outline of pharmaceutical drug discovery & development

1. Issues and Challenges in Drug Discovery and Development Discovering and Developing Medicines Mike Sumner

2. The Drug Discovery and Development process is a progression from Targets and Leads… to Drugs...to Products Products Drugs Targets & Leads Target selection Target to Lead Lead to candidate Candidate selection to FTIH FTIH to PoC PoC to Commit to Phase III Phase III File & Launch Lifecycle mgt 12-24m 12-24m 30-33m 8-12m 12-44m 0-30m 18-66m 10-13m Costs ~ $1 billion per successful product 9 - 16 y

3. Drug Discovery Process chemical diversity (compound library) test safety&efficacy in animals and humans gene screen and identify lead Lead optimisation protein target Drugs Targets & Leads Target Validation & Selection Target to Lead (compounds) Lead to candidate Drugs Candidate progress to FTIH and PoC in patients

5. Genome Disease Potential Drug Target Select protein of interest Pathology Link with disease or disease process Selection of Biological Target Genetics Target Selection Approaches to Finding a Drug Target

14. Optimizing Lead Compounds is an Iterative Process Medicinal Chemistry Biology Lead compounds from Screening Candidate selected for testing in man Developability DMPK Hypothesise, design molecules and synthesise Analyse/ rationalise results Test hypothesis

15. A bsorption D istribution M etabolism E limination Drug Metabolism and Pharmacokinetics (DMPK) Understanding the fate of drug candidates in animals and man

19. Safety Assessment

21. Aspects of a Safety Assessment Acute Responses Chronic Effects Genetic damage? Carcinogenicity? One dose Lifetime use Reproduction Development

26. Chemical Development (CD), in collaboration with Pharmaceutical Development (PD), is charged with delivering a cost effective, efficacious medicine... Drug Substance (DS) Drug Product (DP) Molecules to Medicines

27. Drug Substance synthesis: Scale - up 10-100g 10-100kg Lab scale Factory scale

30. Why Have Proof of Concept? Comprehensive statement describing clinical outcomes necessary to achieve market forecast Product Profile Proof of Concept Clinical evidence giving confidence that the Drug works and is likely to meet the required Product Profile Proof of Concept is achieved when significant risk of further development has been reduced, such as demonstrating safety and potential for efficacy in the patient population Phase IIb and III Spend big $$$$$

32. Consult with Regulatory Authorities FDA: US Food and Drug Administration EMEA: European Medicines Evaluation Agency MHLW: Japan Ministry of Health Labour & Welfare Agencies provide helpful insight into study design and doses Reduce risk of conducting long, expensive studies that don’t lead to approval May change Phase III clinical plan based on feedback

35. Regulatory Authorities Food and Drug Administration European Medicines Agency Ministry of Health Labour and Welfare Therapeutic Goods Administration Health Canada International Conference on Harmonisation Over 120 ‘International’ markets

36. Life Cycle Management What do Product Line Extensions give? New indications expand claims New target patient populations expand patient base New administration routes New formulations Combination therapies expand patient base, improve compliance improve access/ease of use simplify therapy, improve compliance