Drug Discovery and Development Process

Drug Discovery and Development Process

• Drug development takes 12-15 years to market approval.
• Only 1 in 10 drugs in clinical trials is approved.
• Cost to bring a drug to market is estimated at $2.6 billion.
• WHO defines a drug as a substance or product intended to change physiological or pathological states for benefit.

Drug Discovery

• Finding a compound with therapeutic benefits for treating diseases.

• Primary Stages

  • Target Identification: Identifying suitable disease-related targets for drug development (efficient, safe, usable, clinically/commercially viable).
    • Potential targets: proteins and nucleic acids.
    • Technologies:

• Omics-Based Methods:

• Genomics: studies an organism's complete DNA.

• Transcriptomics: studies the complete set of RNA transcripts.

• Proteomics: large-scale study of proteins.

• Metabolomics: studies small molecules (metabolites) in cells and fluids.

• 3D structure analysis: Example: cancer.

• Find disease proteins to inhibit.

• Screen molecules against these targets.

  • Target Validation: Confirming a biological target's direct involvement in a disease process and the therapeutic benefit of modifying it.
    • Target Criteria:

• Effective: Critical to disease process and modulates it therapeutically.

• Safe: Modifying the target does not cause unacceptable side effects.

• Usable: Developing an effective drug to engage the target is feasible.

• Meeting Clinical and Commercial Requirements: including regulatory, IP, market, and commercial viability considerations.

  • Hit Identification/Hit Finding: Identifying compounds potentially binding to a target and affecting its activity.
    • Techniques:

• High-throughput screening.

• Fragment-based drug discovery.

• Structure-based drug design.

• Virtual screening.

• De novo design.

  • Hit-to-Lead and Lead Optimization: Improving hit compounds for preclinical testing.
    • Optimization Process:

• Quantitative Structure-Activity Relationship (QSAR) and Structure-Function Relationship studies.

• ADMET studies (Absorption, Distribution, Metabolism, Excretion, Toxicity).

• Improving properties like potency, efficacy, selectivity, and bioavailability.

• Medicinal chemistry.

• Antibody-Drug Conjugates (ADCs).

Antibody-Drug Conjugates (ADCs)

• Combination of antibody specificity and cytotoxic drug potency for targeted cancer therapy.
• Structure:
• Monoclonal antibody targets cancer antigens.
• Cytotoxic drug (warhead) kills cancer cells.
• Linker connects antibody and drug.
• Mechanism of Action: antibody binds, ADC internalized, cytotoxic drug released, cancer cell destroyed.
• Advantages: targeted delivery, improved therapeutic index, enhanced specificity.
• Examples: Adcetris, Polivy, Padcev, Tivdak.

Preclinical Development (Stage 5)

• Manufacturing and testing lead compound efficiency and safety for regulatory submission.
• Pharmacodynamics (PD): Drug's biochemical and physiological effects; how it interacts with targets and impacts systems.
• Pharmacokinetics (PK): Drug movement in the body (ADME) important for optimal dosage, route, and frequency.

Clinical Development (Stage 6)

• Testing drugs on humans (4 phases).
• Phase 1: Safety and dosage (20-100 volunteers).
• Phase 2: Efficacy and side effects (several hundred volunteers).
• Phase 3: Further efficacy and adverse reaction monitoring (300-3,000 volunteers).
• Phase 4: Continued safety and efficacy monitoring after approval.
• Drug Application and FDA Approval: NDA, OTC, BLA applications.
• Post-marketing monitoring.

Early-Phase Drug Discovery Strategies

- **Target-Based Drug Discovery (TDD):** Uses known relationships between a target and disease.
- **Phenotypic Drug Discovery (PDD):** Observes compound effects without prior target knowledge.

Phenotypic Drug Discovery Benefits

• Unbiased approach: no prior target knowledge.
• Disease relevance: models closely mimic human disease.
• Reduced target validation failure risks.
• Identifies polypharmacology (drugs that target multiple pathways).

Phenotypes in PDD

• Cell metabolism changes (metabolomics).
• Protein activity changes (phosphoproteomics)
• Protein levels changes (proteomics).
• Gene expression changes (transcriptomics).
• Cell shape or structure changes (imaging).

Cell Painting in PDD

• High-content imaging technique to observe cellular changes after drug treatment.
• Multi-dye staining to visualize cell components.
• Image analysis to extract morphological profiles.
• Advantage: unbiased, comprehensive, high-dimensional data, novel target and mechanism identification.
• Compared to High Content Screening (HCS) , which is more focused on predefined phenotypes.

Small Molecule vs. Biological Drugs

• Small Molecule: -Small size, well-defined structure, relatively stable, synthesized by predictable chemical reactions, usually not immunogenic, relatively easy to characterize.
• Biological Drugs: -Large size, complex structure, sensitive to storage/handling, produced in living cells, can be immunogenic, require more characterization studies.

FDA Approved Drugs (1981-2019)

• Drug origin and production method data was provided in percentages.