title: Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis.
abstract: OBJECTIVE
  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.
authors: 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.
authors: Vlad
authors: V
authors: Ratziu
authors: Hôpital Beaujon, INSERM U773, Université Paris Diderot, Paris, France.
authors: Pierre
authors: P
authors: Bedossa
authors: Department of Gastroenterology and Hepatology, Antwerp University Hospital, Faculty of Medicine and Health Sciences, Antwerp University, Antwerp, Belgium.
authors: Sven M
authors: SM
authors: Francque
authors: Département d'Hépatogastroenterologie et Transplantation, Hôpital Saint Eloi, INSERM1040-IRB, Montpellier, France.
authors: Dominique
authors: D
authors: Larrey
authors: 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.
authors: Guruprasad P
authors: GP
authors: Aithal
authors: Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Service d'Hépatologie, INSERM UMR_938, Hôpital Saint-Antoine, Paris, France.
authors: Lawrence
authors: L
authors: Serfaty
authors: Department of Internal Medicine and Nephrology, Fundeni Clinical Institute, Bucharest, Romania.
authors: Mihai
authors: M
authors: Voiculescu
authors: Matei Balş National Institute for Infectious Diseases, Bucharest, Romania.
authors: Liliana
authors: L
authors: Preotescu
authors: Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
authors: Frederik
authors: F
authors: Nevens
authors: Service d'Hépato-Gastro-Entérologie, Hôpital Haut Lévêque, Pessac, France; INSERM U1053, Université Bordeaux Segalen, Bordeaux, France.
authors: Victor
authors: V
authors: De Lédinghen
authors: Department of Internal Medicine I, University Hospital of Regensburg, Regensburg, Germany.
authors: Gabriele I
authors: GI
authors: Kirchner
authors: Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic.
authors: Pavel
authors: P
authors: Trunecka
authors: 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.
authors: Stephen D
authors: SD
authors: Ryder
authors: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, United Kingdom.
authors: Christopher P
authors: CP
authors: Day
authors: Astellas Pharma, Inc, Tokyo, Japan.
authors: Jun
authors: J
authors: Takeda
authors: Astellas Pharma Europe BV, Leiden, The Netherlands.
authors: Klaudia
authors: K
authors: Traudtner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000473:pathology; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D010919:Placebos / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D010919:Placebos; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: Fatty Liver Disease; PDE4; Therapeutic Targets; Treatment