The future of TaiwanJ Pharmaceuticals’ JKB-121 as a NASH treatment is in jeopardy after it failed to demonstrate efficacy in a Phase II placebo-controlled trial, presented at the 2018 International Liver Congress (ILC) in Paris, France. Somewhat surprisingly, a positive response in the placebo arm of the trial meant that it outperformed the study drug in several trial endpoints, sending a warning to drug developers in the NASH space regarding the misinterpretation of positive efficacy in trials in the absence of a placebo control.
TaiwanJ Pharmaceuticals’ JKB-121 acts as an antagonist of TLR4, a receptor involved in cellular inflammation pathways. Preclinical data suggested that TLR4 inhibition could reduce inflammation and fibrosis in the liver, as well as reduce the levels of alanine transaminase (ALT) and aspartate transaminase (AST), both biomarkers of liver damage. Through inhibition of TLR4 by with JKB-121, TaiwanJ Pharmaceuticals hoped to alleviate the symptoms of NASH.
The potential of JKB-121’s for the treatment of NASH was explored in a Phase II, double blind, placebo controlled trial enrolling 65 NASH patients with stage 1-3 cirrhosis. Participants were randomized into three different study arms; a placebo control group, a group receiving 5mg of JKB-121 twice-daily, and a group receiving 10mg of JKB-121 twice-daily. Patients received 24 weeks of therapy, after which there was a 28 week follow-up period. The primary endpoints were safety and a reduction in Liver Fat Content (LFC), and the remission of ALT and AST were secondary endpoints.
After study completion, JKB-121 did not meet the trial endpoints. There was found to be no difference between the three study arms with respect to change in absolute LFC, with all groups experiencing on average a reduction of 4–5%. Furthermore, fewer subjects in the study arms achieved a reduction in absolute LFC of greater than 5% than in the placebo arm, with 32% in the placebo arm, 12% in the 5mg study arm and 18% in the 10mg study arm satisfying this criterion. There were also questions raised over safety, with two participants in the 5mg arm and 6 in the 10mg arm discontinuing due to adverse events.
Overall, it seems unlikely that TaiwanJ Pharmaceuticals will continue investigating JKB-121 for the treatment of NASH. It was suggested at the ILC that the reduced weight loss observed in the study arms over the placebo group could be a result of increased appetite brought on by JKB-121, although this was not supported by observations in the clinic. The strength of the positive response observed in the placebo group is very surprising, and GlobalData suggests that care is taken when interpreting data from NASH clinical trials without a placebo control when the absolute reduction in LFC is 5% or less.
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