Drug Repurposing Strategies: Finding New Uses for Existing Drugs

Introduction

Drug repurposing—also known as drug repositioning or drug reprofiling—is the process of identifying new therapeutic uses for existing drugs that have already been approved or have undergone significant clinical development. In an era where the average cost of developing a new drug exceeds $2 billion and timelines stretch over a decade, drug repurposing offers a compelling alternative path to delivering new treatments to patients more quickly and at lower cost.

The rationale for drug repurposing is straightforward: approved drugs have already demonstrated acceptable safety profiles in humans, have established manufacturing processes, and have well-characterized pharmacokinetic and pharmacodynamic properties. By leveraging this existing knowledge, repurposing can reduce development timelines by 3–5 years and substantially decrease development costs. This article explores the major strategies, computational approaches, clinical success stories, and challenges of drug repurposing. For exploring existing drug databases for repurposing opportunities, visit the CodeDrug database.

Why Drug Repurposing Matters

The Economics of Traditional Drug Discovery

Traditional de novo drug discovery follows a linear pipeline from target identification through lead optimization, pre-clinical studies, and clinical trials. This process is characterized by:

• High attrition rates: Approximately 90% of drug candidates entering clinical trials fail to reach approval
• Long timelines: 10–15 years from discovery to market
• Enormous costs: $2–3 billion per approved drug (including cost of failures)
• Limited novelty: Many approved drugs belong to established mechanistic classes

Advantages of Drug Repurposing

Drug repurposing addresses several of these challenges:

• Reduced risk: Safety data from prior human use significantly de-risks the development process
• Faster development: Skipping early-phase safety trials can save 3–5 years
• Lower costs: Estimated development costs of $300–500 million, compared to $2+ billion for novel drugs
• Existing manufacturing: Established supply chains and formulations can be adapted
• Regulatory familiarity: Prior regulatory history simplifies the approval pathway

Strategies for Drug Repurposing

Activity-Based Approaches

Phenotypic Screening of Approved Drugs

Systematic screening of approved drug libraries against disease-relevant phenotypic assays has yielded numerous repurposing successes. By testing existing drugs in cell-based or organism-based disease models, researchers can serendipitously discover unexpected therapeutic activities. The advantages include:

• Physiological relevance: Phenotypic assays capture the complexity of disease biology
• Novel mechanism discovery: Can uncover entirely new mechanisms of action
• Polypharmacology: May identify drugs that act through multiple targets simultaneously

High-Throughput Screening of Compound Collections

Pharmaceutical companies and academic consortia have assembled collections of thousands of approved and clinically tested compounds. High-throughput screening of these libraries against biochemical or cell-based assays enables rapid identification of hits with new activities.

Computational Approaches

Drug-Target Network Analysis

Network pharmacology approaches construct bipartite graphs connecting drugs to their known targets and targets to diseases. By analyzing these networks, researchers can identify drugs whose targets are connected to new disease indications. Methods include:

• Network proximity analysis: Measuring the distance between drug target proteins and disease-associated proteins in the human interactome
• Module-based approaches: Identifying drugs that target proteins within disease-associated network modules
• Random walk algorithms: Predicting new drug-disease associations by traversing drug-target-disease networks

Transcriptomic Signature Matching

The Connectivity Map (CMap) and Library of Integrated Network-Based Cellular Signatures (LINCS) programs have generated gene expression signatures for thousands of compounds across multiple cell lines. The repurposing logic is based on the principle that:

• Drugs that reverse the disease signature (negative connectivity) are therapeutic candidates
• Drugs that mimic the disease signature (positive connectivity) may exacerbate the condition

This approach has successfully identified repurposing candidates for various cancers, inflammatory diseases, and infectious diseases.

Structure-Based Virtual Screening

When the three-dimensional structure of a disease-relevant protein is available, computational docking can screen approved drug libraries for potential binding. This approach is particularly efficient because:

• The chemical space is limited to known, safe compounds
• Docking algorithms can evaluate thousands of compounds rapidly
• Structural insights guide hypothesis generation

Machine Learning and AI

Artificial intelligence is increasingly applied to drug repurposing:

• Deep learning models: Predict new drug-disease associations from heterogeneous data (chemical structures, genomic data, clinical records)
• Knowledge graph embeddings: Learn vector representations of drugs and diseases from biomedical knowledge graphs to predict novel associations
• Natural language processing: Mine biomedical literature and electronic health records for repurposing signals

Clinical Success Stories

Sildenafil: From Angina to Erectile Dysfunction

Perhaps the most famous drug repurposing story, sildenafil was originally developed by Pfizer as a treatment for angina pectoris. During Phase I clinical trials, healthy volunteers reported an unexpected side effect: penile erections. Recognizing the clinical potential, Pfizer pivoted the development program, and sildenafil (Viagra) was approved for erectile dysfunction in 1998. The drug has since generated over $30 billion in revenue and was later repurposed again as Revatio for pulmonary arterial hypertension.

Thalidomide: From Tragedy to Therapeutic

Thalidomide represents one of the most dramatic stories in pharmaceutical history. Originally prescribed as a sedative and anti-nausea medication for pregnant women in the 1950s, it caused devastating birth defects and was withdrawn in 1961. Decades later, thalidomide was repurposed as an immunomodulatory and anti-angiogenic agent for multiple myeloma and erythema nodosum leprosum. Its derivative, lenalidomide, has become a cornerstone of multiple myeloma treatment.

Other Notable Examples

Drug	Original Indication	Repurposed Indication	Year
Aspirin	Analgesic/anti-inflammatory	Anti-platelet/cardiovascular protection	1980s
Minoxidil	Hypertension	Hair loss (alopecia)	1988
Duloxetine	Depression	Stress urinary incontinence, fibromyalgia	2004
Ketoconazole	Antifungal	Cushing’s syndrome	2007
Raloxifene	Osteoporosis	Breast cancer risk reduction	2007
Metformin	Type 2 diabetes	Cancer prevention, PCOS, anti-aging research	Ongoing
Remdesivir	Ebola (failed)	COVID-19	2020

Emergency Repurposing During COVID-19

The COVID-19 pandemic catalyzed unprecedented drug repurposing efforts. Within months of the outbreak, researchers worldwide screened approved drug libraries for activity against SARS-CoV-2. While many repurposing attempts failed (notably hydroxychloroquine), remdesivir—originally developed for Ebola—received emergency use authorization and full approval for COVID-19 treatment, demonstrating the potential of repurposing in public health emergencies.

Challenges and Limitations

Intellectual Property and Commercial Viability

Repurposing approved drugs faces significant commercial challenges:

• Patent expiration: Many repurposing candidates are off-patent, reducing commercial incentive
• Method-of-use patents: While new indications can be patented, enforcement is difficult when the drug is available generically for other uses
• Off-label prescribing: Physicians may prescribe off-label before a repurposing program reaches approval, undermining commercial returns

Dosing and Formulation Challenges

A drug repurposed for a new indication may require different dosing or formulation:

• Dose differences: The optimal dose for the new indication may differ significantly from the approved dose
• Route of administration: A new indication may require a different delivery route (e.g., topical vs. oral)
• Patient population: Safety and efficacy may differ in the new patient population, requiring dedicated clinical trials

Regulatory Considerations

While repurposing leverages existing safety data, regulatory requirements remain substantial:

• New indications typically require Phase II and Phase III clinical trials demonstrating efficacy
• FDA approval for the new indication requires a supplemental NDA/BLA
• Safety data may need updating if the new indication involves different patient populations or dosing

Systematic and Institutional Approaches

Academic Drug Repurposing Initiatives

Several academic and non-profit initiatives are dedicated to systematic drug repurposing:

• NCATS (National Center for Advancing Translational Sciences): Supports repurposing programs through funding and compound access
• Broad Institute Drug Repurposing Hub: A curated collection of over 6,000 compounds for screening
• REDOX Drug Repurposing Hub: Focuses on rare diseases where commercial incentives are limited

Pharmaceutical Industry Engagement

Pharmaceutical companies are increasingly adopting repurposing as part of their R&D strategy, particularly for:

• Expanding indications for existing pipeline drugs
• Rescuing failed clinical candidates for new indications
• Leveraging existing safety data to enter new therapeutic areas

Future Directions

Integration with Emerging Technologies

• Multi-omics data integration: Combining genomic, transcriptomic, proteomic, and metabolomic data to identify repurposing opportunities
• Real-world evidence: Mining electronic health records and insurance claims data to identify unexpected therapeutic effects
• Organ-on-chip models: Testing approved drugs on disease-relevant microphysiological systems
• AI-driven prediction: Increasingly sophisticated models predicting drug-disease associations from multimodal data

Orphan Disease Focus

Drug repurposing is particularly valuable for rare and neglected diseases, where traditional drug development is economically unfeasible. By repurposing approved drugs, researchers can bring therapies to underserved patient populations at a fraction of the traditional cost.

Conclusion

Drug repurposing has evolved from a serendipitous endeavor to a systematic, data-driven strategy that complements traditional drug discovery. The integration of computational approaches, high-throughput screening, and clinical data mining has created a robust framework for identifying new therapeutic uses for existing drugs. While challenges in intellectual property, dosing, and regulatory pathways persist, the economic and temporal advantages of repurposing make it an increasingly attractive strategy—particularly for rare diseases, public health emergencies, and precision medicine applications. As AI technologies and multi-omics data continue to expand the scope of computational repurposing, we can expect this approach to deliver an increasing number of new therapeutic options for patients. For researchers exploring repurposing opportunities, the CodeDrug database and research tools provide comprehensive drug information and analytical capabilities.