The document discusses the key stages in the drug discovery and development process including target selection, compound screening and hit optimization, selecting a drug candidate through further optimization of properties like absorption and metabolism, safety testing in animals and humans, proof of concept clinical trials in patients, large phase 3 clinical trials for registration and approval, and finally launch and life cycle management. It notes that the entire process from discovery to approval can take 12-16 years and cost over $1 billion.

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

4. Part 1: Target Selection & Compound Screening Topics Target selection & Validation Compound Screening Hit optimisation

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

6. Target Validation - Linking Targets to Diseases and Treatments Target validation is a series of activities, which aim to build confidence that a drug which acts by modifying the function of the target will deliver the efficacy and safety required Degree of target validation varies, depending upon the nature of the disease, type of target etc. A target is never fully validated until a drug acting on it works in patients!

7. Screening to Generate Hits Types of screens Functional assay Binding assay Cell response Compound binds to cell surface receptor - this can be measured in a “binding assay” This can evoke a cellular response - which can be measured in a “functional assay”

8. Screening to Generate Hits - where do the hits come from? High throughput screening (millions of compounds) Multi-well plates (384, 1536) Automated - advanced robotics Knowledge-based rational design Computer modelling Structural knowledge, eg X-ray crystallography Cheminformatics

9. Hit Optimisation Hits from initial screening are rarely adequate for further progression as they stand, so they are further optimised How is this done? Through an iterative cycle of Chemistry (automated arrays) Biological testing in-vitro Key lead criteria: - Potency (“strength” of interaction with target protein) - Selectivity for target (panel of selectivity tests) - Enablers (facilitate further progression of leads)

10. What is meant by “Enablers”? Properties which are desirable but not essential at this stage, e.g. Confirmed mode of action (e.g., competitive inhibitor) Demonstrable structure-activity-relationships (SAR) Physicochemical properties (solubility, lipophilicity, stability, purity, chemical complexity) No difficulties with species differences Acceptable intellectual property situation (no major concerns about patents related to leads) No obvious anticipated safety liabilities (Predictive Toxicology)

11. Summary The starting point for Drug discovery is picking the right target and the right compound(s) “ Picking the winners” It may be 12-16 years and cost >£500M before you find out if you were right ! To reach this point will have taken 3-4 years and cost £1-2M per successful lead!

12. Part 2: Selecting a Drug Candidate Topics Lead optimisation – addition of extra properties (ADME) Safety testing Molecules into Medicines Testing in Humans

13. Objective of this Phase This is a major challenge!!!!! Aiming to combine all desired properties into one molecule – like “winning the lottery” Back-up Program(s) Follow-up Program(s) To optimise lead molecules to identify a single compound with potential to reach the clinic with: - right properties – potency, selectivity, PK etc. - low probability of failure in development

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

16. Animals to Humans Characteristics of the drug candidate………. DMPK studies aim to answer some key questions: What is the relationship between exposure and dose? Is it readily excreted or retained with potential to accumulate? How is the drug metabolised? Are the toxicology species adequate models to make a human safety assessment? What are the safety margins for clinical trials?

17. Challenges to support First Time in Humans? DMPK Assays may need very low limits of quantification (<1ng/mL) especially for inhaled drugs and for the human assay to support FTIH Compounds selected to have low metabolism in vitro so in vitro metabolism studies often generate very small quantities of metabolites Low levels of radioactivity in plasma samples often makes metabolite profiling difficult SENSITIVITY

18. The Bridge Between Animals and Humans Are the toxicology species good models for humans in terms of… Systemic exposure to the drug? Routes of metabolism? Systemic exposure to metabolites? DMPK provides vital data to assess ‘developability’

19. Safety Assessment

20. Animals to Man Conduct initial non-clinical safety studies to assess developability and potential risks for first administration to humans Conduct additional studies to build confidence that longer term clinical trials can be conducted safely, and the medicine can be approved for use To complete safety evaluation and assist in dose selection for first clinical trials, Safety Assessment has to:

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

22. Toxicology - What Do We Examine? EXPERIMENTS Safety Pharmacology (in vitro, rodent, non-rodent) General Toxicology (rodent & non-rodent) Genetic Toxicology (in vitro, in vivo) Carcinogenicity (rodents) Reproductive & Developmental Toxicology (rodent & non-rodent) ENDPOINTS Behaviour, function, physiology Behaviour, function, physiology, clinical biochemistry, pathology Mutation, chromosomal changes Non-genotoxic carcinogens Fertility, pregnancy, Fetal and peri/post-natal development

23. Toxicology Tests More Than the Active Drug Substance Active drug substance Related substances Solvents Degradation products Excipients Other active materials Extractives All medicines contain more than the active drug!

24. Assessments of Margins of Safety Exposure in Animal and Human Data Major considerations Dose administered Extent and duration of systemic exposure Daily systemic exposure Some other factors... Exposure & identity of metabolites between species Exposure in target organs (accumulation?)

25. Preclinical safety studies will … Explore the response at up to maximum achievable doses Primarily designed to detect potential hazards Generate data to enable a risk assessment to be made Assist in dose-selection for initial clinical studies Suggest ‘markers’ to monitor safety in humans Provide a foundation for targeted specialist investigations Preclinical safety studies cannot necessarily… Guarantee safety in humans Predict the human response Define a mechanism for the changes Summary

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

28. Testing in Humans - Key Messages Entry into man is a major milestone Major ethical and safety reviews before approval There are no absolutes in designing a clinical plan - but subject safety is always paramount Initial studies are usually undertaken with healthy male volunteers and at very low doses, with intensive monitoring Verified surrogate or early clinical markers make all the difference – is the drug getting to the right target at the required levels Initial goal is to establish safety & tolerability in man Only then will the drug move into patients and “proof of concept”

29. Part 3: Product development Topics Proof of Concept in Patients Large scale clinical studies Registration & Approval Launch & Life cycle managment

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 $$$$$

31. Objectives of PoC to Commit to Phase III Demonstrate clinical activity & acceptable safety profile in target patient population Establish appropriate dose & regimen for Phase III clinical trials

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

33. Objectives of Phase III Gather primary safety & efficacy information to: Evaluate overall risk-benefit Provide basis for labeling Generate data to support positioning & differentiation Prepare commercial supply sites to pass regulatory inspection

34. Pivotal Phase III Studies Why Determine safety & efficacy in target indication to provide data for regulatory approval What Two adequate, well-controlled, double-blind clinical trials Compare with gold standard, placebo or supportive care How 600 - 3,000 patients 1.5 years to 5 years £4 to 50 million per trial Multiple sites & countries

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