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Lack of Efficacy of an Inhibitor of PDE4 in Phase 1 and 2 Trials of Patients With Nonalcoholic Steatohepatitis

Lookup NU author(s): Professor Chris Day

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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.

Publication metadata

Author(s): Ratziu V, Bedossa P, Francque SM, Larrey D, Aithal GP, Serfaty L, Voiculescu M, Preotescu L, Nevens F, De Ledinghen V, Kirchner GI, Trunecka P, Ryder SD, Day CP, Takeda J, Traudtner K

Publication type: Article

Publication status: Published

Journal: Clinical Gastroenterology and Hepatology

Year: 2014

Volume: 12

Issue: 10

Pages: 1724-1730.e5

Print publication date: 01/10/2014

Online publication date: 12/02/2014

ISSN (print): 1542-3565

ISSN (electronic): 1542-7714

Publisher: W.B. Saunders Co.

URL: http://dx.doi.org/10.1016/j.cgh.2014.01.040

DOI: 10.1016/j.cgh.2014.01.040

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