Drug Discovery Pipeline

The Drug Development Timeline

Bringing a new drug from concept to market typically takes 10-15 years and costs $1-2 billion on average, including the cost of failures. The process follows a sequential pipeline with high attrition at every stage: for every 5,000-10,000 compounds entering discovery, approximately one reaches the market.

The pipeline consists of discovery (3-5 years), preclinical development (1-2 years), clinical trials (6-7 years), and regulatory review (1-2 years).

Discovery Phase Stages

Target identification: Selecting a biological molecule (protein, receptor, enzyme, gene product) whose modulation will alter disease course. Targets emerge from genomic studies, disease biology research, competitor analysis, and clinical observations.

Target validation: Confirming that modulating the target will produce therapeutic benefit. Methods include genetic knockdown/knockout models, tool compounds, human genetic evidence (e.g., loss-of-function mutations that protect against disease), and biomarker studies.

Hit identification: Screening compound libraries against the validated target to identify molecules with measurable activity. High-throughput screening (HTS) tests 100,000-2,000,000 compounds using automated assays. Fragment-based screening uses smaller, simpler molecules (MW 120-250) at higher concentrations. Virtual screening applies computational docking to prioritize compounds.

Hit-to-lead: Confirmed hits are optimized through iterative medicinal chemistry to improve potency, selectivity, and basic drug-like properties. Structure-activity relationships (SAR) guide systematic modification of the chemical scaffold.

Lead Optimization to Candidate

Lead optimization transforms early leads into drug candidates suitable for preclinical development. Medicinal chemists balance multiple parameters simultaneously:

• Potency: IC50/EC50 in the low nanomolar range
• Selectivity: Minimal off-target activity (selectivity panels of 50+ targets)
• ADME properties: Oral bioavailability, metabolic stability, permeability
• Safety: No genotoxicity (Ames test), acceptable hERG liability, clean safety pharmacology
• Physicochemical properties: Lipinski's Rule of Five compliance, solubility, stability

The output is a preclinical candidate (PCC) with a complete data package supporting advancement to GLP toxicology studies and IND-enabling work.

Attrition and Failure Modes

Most drug programs fail. Common failure points include:

• Lack of efficacy (40-50% of Phase II failures): Target hypothesis was wrong or compound exposure was insufficient
• Safety/toxicity (30% of failures): Unacceptable adverse effects in animals or humans
• Pharmacokinetic issues (10%): Poor oral absorption, rapid metabolism, distribution problems
• Commercial/strategic (10-15%): Market changes, competitor approvals, portfolio prioritization

De-risking strategies include biomarker-driven patient selection, adaptive trial designs, and platform technologies that accelerate screening cycles.

Key Takeaways

• Drug discovery spans 10-15 years with >99.9% compound attrition
• Target validation using human genetic evidence reduces late-stage failure risk
• Lead optimization balances potency, selectivity, ADME, and safety simultaneously
• Lack of efficacy is the leading cause of clinical-stage drug program failure