Drug repurposing: the solution might be closer than we think

By Emma Snijders

When Sars-CoV-2 spread at the beginning of 2020, scientists started screening libraries full of drugs for possible treatments. This was the moment when the general public was introduced to drug repurposing. Drug repurposing is the use of existing drugs for a medical condition that is different from what they were originally developed to treat. Repurposing is something that scientists have done for a long time but in recent years, has raised more interest from the public and become more popular with scientists and pharmaceutical companies. Drug repurposing has multiple success stories. For instance, Aspirin, which was initially used for the treatment of pain, fever, or inflammation was repurposed and is now also being used for the treatment of cardiovascular disorders. Another success story is seen with Viagra, which was originally developed to treat hypertension and a heart condition, angina pectoralis, but is now used to treat erectile dysfunction ¹.

Why should we repurpose drugs?

Despite efforts by the government and companies, the number of newly approved drugs by the European Medicines Agency (EMA) remains constant with around 40 newly approved drugs each year ². In Figure 1, the exact number of newly approved drugs per year can be found. Drug repurposing allows to fulfill unmet medical needs and might be a solution for neglected and rare diseases. With the rapid increase in interest in drug repurposing, the question is raised if we can teach old drugs new tricks. Only 10% of newly discovered drug-like molecules make it to market ³. The reasons why so few drugs make it to the market are, amongst others, high toxicity, unmanageable side effects, and lack of efficacy for the intended disease the drug was developed for. For the medicines that are approved by the EMA, the costs for research and development of new drugs are enormous and range from millions to billions of euros. These high costs not only make development a risky venture for the company but also make the final approved medicine costly for the patient once the drug is on the market. However, the increases in investment in drug development have not led to an increase in the number of approved drugs by the EMA. For these reasons, research increasingly focuses on drug repurposing. This can be a possible solution for this problem by using drug-like molecules that left the drug discovery pipeline early and giving it a new target or by using existing drugs and coupling it to other diseases. This way we can teach old drugs new tricks.

The Valley of Death kills many drugs

The process of Research & Development (R&D) of new drugs follows the drug discovery pipeline which consists of the following steps. First, we should find compounds that work against the disease. Then, the drug-like molecule undergoes pre-clinical testing to answer questions about its safety. In this phase, the focus is on exploring the possible side effects via studies in animals. Thirdly, clinical trials are performed to test for effectiveness and safety in patients. If the drug-like molecule passes all these steps it is approved by the EMA.  After these steps the developments do not stop: the fifth and final step is post-market safety monitoring. The complete picture of the drug’s safety evolves over the months and years after approval, often when the drug is already on the market. The EMA continuously monitors for problems, such as side effects, with drugs that are on the market are continuously monitored by the EMA and if necessary cautions to the dosage and usage information are added ⁴. 

To cross the development pipeline and make it from bench to bedside, drugs need to pass the ‘valley of death’ also known as the translational gap. The valley of death and the drug discovery pipeline is visualized in Figure 2. It gets its name from the fact that most drug-like molecules cannot proceed from the discovery phase to clinical trials. This could be due to reasons such as a lack of biological activity against the specific disease the drug was developed for or a lack of investments to bring the drug to the market ⁵. The latter is especially seen in neglected and rare diseases. If the target patient group is smaller, it is harder for pharmaceutical companies to make a profit from their investment ⁶. 

Drug repurposing can play a major role in overcoming the valley of death. If drugs make it through phase 1 of the clinical trials, they are tolerable for humans. After this, phase 2 follows which is known as the ‘edge of the valley of death’. Drugs that fail this phase due to insufficient efficacy or lack of commercial viability are excellent candidates for repurposing⁵. 

The funnel of drug repurposing

Repurposing drugs is faster than developing new ones. The process of drug repurposing only takes 5 to 10 years instead of 13-15 years for conventional drug discovery. By repurposing drugs instead of discovering new ones the developmental phase and phase 1 clinical trials are skipped. If we add up the number of drugs that are currently approved and on the market, to the number of drugs that fail phase 2 clinical trials there are thousands of candidates for repurposing ⁷. However, from the thousands of candidates, a selection needs to be made with potential drugs for repurposing.

There are three steps for drug repurposing: identification of the candidates, testing in preclinical models, and lastly evaluation of efficacy in phase 2 clinical trials ⁸. The identification of drug candidates for repurposing is done through computational or experimental approaches. Figure 3 gives a flowchart of the steps of both approaches.

The computational approach allows researchers to rapidly screen large libraries of drugs and determine their potential binding through modeling and visualization techniques. Computational drug repurposing can be drug-oriented or disease-oriented. In both cases, researchers need to explore publicly available resources for potential drugs to be repurposed. The mining of data and validation of computational models results in a prediction of the therapeutic potential of the drug for a specific disease ⁹. For the experimental approach, there are also two strategies. The first  is based on a known target that the drug should act on. In the second approach, the target is unknown but the desired effect is known. If this is the case, screening is performed to select compounds with the desired effect on, for instance, the development of the disease ¹⁰. After the selection of candidates for repurposing they are tested in pre-clinical models and later on in phase 2,3 and 4 clinical trials. There is an increasing interest in combining computational and experimental approaches.

Setbacks in drug repurposing

Repurposing saves a lot of costs and time since extensive pre-clinical testing is already done and only a selection of potential candidates needs to be made. However, this approach still costs millions of euros and often requires collaborations between the pharmaceutical industry and researchers. Out of the thousands of candidates for repurposing, only a few candidates make the selection. The failure rate of repurposed drugs in phase 2 and 3 clinical trials is as high as the failure rate of newly synthesized compounds ⁵. This shows that no drug is safe from failing in the valley of death even in phase 2 and 3 clinical trials. 

Drug repurposing has many positives but it only reduces and does not eliminate the risks of drug development. To be successful in drug repurposing, multiple barriers need to be overcome. A crucial step in drug repurposing is the screening of compound databases for possible candidates. Unfortunately, Most researchers and companies only publish the data of successful compounds and clinical trials. The data of these shelved and abandoned compounds often disappear and are never published. Therefore, these databases rarely contain shelved compounds and often data from previously performed clinical trials is missing. Besides limited data access, intellectual property rights play an important role, too. Big pharmaceutical companies often even patent shelved compounds that failed because of, for instance, unsuccessful clinical trials. This prevents others from using the compounds without a license ^{11 12}. All of this is hindering the possibilities of drug repurposing.

Besides all the setbacks in drug repurposing, this is the time to call for action and explore drug repurposing besides traditional drug discovery. For neglected and rare diseases drug repurposing might be an outcome to expand, if there are any, the current treatment options. Overall repurposed drugs are generally approved sooner than those that are newly discovered and often cost only half the money. Because of these reasons, repurposing can play a more prominent role in drug development in the future, as long as we find regulated ways to overcome setbacks such as intellectual property and data access issues.

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Further reading:

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3. European Medicines Agency. (2023, 30 March). Medicine evaluation figures – European Medicines Agency. Consulted on 24 April 2023, from https://www.ema.europa.eu/en/about-us/what-we-do/authorisation-medicines/medicine-evaluation-figures#:~:text=(2015%2D2022)-,Human%20medicines,89%20new%20medicines ↩︎
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