NASH KEY OPINION LEADERS SUPPORT PHASE 3 FOR ELAFIBRANOR 

breaking-news


Mid november 2015 

Professor Arun Sanyal, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, commented: “The Phase 2b GOLDEN-505 study demonstrated that, in patients with clearly established NASH with high disease activity, Elafibranor safely led to resolution of steatohepatitis as well as improvement in cardiometabolic risk factors. Of particular importance is the efficacy of Elafibranor on the new consensual definition of resolution of NASH without worsening of fibrosis. Using this new consensual definition which emphasizes the role of cell injury and inflammation as the main drivers of fibrosis evolution, the GOLDEN-505 trial demonstrated that Elafibranor-treated patients who cleared their NASH also experienced a significant reduction in liver fibrosis. Thus, the design of the Phase 3 trial is optimal to confirm the good efficacy/safety ratio of Elafibranor on resolution of NASH at an interim analysis after 72 weeks, and on prevention of cirrhosis in the long-term.” 



AASLD ABSTRACT - HEPATOLOGY - October 2015


ABSTRACT 105

  An international, phase 2 randomized controlled trial of the dual PPAR agonist GFT505 in adult patients with NASH 

  Peroxisome proliferator-activated receptor α-δ dual agonists, such as GFT505, are a promising therapy for NASH as they improve hepatic insulin sensitivity, glucose homeostasis, lipid metabolism, and inflammation. Methods. In this randomized controlled trial (56 European and US centers) 274 patients (pts) (full analysis set, FAS) with histologically-defined non-cirrhotic NASH received GFT505 80 mg or 120 mg QD vs placebo (PLB) for one year. The primary outcome was resolution of NASH without worsening of fibrosis. Data were analyzed according to baseline severity (histological NAS score) and center effect. Biopsies were read by a single pathologist. Results. 237 pts had entry and end-of-treatment biopsies (ITT population). While the a priori primary endpoint did not meet significance, after controlling for baseline severity and center effect, pts in the 120 mg arm had a 1.94 (CI 1.08-3.48, p=0.027) higher relative risk (RR) of achieving the primary end-point compared to PLB, while the RR was 1.68 (0.92-3.05, p=0.091) for the 80 mg arm. Results were similar in the FAS where pts missing the second biopsy were counted as failures. In pts with moderate activity (NAS 4 or 5) the response rate was 27.5% in the 120 mg arm vs. 19.5% for the PLB arm. In those with severe activity (NAS>5) it was 14.8% vs. 0%, respectively. In the 120 pts with NAS>4 from centers that recruited >1 patient/arm, the response rate was 29% and 5% in the 120 mg and PLB arms, respectively, p=0.01. A >2 point NAS reduction was obtained in 48% and 21% of patients respectively, p=0.01. Compared to PLB, the 120 mg arm improved ballooning (45% vs. 23%, p=0.02), inflammation (55% vs. 33%, p=0.05) and steatosis (35.5% vs. 18%, NS). In the 120 mg arm, resolution of NASH, resulted in a significant improvement in fibrosis (mean change -0.67 vs. +0.09 in non-responders, p<0.001). In the ITT population, pts in the 120 mg arm had improved ALT, GGT and ALP, non-invasive fibrosis panels (NFS Angulo score and FibroTest) and systemic inflammatory markers, hsCRP, haptoglobin, fibrinogen, α2macroglobulin. Importantly, cardiometabolic risk markers such as triglycerides, LDL-C, HDL-C, improved significantly in the 120 mg group (ITT population) vs. PLB, as well as HbA1c and FFA in diabetic pts, all on top of standard of care therapies. Tolerability was excellent without weight gain, cardiac events or safety signal. 

Conclusion. In NASH patients 120 mg daily of GFT505 induced histological improvement and resolution of NASH, significantly more often than PLB. The excellent safety and tolerability and the improvement in cardiometabolic risk profile makes GFT505 an ideal drug candidate to be tested in phase 3 trials




 ABSTRACT 162

  Beneficial effects of the dual PPAR agonist, GFT505, on hepatic and cardiometabolic markers in adult NASH patients. 

   Introduction: NASH patients (pts) have a high prevalence of cardiometabolic risk factors, hence cardiovascular disease is the leading cause of death in this population. Having demonstrated the efficacy of GFT505 on the histological reversal of NASH

  here we evaluated the biochemical and cardiometabolic effects of the drug in in this large, international, phase 2 randomized, controlled trial of adult pts with biopsy-proven NASH. Methods: Pts from the ITT population of the GOLDEN505 trial randomized to the GFT505 120 mg (GFT120) and placebo (PBO) arms were compared for treatment effects on plasma lipid, glycemic, insulin resistance, inflammatory and liver markers. Results are expressed as effect size vs. placebo (LS mean - SE). Analyses were conducted for different stages of disease severity based on the NAFLD Activity Score (NAS) at baseline (NAS 3: mild, NAS 4-5: moderate, NAS>5: severe), and fibrosis stage (F0-F1 vs. F2-F3 according to Kleiner et al). Results: Compared to PBO, GFT120 significantly improved GGT (-29.31, 6.36 U/L, p<0.001), AST/ALT ratio (+0.19, 0.04, p<0.001), ALP (-23.85, 2.12 U/L, p<0.001), and ALT (-9.45, 5.05 U/L, p=0.06). GFT120 showed significant benefit on lipid parameters such as TG, LDL-C, HDL-C (-0.55, 0.13 mmol/L, p<0.001; -0.24,0.09 mmol/L, p<0.01; +0.11, 0.03 mmol/L, p<0.001 respectively). In diabetics (40% of the ITT population), GFT120 improved HbA1c (-0.46,0.22%, p<0.05) and free fatty acid (FFA) (-0.15,0.05 mmol/L, p<0.01). Non-invasive scores for fibrosis showed a significant effect of GFT120 vs. PBO for Fibrotest and NAFLD fibrosis score. In those with severe disease (NAS 6-8), the efficacy of GFT120 on cardio-metabolic markers was also observed, with significant effects over PBO on lipid markers such as TG (-0.67,0.22 mmol/L, p<0.01) and total cholesterol (-0.44,0.19 mmol/L, p<0.05). GFT120 also showed significant improvements in HbA1c (-0.55, 0.21%, p<0.05), HOMA-IR (-3.39, 1.4, p<0.05), and FFA (-0.15, 0.06 mmol/L, p<0.05). Liver enzymes were also significantly improved with decreases of ALT (-35.32, 7.44 U/L, p<0.001), AST (-22.57, 6.78 U/L, p<0.01) and GGT (-48.84, 10.73 U/L, p<0.001). These beneficial effects on cardiometabolic and liver markers of GFT120 were also found in patients with advanced fibrosis (stage 2 and 3). 

Conclusion. GFT505 at 120 mg daily shows consistent cardio-metabolic effects in NASH across the whole spectrum of histological severity. It also improved non-invasive scores of steatosis and fibrosis. The cardioprotective profile of GFT505 could be highly beneficial for the treatment of NASH in light of the increased cardiovascular mortality in this condition. 




 ABSTRACT 974

  GFT505 (ELAFIBRANOR) prevents nonalcoholic steatohepatitis (NASH), hepatic fibrosis and hepatocarcinoma in a new disease model   

Background: NAFLD is present in 20-30% of the adult population in developed countries. NASH, cirrhosis and hepatocellular carcinoma will develop in a substantial proportion of people with NAFLD. Recently, the phase 2B GOLDEN-505 trial has demonstrated the efficacy of GFT505 in reversing NASH in patients with advanced disease. In the present study we have assessed the efficacy of GFT505 in preventing NASH, liver fibrosis and hepatocarcinoma development in a new rat model. Methods: Steatohepatitis, NASH and hepatocarcinoma were induced by feeding Wistar rats with a choline-deficient L-amino-acid-defined-diet (CDAA) that was supplemented with 1% cholesterol. In the intervention group, animals also received GFT505 (10mg/kg/day PO) for the entire study period. NASH, fibrosis and hepatocarcinoma development were evaluated by histology. Additional biochemical and molecular analyses were also performed on different relevant biomarkers. Results: CDAA diet administration in Wistar rats causes liver transaminase elevation and fibrosing steatohepatitis that is similar to human NASH pathology. In this study the supplementation of the CDAA diet with 1% cholesterol led to increased NASH incidence (92% vs 58%) and to fibrosis aggravation as evidenced by higher prevalence of cirrhotic animals (42% vs. 8%). NASH development was significantly attenuated in rats on CDAA diet that were also administered GFT505. Consistently, hepatic inflammation, hepatocyte ballooning, oxidative stress and plasma transaminase levels were decreased, whereas plasma levels of FGF-21 and β-hydroxybutyrate, as well as the expression of fatty acid oxidation genes in the liver were increased in rats that received GFT505. Hepatic collagen was lower, fibrosis and cirrhosis development were all significantly prevented by GFT505 administration on CDAA diet. Finally, GFT505 administration completely prevented pre-neoplastic lesion development in rats exposed to CDAA diets as revealed by the GST-P staining. 

Conclusion: GFT505 prevented NASH, fibrosis, cirrhosis and pre-neoplastic lesion development in this novel NASH model. Since the effect of GFT505 on hepatic steatosis was rather modest in this particular model, this study demonstrates that the antifibrotic activity of GFT505 can be dissociated from its hypolipidemic efficacy.




 ABSTRACT 2145


  The hepatic and extra-hepatic profile of resolution of steatohepatitis induced by GFT-505 

   Background: Non-alcoholic steatohepatitis (NASH) is associated with increased liver- and cardio-metabolic risks. It is unknown whether resolution of steatohepatitis (SH) is associated with fibrosis regression and changes in cardio-metabolic risk profile, and whether drug-induced resolution of SH is similar to spontaneous resolution of SH. AIMS: We compared the hepatic and extra-hepatic profile associated with resolution of SH in GOLDEN505, a phase 2 randomized placebo-controlled trial of GFT505, a PPAR agonist. METHODS: Subjects with SH and NAS sup ou égal 4 who received GFT505 120 mg/ day (G120) or placebo (PBO) were studied. SH was defined by the presence of steatosis, inflammation and hepatocyte ballooning. Resolution of SH was defined by loss of any one of these components. Responders (R) were defined as resolution of SH without worsening of fibrosis. R and non-responders (NR) to G120 were compared for hepatic and extra-hepatic activity, and G120 R were compared to PBO R to explore the drug-induced effect of reversal of SH on extra-hepatic improvements. RESULTS: 202 subjects were included. The proportion of R was greater in G120 vs. PBO (22.4% vs. 12.7%; RR 2.01, p<0.05). Comparing G120 R vs. NR, the mean decreases in NAS were -2.67 vs. -0.25 (p<0.0001). This resulted from changes in steatosis (-0.5 vs. +0.06, p<0.0001), inflammation (-0.93 vs. -0.17, p<0.0001) and ballooning (-1.27 vs. -0.13, p<0.0001). Of note, resolution of SH was associated with a significant regression of fibrosis score (-0.67 in R vs. +0.06 in NR, p<0.0001). A similar histological resolution profile was observed in PBO R, notably for fibrosis improvement. G120 R had a greater drop in liver-related markers (LS means, SE) significant for AST (-14.6, 6.22 U/L p=0.02), ALP (-8.57, 4.24 U/L, p<0.05), CK18M30 (-187.53, 74.02 U/L, p=0.01). Similarly, G120 R showed better improvement in cardiometabolic risk markers, significant for fasting plasma glucose (-0.98, 0.45 mmol/L, p=0.03), free fatty acids (-0.1, 0.05 mmol/L, p=0.05), triglycerides (-0.42, 0.16 mmol/L, p=0.01), fibrinogen (-0.43, 0.16g/L, p=0.01). Compared to PBO, drug-induced reversal of SH by G120 was associated with significant improvements in hepatic and extra-hepatic markers, such as ALP (-21.25, 6.89 U/L, p<0.01), and LDL-C (-0.35, 0.16mmol/L, p<0.05), but also TG, fibrinogen, fructosamine, FGF19, and FGF21.  

CONCLUSIONS: Resolution of SH is associated with an improvement in all histological features of NASH, and most importantly with an improvement of fibrosis. Treatment with GFT505 shows significant additional improvements in responders, notably on cardiometabolic markers (lipids, glucose homeostasis, inflammation) and liver markers





 


WWW.NASHBIOTECHS.COM  -  Copyright G DIVRY 2015-2016  - Contact and TERMS OF USE