Drug repositioning: out of the box opportunities despite data and chemistry challenges Christopher A. Lipinski clipinski

1. Drug repositioning: out of the box opportunities despite data and chemistry challengesChristopher A. Lipinskiclipinski@meliordiscovery.com Lipinski Arrowhead SFO 2012

2. Attrition rates by phase The Productivity Crisis in Pharmaceutical R&D, Fabio Pammolli, Laura Magazzini and Massimo Riccaboni, Nature Reviews Drug Discovery 2011 (10) 428-438. Lipinski Arrowhead SFO 2012

3. Target-based drug discovery: D2 D1 R3 R2 R4 R5 R1 R6 E1 E5 E2 E6 E3 E4 E7 DP 1 DP 2 Lipinski Arrowhead SFO 2012

4. ….the real picture D2 D1 R3 R9 R2 R10 R4 R5 R1 R6 E7 R7 E1 E8 E5 R8 R11 R12 E9 E8 E2 E6 E10 DP 3 E3 E4 E7 DP 4 DP 5 DP 1 DP 2 Lipinski Arrowhead SFO 2012

5. 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 Lipinski Arrowhead SFO 2012

6. 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) 507-519. Lipinski Arrowhead SFO 2012

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

8. 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 Lipinski Arrowhead SFO 2012

9. 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 • Melior’s approach involving comprehensive evaluation in a spectrum of animal models independent of candidates mechanism or primary therapeutic area Lipinski Arrowhead SFO 2012

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

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

12. 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 Lipinski Arrowhead SFO 2012