Drug Discovery and Development: Lecture VII - Biologics

Drug Discovery Overview

  • Lecture VII: Biologics

    • Instructor: Dr. Miriam Moriarty

    • Contact: miriam.moriarty@universityofgalway.ie

Drug Development Process

  • Main Stages:

    1. Basic Research

    2. Prototype Design/Discovery

    3. Preclinical Development

    • Interactions with FDA:

      • Pre-IND Meetings

      • End of Safety Update Phase

    • Key Meetings:

      • Phase 2a Meeting

      • End of Phase 2 Meeting

      • Pre-BLA (Biologics License Application) or NDA (New Drug Application) Meeting

    1. Clinical Development

    • Phases:

      • Phase 1: Safety, dosage, and side effects

      • Phase 2: Efficacy and side effects

      • Phase 3: Confirmation of efficacy, monitoring of adverse reactions

    1. FDA Approval

    2. Market Launch Preparation

Comparison: Traditional Drugs vs Biologics

  • Traditional (Small Molecule Drugs):

    • Example: Acetylsalicylic acid

    • Size: 180 Da

    • Structure: Simple, well-defined

    • Manufacturing: Chemical synthesis, easy to produce identical copies

    • Stability: Relatively stable

    • Administration: Often oral (tablet, pill)

    • Immunogenicity: Rarely immunogenic

  • Biologics:

    • Example: Monoclonal antibody

    • Size: ~ 150,000 Da

    • Structure: Complex, many post-translational modifications

    • Manufacturing: Produced in biological systems, similar but not identical products

    • Stability: Unstable, sensitive to storage and handling

    • Administration: Usually by injection or IV infusion

    • Immunogenicity: Often immunogenic

Types of Biologics

  • Categories:

    • Recombinant Proteins: Example: Humulin (Insulin) introduced in 1982

    • Monoclonal Antibodies: Example: Herceptin (Trastuzumab)

    • Antibody Drug Conjugates (ADCs): Example: Kadcyla (Trastuzumab emtansine)

    • Vaccines: Various types including HPV, Hepatitis B

    • Viral and Virus-like Particles (VLP):

    • Recombinant Nucleic Acids

    • Stem Cell Therapy

    • Gene Therapy

    • Immunotherapy

    • Biosimilars

Biologic Sales in 2023

  • Top 10 Biologic Sales:

    1. Keytruda (Pembrolizumab)

    • Manufacturer: Merck & Co

    • Sales: $25.24 Billion

    • Indications: Various types of cancer

    1. Humira (Adalimumab)

    • Manufacturer: AbbVie

    • Sales: $21.24 Billion

    • Indications: Rheumatoid arthritis, Crohn’s disease

    1. Dupixent (Dupilumab)

    • Manufacturers: Regeneron/Sanofi

    • Sales: $11.94 Billion

    • Indications: Immunology

    1. Comirnaty (COVID-19 Vaccine)

    • Manufacturers: Pfizer/BioNTech

    • Sales: $11.20 Billion

    1. Stelara (Ustekinumab)

    • Manufacturer: Johnson & Johnson

    • Sales: $10.90 Billion

    1. Opdivo (Nivolumab)

      • Manufacturers: Bristol Myers Squibb/Ono

      • Sales: $10.27 Billion

    2. Darzalex (Daratumumab)

      • Manufacturer: Johnson & Johnson

      • Sales: $9.72 Billion

    3. Eylea (Aflibercept)

      • Manufacturers: Regeneron/Bayer

      • Sales: $9.02 Billion

    4. Skyrizi (Risankizumab)

      • Manufacturer: AbbVie

      • Sales: $7.71 Billion

    5. Ocrevus (Ocrelizumab)

      • Manufacturer: Roche

      • Sales: $6.42 Billion

Drug Development Process Stages

  • Key steps in the Drug Development Process:

    • Screening leads

    • Process Development

    • Formulation/Stability

    • Preclinical File and IND/CTC (Investigational New Drug/Clinical Trial)

    • Phases: I, II, III

  • Financial Aspects:

    • Cost and Time to Market:

      • Generic Biologics:

      • Cost: $2-3 Million

      • Time: 2-3 years

      • Biosimilars:

      • Cost: $100-300 Million

      • Time: 7-8 years

      • Traditional New Biologics:

      • Cost: $800 Million - $1 Billion

      • Time: 8-10 years

FDA Organizational Structure

  • Key Divisions:

    • Commissioner’s Office (OC)

    • Center for Drug Evaluation and Research (CDER)

    • Center for Biologics Evaluation and Research (CBER)

    • Office of Medical Products and Tobacco (OMPT)

    • Office of Global Regulatory Operations & Policy (OGROP)

    • Center for Devices and Radiological Health (CDRH)

    • Center for Tobacco Products (CTP)

Biologics EMA Structure

  • European Medicines Agency (EMA) Committees:

    • Committee for Human Medicinal Products (CHMP)

    • Committee for Veterinary Medicinal Products (CVMP)

    • Paediatric Committee (PDCO)

    • Committee for Herbal Medicinal Products (HMPC)

    • Committee for Orphan Medicinal Products (COMP)

    • Pharmacovigilance Risk Assessment Committee (PRAC)

    • Committee for Advanced Therapies (CAT)

Structure-Based Drug Design

  • Definition:

    • Structure-based drug design is the relationship between the chemical or 3D structure of a molecule and its biological activity.

  • Key Considerations:

    • Utilizes crystal structures of target proteins and ligands

    • Improves specificity and reduces side effects

Multiple Choice Questions (MCQs)

  • Q1: Structure-based drug design is associated with what?

    • a. Chemical or 3D structure of a molecule and its biological activity.

    • b. Ligand co-crystallization with target protein.

    • c. Uses a natural mediator as the lead compound.

    • d. Not a good starting point.

    • e. Cannot be confirmed by site-directed mutagenesis.

  • Q2: What is a plausible clinical consequence for a patient with renal failure after intravenous cefepime?

    • a. Stomach cramps and vomiting

    • b. Loss of antibacterial action

    • c. Increased renal clearance

    • d. No major effect

    • e. Reduced renal circulation

  • Q3: Characterize the open-label randomized clinical trial for Crizotinib.

    • a. Only the tester knows patient group.

    • b. Neither knows (blinded trial).

    • c. Randomized study essentials.

    • d. Ensures equal opportunity for results.

    • e. Validates statistical significance.

  • Q4: Identify the clinical trial phase for Crizotinib.

    • a. Phase 1a

    • b. Phase 1b

    • c. Phase 2a

    • d. Phase 2b

    • e. Phase 3