A NICE ARTICLE ON NASH IN ‘NATURE’
(by Gery DIVRY)

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Nature is a British interdisciplinary scientific journal, first published on 4 November 1869. It was ranked the world's most cited scientific journal by the Science Edition of the 2010 Journal Citation Reports, is ascribed an impact factor of approximately 42.4, and is widely regarded as one of the few remaining academic journals that publishes original research across a wide range of scientific fields


I just read the article published in 'Nature' one week ago (22 January 2016) One of the most widely read scientific journal in the world and renowned for the reliability and quality of its authors, 

This article entitled :

Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies

Giovanni MussoMaurizio Cassader Roberto Gambino

It is extremely well done and describe all the molecular targets of drug candidates. 

It goes without saying that the scientists will enjoy it,  but at my level, my reading stay basic.

What I noticed is that chapter  on PPAR agonists gives pride to the GFT 505 (Elafibranor) ,and nowhere a supposed failure of the Phase 2b study is mentionned  but rather the fact that the study GOLDEN demonstrated significant efficacy in NASH ..

Below is an extract of the PPAR agonists chapter


«  Peroxisome proliferator-activated receptors. 

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and can be classified into three isotypes designated PPARα, PPARδ (also known as PPARβ) and PPARγ. PPARs form heterodimers with RXR40, and the PPAR–RXR hetero- dimer regulates gene transcription by binding to PPAR response elements (PPREs) 

PPARα is expressed in the liver and other metabol- ically active tissues (including striated muscle, kidney and pancreas) where it upregulates numerous enzymes involved in mitochondrial and peroxisomal fatty acid β-oxidation, microsomal ω-oxidation, plasma fatty acid membrane transporters and ketogenesis41,42, thereby shifting hepatic metabolism towards lipid oxi- dation. PPARα activation also enhances plasma tri- glyceride clearance by upregulating the expression of lipoprotein lipase (LPL) and downregulating hepatic secretion of APOCIII, a LPL inhibitor43 (TABLE 1). Another PPARα target, catalase, ameliorates hydrogen peroxide (H2O2) detoxification and protects hepatocytes from oxidative stress, which is believed to have a crucial role in liver injury in NASH (see below)44.

PPARα also enhances the transcription of FGF21; FGF21 seems to be crucial for the metabolic functions of PPARα, as Fgf21-knockout mice fed a high-fat diet showed hepatic steatosis and impaired fatty acid oxi- dation and ketogenesis41. Therapeutic approaches to interfere with FGF21 directly are discussed in more detail below.

PPARα has anti-inflammatory effects, as it suppresses the acute phase inflammatory response via PPRE- binding-dependent45,46 and PPRE-binding-independent mechanisms47 (TABLE 1). PPARα suppresses cytokine- induced and lipopolysaccharide-induced secretion of interleukin 1 (IL-1), IL-6 and tumour necrosis factor (TNF) and the expression of adhesion molecules inter- cellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) in vitro and in vivo, inde- pendently of direct DNA binding48,49. Importantly, these PPRE-independent effects were sufficient to protect the liver from methionine–choline-deficient diet-induced inflammation and fibrosis, without affecting fatty acid oxidation and lipid accumulation values of 30,000 and 50,000 nM for fenofibrate and bezafibrate, respectively), have hepatoprotective effects in rodent models of NASH51. However, the relatively weak potency of fibrates and other available PPARα agonists, the low expression level of PPARα in human liver rel- ative to rodent liver40 and the observation that PPARα expression decreases with progressive fibrosis may explain the contradictory results of early PPARα agonists in randomized clinical trials6. These results prompted the development of novel, more potent PPARα agon- ists, including the selective PPARα modulator K-877 (EC50 = 1 nM) and the dual PPARα and PPARδ agon- ist GFT505 (EC50 = 6 nM), which activates both PPARα and PPARδ44,47 (TABLE 2).

PPARδ is ubiquitously expressed and has been impli- cated in lipid metabolism and energy homeostasis of var- ious organs, including the liver40. In nonparenchymal cells, PPARδ is anti-inflammatory as it polarizes macrophages from a pro-inflammatory M1 phenotype to an anti- inflammatory, pro-resolving M2 phenotype52; furthermore, unlike PPARα, PPARδ is also expressed at extrahepatic sites where it promotes fatty acid β-oxidation and adaptive thermogenesis53 (TABLE 1).

In preclinical models of NASH, PPARδ agonists enhanced hepatic lipid oxidation and insulin sensitiv- ity and reduced steatosis, inflammation and fibrogene- sis50,54. MBX-8025, a potent selective PPARδ modulator (EC50 = 2 nm), reduced liver enzyme levels, inflamma- tory marker levels, insulin resistance and atherogenic dyslipidaemia in overweight patients with dyslipidaemia55.

Given the complementary effects and tissue distri- bution of PPARα and PPARδ, dual PPARα and PPARδ agonists have been evaluated in patients with NASH. GFT505 showed substantial hepatoprotective effects in rodent models of NASH. In a recently completed Phase IIb placebo-controlled randomized clinical trial (GOLDEN-505), GFT505, administered for 1 year, significantly improved histological steatohepatitis, fibrosis and markers of inflammation and lipid and glucose metabolism in 202 patients with biopsy-confirmed NASH; the GFT505 developer, Genfit, is now planning to evaluate this compound in a Phase III trial. » 

Nature : doi:10.1038/nrd.2015.3 Published online 22 Jan 2016

 

This publication in Nature confirms the good image that now promote the KOL's on Elafibranor.

Conversely, concerning the OCA they are much more critical and I was really surprised by the skepticism displayed.

I supported the same theses in many articles on this site, but seeing my doubts confirmed in an article published in Nature reassures me on what remains of my analytical skills.

You can see this for yourself :


«  On this basis, potent semi-synthetic bile acid FXR agonists have been developed for the treatment of NASH (TABLE 2). Obeticholic acid (OCA; also known as INT-747), a semi-synthetic derivative of chenodeoxy- cholic acid that binds to FXR with an approximately 87-fold higher potency than chenodeoxycholic acid does20, has been recently evaluated in the multicentre, double-blind, randomized FLINT trial16. Although treatment with 25 mg OCA significantly improved the primary histological outcome (as measured by NAFLD activity score) and fibrosis score of patients compared to those of patients treated with placebo, NASH resolu- tion occurred in only 22% of patients treated with OCA after 72 weeks (p = 0.08 versus placebo). Furthermore, although OCA improved the mean liver fibrosis stage in the FLINT trial, an effect not shown by agents previously tested in NASH, the fraction of patients with resolution of advanced fibrosis did not significantly differ between groups, and treatment with 40 mg per day OCA failed to improve fibrosis score in another Phase IIa randomized clinical trial in Japan (see the Intercept Pharmaceuticals press release in Further information). As the presence of NASH and bridging fibrosis are both strong predictors of liver disease progression and liver-related complications1, the clinical relevance of the results of the FLINT trial requires further evaluation. In addition, OCA was not effective in the 47% of study participants who did not have diabetes16,21. Whether individuals with and without diabetes have different rates or pathways for bile acid metabolism warrants future investigation. Last, a 5% decrease in HDLC levels, coupled with a 16% increase in low-density lipoprotein cholesterol (LDLC), was observed in patients treated with OCA as compared to those treated with placebo; the effects of these changes on the long-term risk of cardiovascular disease in patients with NASH is unknown. To investigate these concerns, in September 2015, Intercept initiated a Phase III trial known as REGENERATE, which is expected to enrol approximately 2,000 NASH patients with advanced liver fibrosis at up to 300 centres worldwide. "

Nature : doi:10.1038/nrd.2015.3 Published online 22 Jan 2016


The doubts expressed are clear and uncompromising, for me, it, once again, confirms the leading position of Elafibranor in the future treatment of NASH.






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