Reducing Adverse Effects During Drug Development: The Example of Lesogaberan and Paresthesia

Drug Repurposing Patent Applications April–June 2020

“…Lesogaberan is a peripherally restricted high-affinity GABAB receptor-specific agonist whose development for refractory gastroesophageal reflux disease was discontinued, because Phase II studies showed no meaningful efficacy whereas paresthesia was a problematic adverse event. 10 In immunodeficient mice xenografted with human islets, oral lesogaberan promoted human b cell replication and islet cell survival, suggesting potential utility in diabetes. 11 The inventors' disclosure of its potential utility for nonalcoholic steatohepatitis (NASH) and liver fibrosis is particularly surprising, because GABA has been reported to exacerbate these conditions in a mouse model.. 12 Lesogaberan was identified in silico as a promising candidate compound for NASH, liver cirrhosis, and hepatocellular carcinoma through a modified connectivity mapping approach, that is, comparison of its transcriptomic signature (generated by exposing A549 and MCF7 cell lines to two distinct concentrations and vehicle) to the transcriptional profiles representing 310 distinct human diseases.…”