Drug repositioning: out of the box opportunities despite data and chemistry challenges Christopher A. Lipinski 1Lipinski Arrowhead SFO 2012

Attrition rates by phase The Productivity Crisis in Pharmaceutical R&D, Fabio Pammolli, Laura Magazzini and Massimo Riccaboni, Nature Reviews Drug Discovery 2011 (10) Lipinski Arrowhead SFO

Target-based drug discovery: E1 E5 R2 R3 R4 R5 R6 R1 E2 E3E4 E7 E6 DP 1DP 2 D1 D2 3Lipinski Arrowhead SFO 2012

….the real picture R8 DP 5 E10 E9 E8 E1 E5 R2 R3 R4 R5 R6 R1 E2 E3E4 E7 E6 DP 1DP 2 R7 R9 R10 R11 R12 DP 3 DP 4 E7 E8 D1 D2 4Lipinski Arrowhead SFO 2012

Has drug discovery gone wrong? Prevailing mantra: identify a mechanism and discover a selective ligand for a single target Counter responses: Improve target validation, academic collaboration Spread financial risk – collaborations, outsourcing Phenotypic screening Drug repurposing Multi targeted drug discovery 5 Lipinski Arrowhead SFO 2012

Phenotypic screening advantage The majority of small- molecule first-in-class NMEs that were discovered between 1999 and 2008 were first discovered using phenotypic assays (FIG. 2): 28 of the first-in-class NMEs came from phenotypic screening approaches, compared with 17 from target-based approaches. How were new medicines discovered? David C. Swinney and Jason Anthony Nature Reviews Drug Discovery 2011 (10) Lipinski Arrowhead SFO 2012

Drugs Under Active Development involved in Multiple Programs Source: Thomson Reuters Integrity Within Integrity there are over 20,000 active preclinical drug programs. Here we have taken a sample set of 1000 active preclinical drug programs. Note – this includes all those with anything active in 10 or over programs, hence the apparent increase. 7 Lipinski Arrowhead SFO 2012

Phenotypic observations 30% of 400 compounds profiled show new beneficial biology Up to 90% of new indications are driven by on-target activities Biology is complex and there is a tremendous amount that is not understood Phenotypic screening provides an opportunity to identify new clinically relevant uses of existing molecules driven by action on known molecular targets 8Lipinski Arrowhead SFO 2012

Unbiased Phenotypic Screening Phenotypic Screening as often used – Any route to discovery other than hypothesis- based discovery e.g. Serendipitous finding in the clinic, focused screen in a single model Systematic Unbiased Phenotypic Screen Meliors approach involving comprehensive evaluation in a spectrum of animal models independent of candidates mechanism or primary therapeutic area 9Lipinski Arrowhead SFO 2012

Repurposed diabetes drug 10 Lyn kinase activator new mechanism,one of 264 mechanism possibilities Lipinski Arrowhead SFO 2012

Source: Thomson Reuters Integrity The Key Therapeutic Areas by no. of Associated Targets 11 Lipinski Arrowhead SFO 2012

Conclusions Drug repurposing is independent of drug discovery method Phenotypic screens cast a broad net Reductionist / mechanistic approach unnecessarily limits opportunities – eg. current NCATS repositioning Chemistry structural information required for most computational approaches – eg. current NCATS missing structures 12Lipinski Arrowhead SFO 2012