In the ever-evolving world of pharmaceuticals, an intriguing strategy has gained traction: drug repositioning. Also known as drug repurposing, reprofiling, redirecting, or switching— this approach involves finding new uses for existing medications. While it comes with its own set of challenges, drug repositioning offers several advantages, including a potential solution to the current slowdown in new drug discovery.
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The Emergence of a Game-Changing Concept
Although not entirely new, drug repositioning as a formal concept gained recognition relatively recently. Jourdan et al. (1) trace its emergence to a 2004 article by Ashburn and Thor (2). These pioneers defined drug repositioning as the process of identifying novel applications for existing drugs, often (but not always) after they become generic.
Since then, the concept has expanded. Today, it encompasses not only marketed drugs but also compounds that didn't make it through clinical trials due to toxicity or lack of efficacy, as well as medications withdrawn for safety reasons. However, it's important to note that substances that haven't undergone any clinical investigation don't fall under this umbrella.
Looking at Dimensions to see the trend of the publications and clinical trials in the context of drug repositioning reveals a clear upward trend (caused by covid but even without the covid spike) with 2024 figures already more than double than the 2019 figures in both publications and clinical trials.
The Double-Edged Sword of Drug Repositioning
While drug repositioning offers exciting possibilities, it's not without its hurdles. One of the main challenges lies in intellectual property protection. Since the drug in question has already been patented as a new chemical entity, companies can only protect their repositioned product with a new application patent, possibly supported by a novel formulation process. These patents tend to be narrower in scope, potentially limiting the therapeutic uses they cover.
This limitation can significantly impact the return on investment, potentially discouraging pharmaceutical companies from pursuing repositioning projects. Despite this obstacle, many in the industry see the potential benefits outweighing the risks, especially given the current challenges in developing entirely new drugs.
By reimagining the potential of existing medications, drug repositioning offers a promising path forward in pharmaceutical innovation. It challenges us to look at old drugs with new eyes, potentially uncovering treatments that have been hiding in plain sight all along.
Aspirin: A Case Study in Drug Repositioning
The journey of acetylsalicylic acid, commonly known as aspirin, serves as a compelling example of successful drug repositioning. Originally introduced by Bayer in 1899 as an analgesic, aspirin's potential extended far beyond its initial purpose, showcasing the power of reevaluating existing medications.
In the 1980s, aspirin underwent its first major repositioning. Researchers discovered that at low doses, it could function as an antiplatelet aggregation drug. This groundbreaking finding led to its widespread use in preventing cardiovascular events, an application that continues to this day. The significance of this discovery was underscored when John Vane was awarded the Nobel Prize in Medicine in 1982 for his work on aspirin's mechanisms.
The science behind aspirin's versatility lies in its interaction with cyclooxygenase enzymes. Its analgesic and anti-inflammatory effects stem from inhibiting cyclooxygenase 2 (COX-2), particularly vascular COX-2. This enzyme plays a crucial role in synthesizing prostaglandins, which generate pain and inhibit platelet aggregation. Interestingly, at low doses (<300 mg/day), aspirin shows partial selectivity for COX-1, exerting its antiplatelet aggregation effect. However, this selectivity diminishes at higher doses due to concurrent COX-2 inhibition.
While aspirin's inhibition of COX-1 is responsible for its beneficial antiplatelet effects, it also contributes to its adverse effects on the gastrointestinal tract. This is because COX-1 is involved in synthesizing prostaglandins that protect the gastrointestinal lining.
The story of aspirin's repositioning doesn't end there. Recent research suggests a potential third act for this versatile drug in oncology. Studies have shown that daily administration of aspirin for at least five years may prevent the development of various cancers, particularly colorectal cancer. This protective effect is thought to result from COX-2 inhibition, which blocks the antiapoptotic effect of COX-2 in malignant cells, thereby promoting their apoptotic death.
Aspirin's journey from a simple pain reliever to a potential cancer preventative illustrates the immense value of drug repositioning. It demonstrates how a single compound, when thoroughly studied and creatively applied, can address multiple medical needs across different therapeutic areas.
Summary
Drug repositioning, the practice of finding new therapeutic uses for existing medications, has gained significant momentum in recent years. While early examples of repositioned drugs often emerged through serendipity, modern technology has revolutionized and accelerated this process.
Advanced information technology, particularly in the realm of data mining, has become a powerful tool for identifying potential candidates for repositioning. By leveraging comprehensive databases, researchers can now define detailed descriptors for both drugs and diseases. This approach, facilitated by sophisticated knowledge graphs like the Dimensions Knowledge Graph, enables the establishment of drug-disease pairs and the construction of predictive models for new therapeutic applications.
The shift towards a more systematic and data-driven approach in drug repositioning promises to uncover novel candidates through a rational and efficient process. This method not only expedites the discovery of new uses for existing drugs but also offers a more targeted and scientifically grounded approach to drug repurposing. As this field continues to evolve, it holds the potential to significantly impact drug development, potentially leading to faster, more cost-effective routes to addressing unmet medical needs.
Outlook
The Dimensions Knowledge Graph, powered by metaphactory, is a powerful tool supporting use cases across the entire pharma value chain, as with drug repositioning and pharmaceutical research. Built upon one of the world's largest linked research databases, it bridges the data divide between private and public data, and can integrate data from millions of publications, patents, grants, clinical trials, and other sources, and public datasets and ontologies covering genomics, proteomics, and pharmacology. This ability to link to global research knowledge and public datasets allows researchers to explore complex relationships between diseases, drugs, and targets, supporting sophisticated computational approaches to drug repurposing – something we'll dive deeper into in a follow-up post.
By providing enriched, contextualized data, the Dimensions Knowledge Graph enables intelligent decision-making in pharma and life sciences, potentially leading to significant discoveries and life-saving drugs. It represents a shift from data-centric to knowledge-centric approaches, offering a clear picture of data's meaning and origin, thus creating a reliable roadmap for critical decisions in pharmaceutical research and development.
Bibliography
1 Jourdan, J.P., Bureau, R., Rochais, C., Dallemagne, P. Drug repositioning: a brief overview, Journal of Pharmacy and Pharmacology, 72, 1145–1151 (2020), https://doi.org/10.1111/jphp.13273
2 Ashburn, T., Thor, K. Drug repositioning: identifying and developing new uses for existing drugs. Nature Reviews Drug Discovery, 3, 673–683 (2004), https://doi.org/10.1038/nrd1468
