15.3 Drug development process for antivirals

Antiviral drug development is a complex journey from target identification to market approval. It involves rigorous testing, from lab experiments to large-scale human trials, ensuring new treatments are safe and effective against viral infections.

The process combines cutting-edge science with stringent regulatory oversight. Researchers use advanced techniques to discover potential drugs, then carefully evaluate them through preclinical and clinical stages before seeking approval for widespread use.

Antiviral Drug Development Process

Stages of Drug Development

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• Drug development process consists of five main stages
  • Target identification and validation
  • Lead compound discovery
  • Preclinical studies
  • Clinical trials
  • Regulatory approval and post-market surveillance
• Target identification determines specific viral proteins or processes to inhibit viral replication
• Lead compound discovery uses methods to identify potential antiviral molecules
  • High-throughput screening
  • Structure-based drug design
  • Repurposing existing drugs
• Preclinical studies assess safety and efficacy in cell culture and animal models
  • Evaluate pharmacokinetics, pharmacodynamics, and toxicity
• Clinical trials conducted in three phases to evaluate in humans
  • Phase I: Safety and tolerability
  • Phase II: Efficacy and optimal dosing
  • Phase III: Large-scale efficacy and safety studies
• Regulatory approval requires submitting comprehensive data for review
• Post-market surveillance monitors long-term safety and effectiveness

Drug Discovery Approaches

• Genomic and proteomic approaches identify potential viral targets
  • Essential viral enzymes (viral polymerases)
  • Structural proteins (viral capsid proteins)
  • Host factors required for viral replication (cellular receptors)
• Structural biology techniques determine 3D structure of viral proteins
  • X-ray crystallography
  • Cryo-electron microscopy
• Functional genomics validate importance of targets in viral life cycle
  • RNA interference (RNAi)
  • CRISPR-Cas9 gene editing
• Computational methods predict drug-target interactions
  • Molecular docking
  • Virtual screening of compound libraries
• Biochemical and cell-based assays assess target function and drug effects
• Animal models validate targets and assess therapeutic potential in vivo

Identifying Antiviral Targets

Target Identification Methods

• Genomic and proteomic approaches identify potential viral targets
  • Analyze viral genomes to find essential genes
  • Study viral proteomes to identify crucial proteins
  • Examples: HIV protease, influenza neuraminidase
• Structural biology determines 3D structure of viral proteins
  • X-ray crystallography provides atomic-level protein structures
  • Cryo-electron microscopy visualizes large protein complexes
  • Examples: HIV envelope protein, coronavirus spike protein
• Functional genomics validate target importance
  • RNA interference silences specific genes to assess their role
  • CRISPR-Cas9 creates precise genetic modifications
  • Examples: Identifying host factors for hepatitis C virus entry

Computational and Experimental Validation

• Computational methods predict drug-target interactions
  • Molecular docking simulates binding of compounds to targets
  • Virtual screening rapidly evaluates large compound libraries
  • Examples: In silico screening for SARS-CoV-2 main protease inhibitors
• Biochemical assays assess target function
  • Enzyme activity assays measure inhibition by drug candidates
  • Protein-protein interaction assays evaluate disruption of viral processes
  • Examples: Fluorescence-based assays for viral polymerase activity
• Cell-based screening systems evaluate drug effects on viral replication
  • Viral reporter systems (GFP-tagged viruses)
  • High-content imaging to visualize viral infection in cells
  • Examples: Screening for Zika virus inhibitors using infected cell lines
• Animal models validate targets in vivo
  • Transgenic mice expressing viral proteins
  • Humanized mouse models for human-specific viruses
  • Examples: Ferret models for influenza, rhesus macaques for HIV

Preclinical and Clinical Trials

Preclinical Studies

• In vitro studies evaluate antiviral activity and mechanism
  • Assess cytotoxicity in various cell lines
  • Determine selectivity index (therapeutic window)
  • Examples: Plaque reduction assays, viral yield reduction assays
• Animal studies assess drug properties and efficacy
  • Evaluate pharmacokinetics (absorption, distribution, metabolism, excretion)
  • Measure pharmacodynamics (dose-response relationships)
  • Assess toxicity through acute and chronic exposure studies
  • Test efficacy in animal models of viral infection
  • Examples: Mouse models for hepatitis B, ferret models for influenza

Clinical Trial Phases

• Phase I trials focus on safety and pharmacokinetics
  • Conducted in healthy volunteers or sometimes patients
  • Determine maximum tolerated dose and side effects
  • Evaluate drug absorption, distribution, and elimination
  • Examples: Single ascending dose studies, multiple ascending dose studies
• Phase II trials assess efficacy and optimal dosing
  • Conducted in patients with target viral infection
  • Compare to existing treatments or placebo
  • Determine most effective dose and treatment duration
  • Examples: Randomized controlled trials in hepatitis C patients
• Phase III trials confirm efficacy and safety in large populations
  • Large-scale, multi-center randomized controlled studies
  • Evaluate drug in diverse patient populations
  • Gather data for regulatory approval
  • Examples: Global trials for COVID-19 vaccines and antivirals
• Ongoing safety monitoring throughout clinical trials
  • Pharmacovigilance identifies adverse effects
  • Evaluate potential drug interactions
  • Examples: Regular blood tests, electrocardiograms, patient-reported outcomes

Regulatory Approval for Antivirals

Regulatory Requirements and Documentation

• Comprehensive documentation required for approval
  • Preclinical data on safety and efficacy
  • Clinical trial results from all phases
  • Manufacturing information and quality control measures
• Investigational New Drug (IND) application initiates clinical trials
  • Submitted to regulatory agencies (FDA, EMA)
  • Details preclinical data and proposed clinical protocols
  • Examples: IND submissions for novel influenza antivirals
• Good Laboratory Practices (GLP) ensure data quality
  • Standardized protocols for preclinical studies
  • Proper documentation and record-keeping
• Good Manufacturing Practices (GMP) maintain product consistency
  • Quality control measures for drug production
  • Examples: Sterility testing, batch release criteria

Approval Process and Post-Marketing Surveillance

• New Drug Application (NDA) or Biologics License Application (BLA) for approval
  • Includes detailed safety and efficacy data
  • Manufacturing processes and proposed labeling
  • Examples: NDA for remdesivir as COVID-19 treatment
• Regulatory agencies may require additional studies
  • Address specific safety concerns
  • Evaluate long-term effects of antivirals
  • Examples: Post-approval studies on cardiovascular effects of HIV medications
• Expedited approval pathways for urgent needs
  • Fast Track designation for serious conditions
  • Breakthrough Therapy designation for substantial improvements
  • Emergency Use Authorization for public health emergencies
  • Examples: EUA for COVID-19 vaccines and treatments
• Post-marketing surveillance monitors real-world use
  • Periodic safety update reports submitted to agencies
  • Adverse event reporting systems
  • Long-term efficacy studies
  • Examples: Monitoring for rare side effects of widely used antivirals