Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis

  • Clin Gastroenterol Hepatol. 2014 Oct;12(10):1724-30.e5. doi: 10.1016/j.cgh.2014.01.040.
Vlad Ratziu  1 ,  Pierre Bedossa  2 ,  Sven M Francque  3 ,  Dominique Larrey  4 ,  Guruprasad P Aithal  5 ,  Lawrence Serfaty  6 ,  Mihai Voiculescu  7 ,  Liliana Preotescu  8 ,  Frederik Nevens  9 ,  Victor De Lédinghen  10 ,  Gabriele I Kirchner  11 ,  Pavel Trunecka  12 ,  Stephen D Ryder  5 ,  Christopher P Day  13 ,  Jun Takeda  14 ,  Klaudia Traudtner  15
Affiliations
  • 1. Université Pierre et Marie Curie, Assistance Publique Hôpitaux de Paris, Hôpital Pitié Salpêtrière, INSERM UMR_S 938, Paris, France. Electronic address: [email protected].
  • 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.
PMID: 24530600 DOI: 10.1016/j.cgh.2014.01.040
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.

Keywords
Fatty Liver Disease; PDE4; Therapeutic Targets; Treatment.
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