Vlad Ratziu1, Pierre Bedossa2, Sven M Francque3, Dominique Larrey4, Guruprasad P Aithal5, Lawrence Serfaty6, Mihai Voiculescu7, Liliana Preotescu8, Frederik Nevens9, Victor De Lédinghen10, Gabriele I Kirchner11, Pavel Trunecka12, Stephen D Ryder5, Christopher P Day13, Jun Takeda14, Klaudia Traudtner15. 1. Université Pierre et Marie Curie, Assistance Publique Hôpitaux de Paris, Hôpital Pitié Salpêtrière, INSERM UMR_S 938, Paris, France. Electronic address: vlad.ratziu@upmc.fr. 2. Hôpital Beaujon, INSERM U773, Université Paris Diderot, Paris, France. 3. Department of Gastroenterology and Hepatology, Antwerp University Hospital, Faculty of Medicine and Health Sciences, Antwerp University, Antwerp, Belgium. 4. Département d'Hépatogastroenterologie et Transplantation, Hôpital Saint Eloi, INSERM1040-IRB, Montpellier, France. 5. National Institute for Health Research (NIHR) Biomedical Research Unit in Gastrointestinal and Liver Diseases, Nottingham University Hospitals NHS Trust and The University of Nottingham, Nottingham, United Kingdom. 6. Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Service d'Hépatologie, INSERM UMR_938, Hôpital Saint-Antoine, Paris, France. 7. Department of Internal Medicine and Nephrology, Fundeni Clinical Institute, Bucharest, Romania. 8. Matei Balş National Institute for Infectious Diseases, Bucharest, Romania. 9. Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium. 10. Service d'Hépato-Gastro-Entérologie, Hôpital Haut Lévêque, Pessac, France; INSERM U1053, Université Bordeaux Segalen, Bordeaux, France. 11. Department of Internal Medicine I, University Hospital of Regensburg, Regensburg, Germany. 12. Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic. 13. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, United Kingdom. 14. Astellas Pharma, Inc, Tokyo, Japan. 15. Astellas Pharma Europe BV, Leiden, The Netherlands.
Abstract
BACKGROUND & AIMS:ASP9831 is a phosphodiesterase-4 inhibitor developed to treat nonalcoholic steatohepatitis (NASH); it showed potent anti-inflammatory and antifibrotic effects in preclinical studies. We evaluated the efficacy and safety of ASP9831 in patients with NASH. METHODS: In a phase 1 trial, we determined the optimal therapeutic window of ASP9831 in healthy volunteers and evaluated 2 doses (50 and 100 mg) in patients with NASH. Based on the positive outcomes of the phase 1 study, we performed a phase 2 trial to compare the biochemical effects of ASP9831 vs placebo. Patients with NASH were assigned randomly to groups given either 50 mg (n = 33) or 100 mg (n = 33) ASP9831 twice daily, or placebo (n = 30), for 12 weeks. The primary end point was the mean percentage change, from baseline to the end of ASP9831 administration, in serum level of alanine aminotransferase (ALT); secondary outcomes included changes in aspartate aminotransferase (AST) levels, ratio of AST:ALT, and various biomarkers of NASH. RESULTS: After 12 weeks of administration, there was no significant change in mean serum levels of ALT (P = .42) or AST (P = .20) or other biomarkers in any group, and no significant differences were observed among groups. Most adverse events were mild; gastrointestinal disorders occurred more frequently in the ASP9831 groups than the placebo group. CONCLUSIONS: Despite a relevant mechanism of action, ASP9831 did not significantly alter the biochemical markers of NASH, compared with placebo, in a clinical trial. This highlights the difficulties of developing therapeutics for NASH and the need for more extensive preclinical testing of mechanisms of potential drug candidates. Clinicaltrialsregister.eu: 2005-001687-31; EudraCT numbers: 2007-002114-19.
RCT Entities:
BACKGROUND & AIMS:ASP9831 is a phosphodiesterase-4 inhibitor developed to treat nonalcoholic steatohepatitis (NASH); it showed potent anti-inflammatory and antifibrotic effects in preclinical studies. We evaluated the efficacy and safety of ASP9831 in patients with NASH. METHODS: In a phase 1 trial, we determined the optimal therapeutic window of ASP9831 in healthy volunteers and evaluated 2 doses (50 and 100 mg) in patients with NASH. Based on the positive outcomes of the phase 1 study, we performed a phase 2 trial to compare the biochemical effects of ASP9831 vs placebo. Patients with NASH were assigned randomly to groups given either 50 mg (n = 33) or 100 mg (n = 33) ASP9831 twice daily, or placebo (n = 30), for 12 weeks. The primary end point was the mean percentage change, from baseline to the end of ASP9831 administration, in serum level of alanine aminotransferase (ALT); secondary outcomes included changes in aspartate aminotransferase (AST) levels, ratio of AST:ALT, and various biomarkers of NASH. RESULTS: After 12 weeks of administration, there was no significant change in mean serum levels of ALT (P = .42) or AST (P = .20) or other biomarkers in any group, and no significant differences were observed among groups. Most adverse events were mild; gastrointestinal disorders occurred more frequently in the ASP9831 groups than the placebo group. CONCLUSIONS: Despite a relevant mechanism of action, ASP9831 did not significantly alter the biochemical markers of NASH, compared with placebo, in a clinical trial. This highlights the difficulties of developing therapeutics for NASH and the need for more extensive preclinical testing of mechanisms of potential drug candidates. Clinicaltrialsregister.eu: 2005-001687-31; EudraCT numbers: 2007-002114-19.