Building a Drug Repurposing Network (DR3N) for the CTSA Consortium: Inspiration: Ovarian Cancer Collaboration Drug Repurposing: What and Why Harnessing The Power of Collaboration DR3N: The Three R’s Drug Rescue for stalled Pharma products Drug Repurposing based on experimental or computational evidence Drugs for Repositioning based on off-label indications Clinical & Translational Science Center CTSC

Inspiration: Ovarian Cancer Drug Repurposing Concept: GTPases/Receptor Traffic Screen: Sklar Multiplex/NSAIDS Cheminformatics: Oprea Ketorolac Retrospective Trial: Cook Pain Treatment/Survival Cells/Animals: Mechanism (R-enantiomer) Prospective Trial: Muller Hits Target Outcomes: Pubs, Patents, Trials, $ Wandinger-Ness Hudson

Approved drugs and devices WHY REPURPOSING? > 6,000+ Rare diseases > 100,000,000 people 1,000s Approved drugs and devices 1 2 2 Success rate of 10-30% demonstrating clinical benefit for patients based on Cures Within Reach past success rate (13 successes from 50 clinical trials). Success considered when clinical results proved the repurposed therapy works and are robust enough for physicians to use to prescribe off label OR when a project moves to a phase II/III trial on the way to commercialization. There is other support for this success rate. Repurposing generic drugs is much akin to moving a NME from phase II to phase III, since both are already proven safe for human use and have some clinical anecdotal success. Estimates of success rates for molecules moving from phase II to phase III range from 13%-32%. See this from the Institute of Medicine: “Drug repositioning or repurposing holds many appeals. Typically these drugs have been extensively profiled and studied in terms of safety, efficacy and toxicity, thereby decreasing the amount of preclinical research required. This streamlined process saves time and money, with repurposed drugs generally being approved in much shorter timelines (3-12 years) and at about 60% of the cost of typical development. While approximately 10% of new drug applications gain market approval, repurposed drugs approach approval rates near 30%, presenting a significant market-driven incentive for companies that also aligns with patient desires for new therapeutics.” Cost <$500,000 based on Cures Within Reach experience in clinical trials so far. And CWR repurposing clinical trials average is under $100,000 1=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619623/; http://bioinformatics.oxfordjournals.org/content/early/2013/06/08/bioinformatics.btt279.full.pdf 2=http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study, http://bioinformatics.oxfordjournals.org/content/early/2013/06/08/bioinformatics.btt279.full.pdf

Network Hubs/Sites: Partners & Expertise Leaders Expertise Specialization Notable UNM CMD Sklar High throughput flow cytometry; Suspension cell and molecular targets Multiplexed and multiparameter analysis BSL2/BSL3 access Repurposing trials UNM TID Oprea Drug discovery analytics; Target Prioritization for Illuminating the Druggable Genome (IDG) Databases: DrugsDB.com TargetCentral.ws IDG Knowledge Management Center KUMC/ IAMI Weir Pharmaceutics; GMP, formulation, drug delivery Public-Private Partnerships / Learning Experiences Commercialization UNC Roth Genome-wide GPCR-ome testing & de-orphanization; NIMH Psychoactive Drug Screening Program Site Bioactives/natural products; hERG/ ion channels; efflux transporters Drug limitations and removal for liabilities NCATS Simeonov Discovery Drug Libraries Drug Combinations Initiatives for drug repurposing, rare/ neglected diseases Cures Within Reach Bloom Fund raising for trials CureAccelerator website Economic Incentives Overcoming Philanthropic and Commercial Barriers Pre-competitive consortia Impact Bonds Sklar Oprea Weir Roth Simeonov Bloom

DR3N: A CTSA Resource to Speed and Facilitate New FIRST-IN-HUMAN STUDIES lsklar@salud.unm.edu