Drug Discovery Now (PHRM20001) PDF

Source: Unsplash. Photo by Kendal. DRUG DISCOVERY (NOW) Dr Makhala Khammy Dept Biochemistry and Pharmacology PHRM20001: HOW DRUGS WORK Learning outcomes Describe the major steps in current drug discovery and development including: • Target identification and validation and why they are key ste...

Source: Unsplash. Photo by Kendal. DRUG DISCOVERY (NOW) Dr Makhala Khammy Dept Biochemistry and Pharmacology PHRM20001: HOW DRUGS WORK Learning outcomes Describe the major steps in current drug discovery and development including: • Target identification and validation and why they are key steps in drug discovery • Phenotype-based drug discovery and target-based drug discovery and their key differences • Lead discovery and optimisation including rationale drug design • Preclinical assessment of toxicity and safety • Clinical assessment of efficacy, toxicity and safety Drug discovery then vs now Then: A reflection of limited techniques, knowledge, infrastructure and resources Now: Rapid technological advances facilitate rationale drug discovery and design. Uses information about: • 3D structure of receptors and ligands and ligand-receptor interactions • Physiology and pathophysiology (molecular, tissues and systems) • Mechanism of action of drug Drug Discovery Choosing a disease Target Identification and validation Lead compound identification Lead optimisation Preclinical development Drug Development Clinical trials Phase I Phase II Post-marketing surveillance Phase III Regulatory and marketing approval Choosing a disease Unmet medical need Economic viability (esp. Pharmaceutical perspective) • Drug Discovery is long, expensive and risky Size of target population (e.g., orphan diseases) Also difficult to perform statistically robust clinical studies • Purchasing power Less in low- and middle-income countries • Feasibility of drug development Lower risk = likely lower costs and draws more funding Information about the disease E.g., unknown disease mechanism or diagnostic difficulties makes it difficult to evaluate impact on individual and society Interest (e.g., publicly funded biomedical research) DiMasi et al; J Health Econ. 2016;47:20-33 Choosing a disease Target Identification and validation Lead compound identification Lead optimisation Preclinical development Clinical trials Phase I Phase II Post-marketing surveillance Phase III Regulatory and marketing approval What makes a drug target a good target? Clinical need and commercial potential Involved in pathophysiology of disease Good target-related safety Hidden Primarily expressed on tissues of interest. On-target adverse effects manageable. Druggable – target can be altered in desired manner by low molecular weight compound 3D structure helpful Assays available for high-throughput screening (or assays can be developed) Druggability Likelihood that target can be modulated by low molecular weight compounds with ‘drug-like’ properties Human genome ~20,00022,000 Can be predicted • Use information about structure and endogenous ligand Druggable genome ~3,000 Drug targets ~600-1,500 Diseasemodifying genes ~3,000 • Use information about its family Previous successfully targeted proteins? • Not perfect Modified from Hopkins, A., Groom, C. The druggable genome. Nat Rev Drug Discov 1, 727–730 (2002). Target identification and validation Evidence that target is involved in disease pathogenesis Evidence that modifying the target alters disease state Target identification and validation: • requires understanding of molecular mechanisms of disease • sometimes relatively straightforward (monogenic diseases) but often not (polygenic diseases) • can use big data Translational relevance? Clinical Pharmacology & Therapeutics, Volume: 99, Issue: 3, Pages: 285-297, First published: 11 December 2015, DOI: (10.1002/cpt.318) Assay development and screening Hit and lead identification Target identification and assessment Development of assay amenable to highthroughput screening Screening Often biochemical or cellular Large small molecule library Can assess binding and/or functional activity Focused library – can be aided by structure-based drug design or ligand-based drug design Ideally surrogate for clinical endpoint Hit evaluation Confirm hits • • Physiochemical properties and selectivity (often in silico) • PD (rank potency) • Toxicity Target- vs phenotype-based You have identified and validated a target. You develop assays and screen compound libraries to identify ‘hits’. You have a compound eliciting a desired phenotype. You identify the target retrospectively. Terstappen, G., Schlüpen, C., Raggiaschi, R. et al. Target deconvolution strategies in drug discovery. Nat Rev Drug Discov 6, 891–903 (2007). Good PK properties (ADMET) Selective Lead optimisation Efficacy in animal models We have leads! But is it a good lead? Uses medicinal/synthetic chemistry • Generate (or get existing) structural analogues Evaluate structure-activity relationships • • • Re-examine PD, PK, toxicity, selectivity etc… Computational approaches and experimental approaches • Iterative process Safe and non-toxic Preclinical development: What’s in an IND dossier? IND dossier - submission made to FDA to allow drug to be considered for clinical testing Information includes: • Toxicity profile • Pharmacological profile (in vitro and in vivo) Pharmacodynamic and pharmacokinetic data (ADME), information about dose, frequency, route of administration • Chemical/manufacturing info. Composition/source for natural products. • Formulation Combination of drug substance with other substances, often to aid administration/compliance, stability/shelf-life. • Proposed clinical plans/protocols Toxicity testing Nephrotoxic Involves in silico, in vitro and in vivo assessment Hepatotoxic Cell death (necrosis/apoptosis) Hypersensitivity/ immunosuppression DRUG-INDUCED TOXICITY* (biopharmaceuticals) Acute toxicity (in vivo) Genotoxic Chronic toxicity (repeated dosing in vivo) (damages DNA) Immunotoxicity epigenetic Pre-clinical assessments depend on intended clinical use Carcinogenic (promotes cancer formation) Mutagenic Teratogenic (promotes congenital malformations) *drug itself and/or reactive metabolites Pharmacological characterisation (inc. safety) Systematic and hierarchical! Pharmacological assays should reflect disease Can be used to assess safety by identifying pharmacodynamic effects of a substance on physiological functions. Adverse effects may be, predictable • related to mechanism of action on desired target in intended tissue or unintended tissue • related to off-target effect associated with chemical class unpredictable • unrelated to mechanism of action Drug Discovery Choosing a disease Target Identification and validation Lead compound identification Lead optimisation Preclinical development Drug Development Clinical trials Phase I Phase II Post-marketing surveillance Phase III Regulatory and marketing approval Clinical trials Treatment, Prevention, or Diagnostic/Screening trials Test the compound in humans to determine • tolerability • effectiveness • whether the compound elicits adverse effects • whether the compound elicits other beneficial effects Four major phases Image: Why Australia for Clinical Trials 2021. https://www.austrade.gov.au/international/buy/australian-industrycapabilities/health-and-wellbeing Phase I Aka First-in-Human trials Not always Test compound in humans for the first time No. people enrolled: Small group of healthy volunteers (20-80) Study purpose(s): Is the drug safe? What are the adverse effects? Is the drug tolerable? Pharmacokinetics/Pharmacodynamics Duration (approximate): Several months Phase II No. people enrolled: Larger group of healthy volunteers (several hundred) or Small group of diseased patients Study purpose(s): Is the drug safe? Dose - how much and how often? How effective is the drug (is it working as intended in the specific target population)? Duration (approximate): Months to 2 years Phase III No. people enrolled: Large number of patients with the disease (several hundred to several thousand) Study purpose(s): How effective is the drug (is it working as intended in the specific target population)? Often compared to standard intervention, another experimental intervention or non-interventional standard care. Continued monitoring of adverse effects Duration (approximate): 1-3 years Phase IV – Post-marketing surveillance No. people enrolled: General population Study purpose(s): How effective is the drug in the general population? Continued monitoring of safety and adverse effects Duration (approximate): Forever? Boxed warning Withdrawn Black Triangle Scheme Drug discovery and development pipeline Drug discovery Target identification & validation, lead identification and optimisation 3-4 years Preclinical Regulatory review, approval & launch Clinical trials Compound effectiveness, safety and toxicity assessed in cells and animals 2-3 years Phase I (FIH) Phase II Phase III 20-100 healthy volunteers 100’s patients 1000’s patients Phase IV 1-2 years 6-7 years IND Post-marketing surveillance NDA NCE/NBE applications - AUS Drug discovery and development – fails, fails, fails Cook et al, Nat Rev Drug Discov. 2014;13:419-31 Drug discovery and development in the future Identifying failures early Cooperation between industry and academia to develop new robust technologies that can be used in the drug discovery and development pipeline Luck! To learn more… PHRM30008 Drugs: From Discovery to Market Thanks for tuning in! Dr Makhala Khammy Dept Pharmacology & Therapeutics PHRM20001: HOW DRUGS WORK