peroxisome Proliferator−Activated Receptor−α and −δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening

Ratziu, Vlad; Harrison, Stephen A.; Francque, Sven; Bédossa, Pierre; Lehert, Philippe; Serfaty, Lawrence; Romero–Gómez, Manuel; Boursier, Jérôme; Abdelmalek, Manal F.; Caldwell, Steve; Drenth, Joost P.H.; Anstee, Quentin M.; Hum, Dean W.; Hanf, R.; Roudot, A.; Megnien, Sophie Jeannin; Staels, Bart; Sanyal, Arun J.; Mathurin, Philippe; Gournay, Jérôme; Nguyen‐Khac, Eric; Lédinghen, Victor de; Larrey, Dominique; Tran, Albert; Bourlière, Marc; Maynard-Muet, M.; Asselah, Tarik; Henrion, Jean; Nevens, Frederik; Cassiman, David; Geerts, Anja; Moreno, Christophe; Beuers, Ulrich; Galle, Peter R.; Spengler, U; Bugianesi, Elisabetta; Craxı̀, Antonio; Angélico, M.; Fargion, Silvia; Voiculescu, M; Gheorghe, Liliana; Preoţescu, Liliana; Caballería, Juan; Andrade, R.J.; Crespo, Javier; Callera, J. L.; Ala, Aftab; Aithal, Guruprasad P.; Abouda, George; Luketic, Velimir A.; Huang, Mao-Yu; Gordon, Stuart C.; Pockros, Paul J.; Poordad, Fred; Shores, Nathan J.; Moehlen, Martin; Bambha, Kiran; Clark, Virginia; Satapathy, Sanjaya K.; Parekh, Samir; Reddy, R. K.; Sheikh, Muhammad Y.; Szabó, Gyöngyi; Vierling, John M.; Foster, Timothy E.; Umpiérrez, Guillermo E.; Chang, Chih-Jen; Box, Terry; Gallegos‐Orozco, Juan F.

doi:10.1053/j.gastro.2016.01.038

Cited by 895 publications

(719 citation statements)

References 38 publications

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“…Selective PPARδ agonists have not been investigated in patients with NASH, but in overweight subjects GW501516 and MBX‐8025 improved metabolic parameters during a 2‐week and 8‐week duration trial, respectively 17, 18. More recently, the dual PPARα/δ agonist elafibranor (GFT505) achieved improvement in steatohepatitis without fibrosis worsening in patients with a NAS score ≥4 and decreased fibrosis in the subgroup of patients with NASH who responded to GFT505 47. PPARγ activation by pioglitazone significantly improves steatosis, ballooning, and inflammation as well as metabolic markers in patients with NASH after 6 or 12 months of treatment 48.…”

Section: Discussionmentioning

confidence: 99%

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

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115

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IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524–537)

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Section: Discussionmentioning

confidence: 99%

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Wettstein

Luccarini

Poekes

et al. 2017

Hepatology Communications

Self Cite

115

View full text Add to dashboard Cite

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“…Interestingly, the induction of these genes was blunted by both elafibranor (GFT505), a mixed PPARα/δ agonist active in murine models of NASH (59) and in NASH patients (60) (Figure 6A Data are expressed as the mean ± SEM (n = 9) and were compared using a 2-tailed t-test. A P < 0.001, B P < 0.05.…”

Section: Dpt Expression Is Downregulated Upon Pparα Activation In Vivomentioning

confidence: 99%

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

et al. 2017

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“…Concerning side effects, elafibranor was well tolerated and did not cause weight gain or cardiac events. Only a mild, reversible increase in serum creatinine was observed, indicating renal side effects [72].…”

Section: Dual Ppar Agonists Clinical Trialsmentioning

confidence: 98%

“…the dual PPARα/δ agonist elafibranor [72], have been studied in clinical trials. Furthermore, vitamin E [12], the FXR agonist obeticholic acid [73] and succeeding compounds as well as insulin-sensitizing agents, particularly metformin are investigated as therapeutic option for the treatment of NAFLD or NASH.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

Gellrich¹,

Merk²

2017

Nuclear Receptor Research

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Abstract. A long neglected hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) arise as serious health burden with alarming global prevalence. The disease complex is currently attracting considerable interest of drug discovery and many experimental approaches are studied in all stages of clinical development. Peroxisome proliferator-activated receptors (PPARs) have a successful history as pharmaceutical targets in the treatment of several aspects of the metabolic syndrome and, therefore, a putative therapeutic value of PPAR modulators in NAFLD/NASH is obvious. However, so far only the PPAR / agonist elafibranor has revealed clear efficacy and reached an advanced stage of development while the far more established PPAR subtypes PPAR and PPAR have disappointed. Still, clinical trial design and population might have obscured beneficial activities and, in addition, synergistic multi-target approaches as well as selective PPAR modulators could generate safer approaches with higher therapeutic efficacy.

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Elafibranor, an Agonist of the Peroxisome Proliferator−Activated Receptor−α and −δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening

Cited by 895 publications

References 38 publications

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

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