Juan P Arab1,2, Tejasav S Sehrawat1, Douglas A Simonetto1, Vikas K Verma1, Dechun Feng3, Tom Tang4, Kevin Dreyer4, Xiaoqiang Yan4, William L Daley4, Arun Sanyal5, Naga Chalasani6, Svetlana Radaeva7, Liu Yang8, Hugo Vargas9, Mauricio Ibacache10, Bin Gao3, Gregory J Gores1, Harmeet Malhi1, Patrick S Kamath1, Vijay H Shah1. 1. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. 2. Department of Gastroenterology, School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile. 3. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD. 4. Generon Corporation Ltd., Shanghai, China. 5. Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA. 6. Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN. 7. National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. 8. Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL. 9. Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ. 10. Division of Anesthesiology, School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile.
Abstract
BACKGROUND AND AIMS: Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH. APPROACH AND RESULTS: A phase-2 dose-escalating study was carried out. F-652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42. CONCLUSIONS: F-652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH.
BACKGROUND AND AIMS: Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of humaninterleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH. APPROACH AND RESULTS: A phase-2 dose-escalating study was carried out. F-652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42. CONCLUSIONS:F-652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH.
Authors: Mingquan Zheng; William Horne; Jeremy P McAleer; Derek Pociask; Taylor Eddens; Misty Good; Bin Gao; Jay K Kolls Journal: Infect Immun Date: 2016-01-04 Impact factor: 3.441
Authors: Winston Dunn; Laith H Jamil; Larry S Brown; Russell H Wiesner; W Ray Kim; K V Narayanan Menon; Michael Malinchoc; Patrick S Kamath; Vijay Shah Journal: Hepatology Date: 2005-02 Impact factor: 17.425
Authors: Helga Paula; Sumeet K Asrani; Nicholas C Boetticher; Rachel Pedersen; Vijay H Shah; W Ray Kim Journal: Am J Gastroenterol Date: 2010-02-23 Impact factor: 10.864
Authors: Roger Williams; Graeme Alexander; Iain Armstrong; Alastair Baker; Neeraj Bhala; Ginny Camps-Walsh; Matthew E Cramp; Simon de Lusignan; Natalie Day; Anil Dhawan; John Dillon; Colin Drummond; Jessica Dyson; Graham Foster; Ian Gilmore; Mark Hudson; Deirdre Kelly; Andrew Langford; Neil McDougall; Petra Meier; Kieran Moriarty; Philip Newsome; John O'Grady; Rachel Pryke; Liz Rolfe; Peter Rice; Harry Rutter; Nick Sheron; Alison Taylor; Jeremy Thompson; Douglas Thorburn; Julia Verne; John Wass; Andrew Yeoman Journal: Lancet Date: 2017-11-29 Impact factor: 79.321
Authors: Tejasav S Sehrawat; Juan P Arab; Mengfei Liu; Pouya Amrollahi; Meihua Wan; Jia Fan; Yasuhiko Nakao; Elisa Pose; Amaia Navarro-Corcuera; Debanjali Dasgupta; Chieh-Yu Liao; Li He; Amy S Mauer; Emma Avitabile; Meritxell Ventura-Cots; Ramon A Bataller; Arun J Sanyal; Naga P Chalasani; Julie K Heimbach; Kymberly D Watt; Gregory J Gores; Pere Gines; Patrick S Kamath; Douglas A Simonetto; Tony Y Hu; Vijay H Shah; Harmeet Malhi Journal: Hepatology Date: 2020-10-30 Impact factor: 17.425