Pharmacological characterization of second generation FXR agonists as effective EphA2 antagonists: A successful application of target hopping approach

Article

Author: Ballabeni, Vigilio ; Giorgio, Carmine ; Barocelli, Elisabetta ; Ferrari, Francesca Romana ; Galvani, Francesca ; Zappia, Alfonso ; Tognolini, Massimiliano ; Mor, Marco ; Bertoni, Simona ; Scalvini, Laura ; Lodola, Alessio

It is well demonstrated the key role of Eph-ephrin system, specifically of EphA2 receptor, in supporting tumor growth, invasion, metastasis and neovascularization. We previously identified FXR agonists as eligible antagonists of Eph-ephrin system. Herein we characterize new commercially available FXR (Farnesoid X Receptor) agonists as potential Eph ligands including Cilofexor, Nidufexor, Tropifexor, Turofexorate isopropyl and Vonafexor. Our exploration based on molecular modelling investigations and binding assays shows that Cilofexor binds specifically and reversibly to EphA2 receptor with a Ki value in the low micromolar range. Furthermore, Cilofexor interferes with the phosphorylation of EphA2 and the cell retraction and rounding in PC3 prostate cancer cells, both events depending on EphA2 activation. In conclusion, we can confirm that target hopping can be a successful approach to discover new moiety of protein-protein inhibitors.

01 Mar 2023·Journal of Hepatology

Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH

Article

Author: Loustaud-Ratti, Véronique ; Scalfaro, Pietro ; Vonderscher, Jacky ; Wolf, Myles ; Bureau, Christophe ; Ratziu, Vlad ; Harrison, Stephen A ; Girma, Hugo ; Abdelmalek, Manal ; Alkhouri, Naim ; Sanyal, Arun ; Francque, Sven ; Couchoux, Harold ; Lawitz, Eric ; Darteil, Raphaël

BACKGROUND & AIMSThe LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH).METHODSThis double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12.RESULTSOne hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively.CONCLUSIONSIn patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit.CLINICAL TRIAL NUMBER (EUDRACT)2018-003119-22.CLINICALTRIALSGOV IDENTIFIERNCT03812029.IMPACT AND IMPLICATIONSNon-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease worldwide. Affected patients are also at higher risk of developing chronic kidney disease. There are no approved therapies and only few options to treat this population. The phase IIa LIVIFY trial results show that single daily administration of oral vonafexor, an FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials, with the aim of addressing the unmet medical need in NASH.

01 Dec 2021·Journal of Viral HepatitisQ2 · MEDICINE

Farnesoid X receptor agonist for the treatment of chronic hepatitis B: A safety study

Q2 · MEDICINE

Article

Author: Andre, Patrice ; Girma, Hugo ; Tangkijvanich, Pisit ; Erken, Robin ; Radreau‐Pierini, Pauline ; Vonderscher, Jacky ; Barzic, Noelie ; Flisiak, Robert ; Laveille, Christian ; Scalfaro, Pietro ; Kootstra, Neeltje ; Darteil, Raphael ; Reesink, Henk ; Roy, Elise

AbstractThe nuclear farnesoid X receptor (FXR) regulates bile acid homeostasis and is a drug target for metabolic liver diseases. FXR also plays an important role in hepatitis B virus (HBV) DNA transcription. In vitro and in mice, FXR agonist treatment leads to inhibition of viral replication and a decline in viral proteins, pregenomic RNA (pgRNA) and HBV DNA levels. We aimed to translate this to a clinical use by primarily evaluating the safety and secondary the anti‐viral effect of Vonafexor, a FXR agonist, in chronic hepatitis B (CHB) patients. In total, 73 CHB patients were enrolled in a two‐part Phase Ib double‐blind, placebo‐controlled trial. Patients were randomized to receive oral Vonafexor (100, 200 and 400 mg once daily, or 200 mg twice daily), placebo, or entecavir (Part A, n = 48) or to receive Vonafexor (300 mg once daily or 150 mg twice daily), or placebo, combined with pegylated‐interferon‐α2a (Part B, n = 25) for 29 days. Patients were followed up for 35 days. Enrolled CHB patients were mostly HBeAg‐negative. Vonafexor was overall well tolerated and safe. The most frequent adverse events were moderate gastrointestinal events. Pruritus was more frequent with twice‐daily compared with once‐daily regimens (56%–67% vs. 16%, respectively, p < 0.05). Vonafexor monotherapy of 400 mg once daily decreased HBsAg concentrations (–0.1 log10 IU/mL, p < 0.05), and Vonafexor/pegylated‐IFN‐α2a combination therapy decreased HBcrAg and pgRNA. In conclusion, Vonafexor was safe with a decline in HBV markers observed in CHB patients suggesting a potential anti‐viral effect the therapeutic potential of which has to be evaluated in larger trials.

News (Medical) associated with Vonafexor

03 Jan 2024

·www.businesswire.com

ENYO Pharma Announces a €39 Million Series C Financing and FDA Clearance to Advance Vonafexor in a Phase 2 Clinical Trial for Patients With Alport Syndrome

LYON, France--( BUSINESS WIRE )--ENYO Pharma (“ENYO”) announced that it has received clearance of its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA) to initiate a Phase 2 clinical study of Vonafexor, a highly selective FXR agonist, for the treatment of Alport Syndrome. Furthermore, ENYO announced the first closing of a 39 million € Series C equity financing, positioning ENYO as an emerging biotechnology company in the field of renal diseases. The financing will support the Phase 2 Alpestria-1 study and further profiling of Vonafexor in other kidney diseases, such as Autosomal Dominant Polycystic Kidney Disease (ADPKD). The financing was co-led by OrbiMed and Morningside Ventures with participation from other existing investors including AndEra Partners, Bpifrance InnoBio and Bpifrance Large Ventures. The clearance of ENYO’s IND represents a significant milestone for the company as it embarks on its first clinical trial focusing on renal disease. ENYO’s lead candidate Vonafexor, as well as fast follower EYP651, are highly specific FXR agonists given as once-daily oral treatments. Both compounds have strong fibrolytic and anti-inflammatory properties that are broadly applicable across several renal diseases. Vonafexor effect on renal function (eGFR) was already shown in the Phase 2 LIVIFY study of patients with both kidney impairment and fibrotic liver disease. Preclinical studies in both Alport syndrome and Chronic Kidney Disease mouse models showed beneficial effects of Vonafexor on kidney remodeling and function in a curative mode. In 2023, Vonafexor was granted as Orphan Drug Designation (ODD) by both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) for Alport syndrome. ” We are delighted with this support from our existing investors” said Dr. Jacky Vonderscher, CEO at ENYO Pharma. “ There are huge unmet needs in many kidney diseases with fibrosis or inflammatory components. These patients almost invariably progress to end-stage kidney disease despite current therapies. The results already obtained with Vonafexor, our highly differentiated anti-inflammatory and fibrolytic lead compound, in patients with moderate kidney impairment and in several preclinical protocols, make us confident that it will greatly benefit to those patients with rare kidney diseases like Alport syndrome. “ ” Kidney diseases were somewhat neglected for decades, and it is refreshing to see a team like ENYO pursuing with persistence the development of Vonafexor for the benefit of these patients. “ said Iain Dukes of OrbiMed . About ENYO Pharma: For more information : ENYO Pharma – Developing therapeutics for diseases with impaired kidney function About OrbiMed: For more information : OrbiMed

Phase 2Orphan DrugIND

13 Jan 2021

·www.globenewswire.com

Nonalcoholic Steatohepatitis Drug Pipeline Analysis Review, 2020

Los Angeles, USA , Jan. 13, 2021 (GLOBE NEWSWIRE) -- Nonalcoholic Steatohepatitis Drug Pipeline Analysis Review, 2020 NASH Drug Pipeline Shows Promise as 95+ companies are working for Nonalcoholic Steatohepatitis Drug Development “Nonalcoholic Steatohepatitis (NASH) Pipeline Insight, 2020” by DelveInsight highlights the details around the NASH pipeline scenario, unmet needs, and NonAlcoholic Steatohepatitis therapeutic assessment of the key pipeline therapies. Some of the key Nonalcoholic Steatohepatitis Pipeline Highlights Nonalcoholic Steatohepatitis (NASH) is a form of fatty liver disease that can cause inflammation, and over the long term, can lead to scarring of the liver. Nonalcoholic Steatohepatitis symptoms include fatigue and pain in the upper right abdomen. There is no standard treatment for NASH patients, but lifestyle changes have influenced its progression. Get access to NASH Treatment Pipeline Sample Report NASH Pipeline Therapeutics ENYO Pharma develops EYP001, which is an orally bioavailable synthetic non-steroidal, non-bile acid FXR agonist small molecule that is also developed for NASH. FXR agonists could become the backbone of any future NASH therapies. The pioneering ENYO founding team discovered that FXR agonists interfere with the interaction between FXR and HBx, a hepatitis B viral protein essential for replicating the virus. It has demonstrated its efficacy in a Stelic mouse model (STAMTM) with a significant positive impact on most of the NASH key parameters (Fibrosis, Steatosis, Inflammation, Ballooning, triglycerides, and NAS). It differentiates from other FXR agonists with a potentially better C4/FGF19 balance. To learn more about NASH Drugs Development, request NASH Treatment Pipeline Sample Report Scope of Nonalcoholic Steatohepatitis Drug Pipeline Report Key Questions regarding Current NASH Treatment Landscape and Emerging Therapies Answered in the Pipeline Report Table of Contents Browse Detailed TOC, Emerging Drugs and Key Companies @ NASH Pipeline Scenario Related Reports DelveInsight's Nonalcoholic Steatohepatitis (NASH) Market Insights, Epidemiology and Market Forecast - 2030 report provides a detailed overview of the disease and in depth understanding of historical and forecasted epidemiology. DelveInsight's Nonalcoholic Steatohepatitis (NASH) Epidemiology Forecast 2030 report delivers an in-depth understanding of the disease, historical, and forecasted epidemiology of Nonalcoholic Steatohepatitis (NASH) in the United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan. DelveInsight' s Non Alcoholic Fatty Liver Disease (NAFLD) Market Insights, Epidemiology and Market Forecast - 2030 report provides a detailed overview of the disease and in depth understanding of historical and forecasted epidemiology. DelveInsight's Non Alcoholic Fatty Liver Disease (NAFLD) Epidemiology Forecast 2030 report delivers an in-depth understanding of the disease, historical, and forecasted epidemiology of Non Alcoholic Fatty Liver Disease (NAFLD) in the United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan. Non Alcoholic Fatty Liver Disease (NAFLD) Global API Manufacturers, Marketed and Phase III Drugs Landscape, 2020 " report by DelveInsight offers comprehensive insights on marketed and Phase III products for Non Alcoholic Fatty Liver Disease (NAFLD). Non Alcoholic Fatty Liver Disease (NAFLD) Pipeline Insight, 2020 report by DelveInsight outlays comprehensive insights of present clinical development scenario and growth prospects across the Non Alcoholic Fatty Liver Disease (NAFLD) market. DelveInsight's Hepatitis C Market Insights, Epidemiology and Market Forecast - 2030 report provides detailed insights on historical and forecasted epidemiology. About DelveInsightDelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports Pharma companies by providing end to end comprehensive solutions to improve their performance.

Small molecular drug

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Nephritis, Hereditary	Phase 2	-	ENYO Pharma SAStartup	-
Hepatitis B, Chronic	Phase 1	KR	ENYO Pharma SAStartup	12 May 2020
Hepatitis B, Chronic	Phase 1	HK	ENYO Pharma SAStartup	12 May 2020
Hepatitis B, Chronic	Phase 1	HK	ENYO Pharma SAStartup	12 May 2020
Nonalcoholic Steatohepatitis	Phase 1	US	ENYO Pharma SAStartup	30 Jan 2019
Nonalcoholic Steatohepatitis	Phase 1	GB	ENYO Pharma SAStartup	30 Jan 2019
Nonalcoholic Steatohepatitis	Phase 1	PR	ENYO Pharma SAStartup	30 Jan 2019
Nonalcoholic Steatohepatitis	Phase 1	BE	ENYO Pharma SAStartup	30 Jan 2019
Nonalcoholic Steatohepatitis	Phase 1	FR	ENYO Pharma SAStartup	30 Jan 2019
Hepatitis B, Chronic	Preclinical	KR	ENYO Pharma SAStartup	12 May 2020

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03812029 (CTgov)	Phase 2	Nonalcoholic Steatohepatitis	120	Placebo (Placebo Part B)	rmposhrfop(ezfdtaoedr) = qtkpdtrmee gnppzltoii (ahjiqjhunv, ouwxqeztxz - ajgndpbtwt) View more	-	06 May 2023
				Vonafexor (Vonafexor 100 mg QD Part B)	rmposhrfop(ezfdtaoedr) = htghfiefgn gnppzltoii (ahjiqjhunv, kmboyczouy - xyslmpjwst) View more
NCT04465916 (CTgov)	Phase 2	Hepatitis B, Chronic	26	Nucleotide analogue (Entecavir or Tenofovir Disoproxil)+EYP001a (Experimental Arm)	mewpeelfjr(ozqfhujdtp) = gpumaatxlc uzpdhkuhkw (jrlijeloql, bywrkhnaok - myrbyowqac) View more	-	12 Oct 2022
				Nucleotide analogue (Entecavir or Tenofovir Disoproxil) (Control Arm)	mewpeelfjr(ozqfhujdtp) = qasqyalmis uzpdhkuhkw (jrlijeloql, ycgttoklcm - sxvyknzdrn) View more
NCT04365933 (EYP001-203, BusinessWire) Manual	Phase 2	Hepatitis B, Chronic	20	Entecavir+Peginterferon alfa-2a+Vonafexor	(isqclxqehu) = ycqqoribmt zyxfgbirmq (zffalqsdpd )	Positive	30 Jul 2021
				Peginterferon alfa-2a+Vonafexor	(isqclxqehu) = ldhuseygub zyxfgbirmq (zffalqsdpd )
UEGW2019	Not Applicable	-	-	EYP001	wtxeoqwpci(flsfazxfjv) = FGF19 protein was also stimulated significantly by EYP001 fzdvksatlf (zoqbraofma )	-	01 Oct 2019

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