Repurposing old molecules for new indications: Defining pillars of success from lessons in the past

Abstract

Drug repurposing or studying existing drugs for potential therapeutic utility in newer indications has been identified as an attractive option for treating a number of diseases. Various strategies of drug repurposing include serendipitous observation of drug's unexpected effects, directing the failed investigational drugs to new indications and currently adopted systematic approach to identify, screen and develop existing drug molecules for new off-label indications. Drug repurposing is able to constructively overcome the bottleneck restraints encountered during traditional de novo drug development process in grounds of timelines, cost and resources. However, success rates of drug repurposing programs are not very impressive. Through a meticulous examination of some failed repurposing attempts we aimed to identify key factors leading to high attrition rate in such studies. Based on the fundamental elements of knowledge and evaluation, we have defined four pillars toward improving success rate in drug repurposing programs viz. sound knowledge of the repurposed drug's pharmacological characteristics (pillar 1: drug pharmacology); drug formulation considerations in new indication (pillar 2: drug formulation); evaluation in representative biological assays with translational potential (pillar 3: evaluation in biological assays); and robust clinical trial methodologies including biomarker driven approach to provide conclusive evidence of repurposed drug's efficacy in new indication (pillar 4: clinical evaluation). In addition to the pharmacological challenges, certain regulatory concerns, including lack of clear guidelines for evaluation and market exclusivity pose hurdles in the application of drug repurposing, which may however be overcome to a great extent by adopting some strategies as discussed in this review.

Keywords: Compound recycling; Drug repurposing; Drug rescue; Extended profiling; Formulation; Market exclusivity; Repositioning model.