Pharmaceutical Industry & Drug Discovery

• Pharmaceutical industry emerged from biomedical sciences (pharmacology), chemistry (synthetic organic chem), therapeutics, and understanding disease mechanisms

Key Dates in Pharmaceutical Industry

• 1909: Paul Ehrlich demonstrated syphilis treatment using arsenical compounds
• 1932: 'Prontosil', the first sulphonamide antibacterial, was developed by Bayer, leading to an era of drug development led by chemists
• 1960s-80s: 'Rational drug design' era, with beta blockers and ACE inhibitors, led by pharmacologists like Sir James Black
• 1961: Thalidomide withdrawn due to harmful effects on foetus development
• 1990s: Drug discovery revolutionized by high throughput screening and combinatorial chemistry
• 2000 to date: Increasing development of 'biologicals' e.g., human insulin and anti-cancer antibodies
• 2002: Human genome mapped
• Pharma industry about 100 years old

Drug Discovery Process

• Basic research needed to understand physiology, disease mechanisms; adrenaline relaxes airway smooth muscles to cause bronchodilation and asthma that causes bronchoconstriction
• Identification of potential drug molecular targets (proteins) plays a crucial role in disease i.e. adrenaline acts on beta receptor on bronchial smooth muscle
• Hypothesis made that a drug mimicking adrenaline effects will relieve asthma symptoms

Other Considerations

• Safety (patient & environment), ethical(cognitive enhancers), intellectual property, and cost

Assay System

• Measures whether a drug has desired effect, also used to filter for desired effects

Drug Sources and Clinical uses

• Morphine is derived from opium poppy and is used as an analgesic
• Penicillin is derived from fungus penicillium and is used as an antibiotic
• Digoxin is derived from woolly foxglove plant and is a cardiac glycoside
• Paclitaxel is derived from pacific yew tree and is a mitotic inhibitor
• Quinine is derived from bark of cinchona tree and used to treat malaria
• Hirudin is derived from saliva of medicinal leech and is an anti-coagulant
• Botulinum toxin in derived from bacterium clostridium botulinum and is used for botox and migrainetreatment

Compounds in Pharma

• Pharma companies utilize chemical libraries with chemical compounds, with each being a potential drug molecule
• Combinatorial chemistry boosts the amount of potential drug molecules

Screening Methods

• High-throughput screening tests lots of compounds for potential activity very quickly

Combinatorial Chemistry

• Rapidly create and test chemical compounds in drug discovery and materials science
• Synthesis of Diverse Compounds: variations of a compound generated simultaneously with different building blocks

High-Throughput Screening

• Screening resulting compounds for biological activity or effectiveness
• Goal to identify potential drug candidates/materials faster, space exploration

Structure Activity Relationships

• Optimize promising drugs that show how chemical structure relates to biological activity
• Enzyme inhibition, receptor binding
• Identify structual chemical features important for activity

Animal Models

• Used for testing pharmacokinetics, toxicology & safety pharmacology

• Pre-clinical stage lasts 5-10 years, results in 1 or 2 drug candidates for human trials

• Patent granted early in pre-clinical stage, lasts 20 yrs i.e. pressure to market to recover costs

Clinical Trials in Drug Development

• Pre-clinical, clinical, post market stages; costs £250-500 million overall

Phase I

• Is exploratory and tested on 2 mammal species for toxicity, 6 months-year
  • Checks for safety and tolerability
  • Small number of healthy volunteers (40-60)
  • Includes placebo-controlled, randomized, double-blind
  • Phase 1a - Escalating single dose; placebo-controlled, randomised, double blind
  • Phase 1b - Repeated dose; placebo-controlled, randomised double blind

Phase II

• Efficacy proof of concept and safety
  • Checks for clinical effectiveness and confirms safety + tolerability
  • Phase lla
    • Exploratory phase
      • 50-200 patients for 1 year
      • Go-no-go decision before progressing

Phase IIb

• Confirmatory:
  • 200-500 patients for 2 years
  • Safety and efficacy compared to placebo or current randomized treatment, double-blind design

Phase III

• Confirmatory:
• Full evaluation of effectiveness, compares to treatment
• Tested in 2000-10,000 patients in multi-centres with different groups
• Lasts several years, especially if chronic
• Provides data to support registration; can be used in specified condition after approval to recuperate developmental costs

Drug Regulatory

• Regulated by EMA, MHRA UK, FDA i.e. must submit drug information to them

Phase IV

• Ongoing trials after drug is approved
  • Pharmacovigilance, post-market surveillance, “Yellow Card” system in UK
  • Monitor consequences/exposure in thousands of patients
    • Monitor rare long-term effects and unpredictable drug interactions
    • Yield information on efficacy in sub-groups