2PHA406 Drug Design bantingl.myweb.port.ac.uk/ 2PHA406.html

1. 2PHA406 Drug Designhttp://bantingl.myweb.port.ac.uk/2PHA406.html Dr. Lee Banting

2. Unit introduction The Pharmaceutical Industry - an overview Drug Targets Technology Virtual Drug Design - Theory, role, practice Combinatorial Chemistry, HTS Case Study

3. The Pharmaceutical Industry – company rankings (Adapted from Arrowsmith J, Nat.Rev. Drug. Disc.,11,17 (2012)

4. The process, the probability of success (%), the ‘asset’ in process, the timescale (y) and the cost (£M) The Pharmaceutical Industry – the process Submission to launch Launch Target-to- hit Hit- to- lead Lead opt. Preclin Phase I Phase II Phase III Discovery Development 80% 75% 85% 69% 54% 34% 70% 91% 24.3 19.4 14.6 12.4 8.6 4.6 1.6 1.1 1 Attrition 1 1.5 2.0 1.0 1.5 2.5 2.5 1.5 15.5 12.5 95 40 83 120 152 28 546 (Based on Eli-Lilly Adapted from Paul, S.M., etal, Nat.Rev. Drug. Disc.,9,203 (2010)

5. The Pharmaceutical Industry - an alternate overview Drug discovery and development process (Adapted from http://www.abpi.org.uk/publications/briefings/Dev_Medicines.pdf)

6. Industry’s experience with compound progress (success helps to further define drug structural features) Pharmacology Absorption (ADME) Toxicity (Safety) The Pharmaceutical Industry – progress hurdles A X Available to be a drug B C X X D

7. The Pharmaceutical Industry - Productivity vs. investment (Taken from Pharma 2020: Virtual R&D Which path will you take? PWC, 2007)

8. The Pharmaceutical Industry - pressures Industry profitability and growth challenged by strained healthcare budgets Generics, although clearly keeping drug prices down, are approaching 70% of all prescriptions Key patent expirations due in the next few years will threaten sales to the tune of £130 billion losing £73 billion to generics Companies are pressured (unrealistically) by their investors for good returns and this has required them to maintain a good product pipeline (NDEs) and profitability. R&D leaders are made to justify expenditure Increasing pace of technology

9. The Pharmaceutical Industry - effect of patent expiration and loss of revenue to generics

10. The Pharmaceutical Industry – coping strategies Industry profitability and growth challenged by strained healthcare budgets –governmental politics, ‘navigate’ NICE to maximise drug appraisals Generics, although clearly keeping drug prices down, are approaching 70% of all prescriptions – patent extension by reformulation or new claims (see here), acquire generic companies Key patent expirations due in the next few years will threaten sales to the tune of £130 billion losing £73 billion to generics – downsizing, patent extension by reformulation, maintain a healthy pipeline, merge with other companies, acquire SMEs with specialist pipeline, license products from SMEs, repurposing (new uses for old drugs, see here) Companies are pressured (unrealistically) by their investors for good returns and this has required them to maintain a good product pipeline (NDEs) and profitability. R&D leaders are made to justify expenditure – educate investors to realise the nature of the business Increasing pace of technology – use outsourcing for expertise and equipment

11. The Pharmaceutical Industry – mergers, acquisitions and ‘tings’ Pfizer acquired Warner-Lambert (2000), Pharmacia (2003) and Wyeth (2009) Sanofi merged with Synthélabo (Sanofi-Synthélabo 1999) hostile takeover of Aventis (Sanofi-Aventis 2004) then bought Genzyme (2011) now known as Sanofi S.A. Boehringer Ingelheim and the US company Neurocrine have agreed to develop small molecule GPR119 agonists in Type II diabetes, which are designed to increase insulin production, and includes a $10m up-front fee plus royalties and milestones.

12. The Pharmaceutical Industry – more on mergers, acquisitions (Adapted from Arrowsmith J, Nat.Rev. Drug. Disc.,11,17 (2012)

13. The Pharmaceutical Industry – Pharma 2020 transforming the ‘business of R&D’ within the next 10 years. What happens now? R&D Revenue return (Adapted: Measuring the return from innovation Is R&D earning its investment, Deloitte (2011)

14. The Pharmaceutical Industry – Pharma 2020 Optimise revenue and innovation • Ensuring increased pipeline and its optimal competitive positioning – efficiency gains ‘box clever’ • Raising late stage success rates – better prediction of asset failure • Increase product differentiation – oral drugs – biologics – nanotechnology – diagnostics • • Nurturing a scientific ethos that accesses the best scientific talent to better identify and research the most promising assets to progress, regardless of origin. Refreshing the R&D talent pool to build out new skills and capabilities that reflect the heightened value and commercial focus that is needed to complement outstanding scientific talent – scientific ‘eugenics’, potential ruthless turn over of staff ensuring survival of the fittest • • Sharing across companies scientific insights regarding failed assets and studies in early development – being selfless (Adapted: Measuring the return from innovation Is R&D earning its investment, Deloitte (2011)

15. The Pharmaceutical Industry – Pharma 2020 - Reduce costs • • Building on the first generation of outsourcing relationships to realize greater and more sustainable improvements in cost, speed and quality of delivery, e.g. through • Implementing the reduction of the distinction between internally and externally sourced innovation in capital allocation decision making – less reluctance to use monies creatively • Sponsorship of organizations collaborating to identify areas of simplified and standardized working and tools achieving scale of economies – clever outsourcing • • Using multiple approaches to increase the opportunities for harnessing external innovation, e.g. establishing early stage alliances, forming joint ventures or risk-sharing partnerships (Adapted: Measuring the return from innovation Is R&D earning its investment, Deloitte (2011)

16. The Pharmaceutical Industry – Pharma 2020 – Improve timing • Applying lean processing - reduce the ‘dead time’ between asset development phases, shorten the critical path to regulatory submission • Improve identification of clinical trial participants and investigator selection - develop and enhance relationships with appropriate healthcare providers • Selecting disease areas within a portfolio – use scientific expertise and understanding of disease area cycle times, degree of unmet need, patient saturation and market potential “The government believes that as a result Britain can become a world leader in the field of life sciences - an industry already worth £50bn a year and employing 160,000 people - because of the expertise within the NHS and its strong university-based research.” (see here) (Adapted: Measuring the return from innovation Is R&D earning its investment, Deloitte (2011)

17. The Pharmaceutical Industry – Pharma 2020 – Quick win fast fail paradigm Higher probability of success Preclinical development Proof of concept Confirmation, dose finding Commercialization £ £ Abundance of drug discovery Product decision First human dose Candidate selection First human dose R&D sweet spot Launch (Based on Eli-Lilly Adapted from Paul, S.M., etal, Nat.Rev. Drug. Disc.,9,203 (2010)