TY - JOUR
T1 - Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH
AU - Ratziu, Vlad
AU - Harrison, Stephen A.
AU - Loustaud-Ratti, Véronique
AU - Bureau, Christophe
AU - Lawitz, Eric
AU - Abdelmalek, Manal
AU - Alkhouri, Naim
AU - Francque, Sven
AU - Girma, Hugo
AU - Darteil, Raphaël
AU - Couchoux, Harold
AU - Wolf, Myles
AU - Sanyal, Arun
AU - Vonderscher, Jacky
AU - Scalfaro, Pietro
N1 - Funding Information:
The study was supported and funded by ENYO Pharma, SA., Lyon, France.
Funding Information:
The authors acknowledge the support of the following clinical investigators: Anja Geerts (University Hospital Gent), Christophe Van Steenkiste (General Hospital Maria Middelares), Christophe Moreno (Université Libre de Bruxelles (ULB) - Hopital Erasme), Victor De Ledinghen (CHU Bordeaux - Hôpital Haut-Lévêque), Guru Aithal (Nottingham NHS Treatment Centre), Michael Allison (Cambridge University - Addenbrooke's Hospital), William Alazawi (The Royal London Hospital), Roger McCorry (Royal Victoria Hospital), Kosh Agarwal (King's College Hospital), William Bowman (Sensible Healthcare, LLC), Jeffrey Williams (Summit Clinical Research, LLC), Gary Reiss (Tandem Clinical Research), Reem Ghalib (Texas Clinical Research Institute), John Lentz III (Georgia Clinical Research, LLC), Samir Arora (Aventiv Research, Inc.), Brian Borg (Southern Therapy and Advanced Research LLC), Christopher Christensen (Texas Digestive Disease Consultants), Bradley Freilich (Kansas City Research Institute), Nadege Gunn (Pinnacle Clinical Research - Austin, TX), Marcel Twahirwa (Doctor's Hospital at Renaissance (DHR) - Transplant Institute and Liver Specialty Center), Alexander White (Progressive Medical Research), Johnny White (Bioclinica Research), Blake Jones (Innovative Clinical Research – Lafayette), Paul Thuluvath (Mercy Medical Center - Baltimore, Maryland), Robert Murphy (Arkansas Gastroenterology - North Little Rock), Ann Moore (Arizona Liver Health – Glendale), Joseph Galati (American Research Corporation), Stanley Hsin-Wei Hsia (National Research Institute - Huntington Park), Grisell Ortiz-Lasanta (Fundacion de Investigacion (FDI), Malisa Agard (ClinCloud LLC), Ravi Ravinuthala (Consultants for Clinical Research – Cincinnati), Guy Neff (Covenant Research, LLC), Lincoln Hernandez (Tandem Clinical Research GI- New York). The authors also acknowledge the support of Maud Fischer, Gregory Hood and all the Medpace, Inc. team for the overall management of the clinical trial, Charlotte Erpicum, Henrike Puchta and the rest of Perspectum Diagnostics, Ltd. team for the imaging management and analyses, Sophie Jeannin, Gail Hinkson, Genevieve Long and the rest of Summit Clinical Research for Summit networks sites management and support, Amrita Basu, Sam Anderson, and the rest of Agilex Biolabs, Ltd Pty. team for the sample bioanalyses, Christian Laveille, Stéphanie Blaizot and the rest of Calvagone Sarl. for the PK and PD analyses and population PK/PD modelling, Adriana Marinescu, Marion Odoul, Nathalie Roux-Drevet, Virginie Le Meaux, and the rest of ENYO Pharma team for the overall management and support. Medical writing support provided by Dr. Lynsey Meikle PhD of Terminal 4 Communications and was supported financially by ENYO Pharma, Inc. Lyon, France.
Publisher Copyright:
© 2022 The Authors
PY - 2023/3
Y1 - 2023/3
N2 - Background & Aims: The 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). Methods: This 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. Results: One 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. Conclusions: In 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. ClinicalTrials.gov Identifier: NCT03812029. Impact and implications: Non-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.
AB - Background & Aims: The 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). Methods: This 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. Results: One 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. Conclusions: In 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. ClinicalTrials.gov Identifier: NCT03812029. Impact and implications: Non-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.
KW - ALT
KW - MRI-PDFF
KW - NASH
KW - eGFR
KW - farnesoid X receptor
KW - fibrosis
KW - liver fat reduction
KW - randomised clinical trial
KW - steatosis
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U2 - 10.1016/j.jhep.2022.10.023
DO - 10.1016/j.jhep.2022.10.023
M3 - Article
C2 - 36334688
AN - SCOPUS:85145294120
SN - 0168-8278
VL - 78
SP - 479
EP - 492
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 3
ER -