Drug repurposing

ALAN TALEVI

Comprehensive Pharmacology

Elsevier

Año: 2021; p. 813 - 824

Drug discovery and development is doubtlessly a lengthy, expensive, and risky business. De novo drug development takes an average of about 12?13 years from concept to market (Van Norman, 2016; Seyhan, 2019). The mean investment to bring a new drug to the market has recently been estimated in about 1.3 billion US dollars, accounting for the costs of failed trials andcapitalized investment (Wouters et al., 2020) whereas previous estimations were much less optimistic (DiMasi et al., 2016).On average, less than 10% of the drugs that make it to clinical trials survive to approval (Hay et al., 2014; Seyhan, 2019). The previous figures, however, can vary substantially across therapeutic areas.In 2014, AstraZeneca published the outcome of a comprehensive longitudinal review of their small-molecule drug projects from 2005 to 2010. A framework to guide R&D projects was established in the company, based on the five most important technical determinants of project success and pipeline quality, which they described as ?the five R?s?: the right target, the right patient, theright tissue, the right safety, and the right commercial potential (Cook et al., 2014). They also disclosed the reasons for project closure. Interestingly, safety issues explained the shutting down of 82%, 62% and 35% of failures at preclinical, Phase I and Phase IIa stages, with failures due to lack of efficacy progressively increasing from preclinical to Phase IIb studies. On the other hand,inappropriate PK/PD explained around 15% of closures at Phase I.This possibly explains why drug repurposing (this is, finding new therapeutic uses for already known drugs, including approved, withdrawn, and abandoned drugs and also drugs in the pipeline) has gained so much momentum in the last decade. The term was coined at the beginning of the 21st century. Whereas the approach had already led to the introduction of several new uses fortherapeutic agents during the 20th century, such discoveries had mostly arisen from serendipity or trial and error assays. In the last years, though, drug repurposing has been implemented in a systematic manner and integrated in the life cycle management of pharmaceutical products: it has been estimated that about one-third of the recent drug approvals and that repurposed drugs atpresent generate around 25% of the annual profits within the pharmaceutical industry