Drug Repurposing: The Discovery of New Uses for Existing Pharmaceutical Drugs

Drug repurposing involves the process of identifying and making available to patients an active pharmaceutical ingredient (pharmaceutical drug) that is already approved by health authorities regarding its safety and efficacy, to treat a different disease than that for which the drug was originally approved (Ashburn and Thor, 2004). Instead of developing a new medicine (pharmaceutical drug), researchers and pharmaceutical companies explore the potential of existing drugs to treat different diseases or medical issues. In early 2020, as the global spread of SARS-CoV-2 (coronavirus) emerged, medical professionals and scientists promptly turned their attention towards identifying drugs that could fight the coronavirus and its deadly symptoms. Consequently, hundreds of clinical trials were initiated with the aim of repurposing existing drugs from the vast pharmaceutical arsenal to combat COVID-19 (Vaz, Vassiliades et al. 2023). The history of medicine has been marked by several examples of drug repurposing, and some concepts, advantages, and challenges related to this strategy will be discussed below.

Definition and Scientific Basis of Drug Repurposing

Drug repurposing (also referred to as drug repositioning or drug reprofiling) is a drug discovery strategy in which an existing approved drug can be utilized as a therapeutic agent for a different disease than the one for which it is already used (Ashburn and Thor, 2004). However, before delving further into this drug discovery strategy, we first need to understand the steps involved in developing a new medicine. During drug development, there are important steps to test the safety and efficacy of pharmaceutical drugs in human subjects (clinical trials), which normally comprise four phases (Figure 1).

Figure 1. Clinical trial development diagram. Clinical studies consist of preclinical and clinical phases, each serving a specific purpose in the drug development process. Preclinical studies involve laboratory and animal testing. The clinical phase involves testing the drug candidate in human subjects and it is divided into four phases.

In phase I, the new drug is tested for the first time in humans to evaluate its safety (e.g., identify side effects, safe dosage range) in a small group of people (e.g., 20–80). In phase II, the drug's safety and efficacy (optimal dosing regimen) are evaluated further in a large cohort (hundreds of subjects), including individuals with the targeted condition. In phase III, efficacy is then studied in large groups of participants (ranging from several hundred to thousands). The new drug is compared with standard or similar treatments, adverse effects are monitored, and substantial evidence of efficacy and safety is collected for regulatory approval. Phase IV, also called Post-Marketing Surveillance, occurs after the drug is approved and made available to the public. At this stage, researchers track drug safety in the general population, adverse effects associated with widespread use, and optimal use (Zhang, Zhou et al. 2020).

When a drug is approved by a regulatory agency such as the FDA (Food and Drug Administration) and the EMA (European Medicines Agency), information regarding its safety, pharmacokinetics (how the drug is absorbed, distributed, metabolized, and eliminated by the body), and drug formulation (combination of different ingredients to achieve the desired characteristics of the product) is already researched by pharmaceutical companies in the clinical trial, reducing the cost and time required for drug repositioning. Even so, drug repurposing still involves some steps to identify and evaluate the potential new therapeutic uses for an existing drug (Figure 2).

Figure 2. Estimated time and the main steps in drug discovery and drug repurposing. The discovery of a new drug takes 10–17 years and comprises basic discovery, drug design, in vitro and in vivo experimentation (including identifying safety and efficacy), clinical trials and finally drug registration and availability on the market. In contrast, drug repurposing takes only 3–9 years as it can bypass several processes that have been completed for the original disease treatment recommendation (Zhang et al., 2020).

Advantages of Drug Repurposing

Due to the high costs and lengthy timelines associated with new drug discovery and development, repurposing existing drugs to treat common, emerging, or rare diseases has gained considerable attention as it reduces overall development costs and timelines, provides faster patient access to treatments, and accelerates the pace of medical innovation (Pushpakom, Iorio et al. 2019).

The advantages of drug repurposing consist essentially of simplifying regulatory procedures for the introduction of a previously approved medicine on the market, saving cost and time. The process of repurposing drugs takes advantage of pre-existing data, particularly regarding drug safety and toxicity (when a substance can cause harm or damage to the body). This strategy can significantly expedite the initial stages of drug development, resulting in substantial time and cost savings. In fact, compared to the development of entirely new drugs, repositioning can be over 80% cheaper and increase the chances of introducing it on the market by 150% compared with a novel drug (Jourdan, Bureau et al. 2020). This can be very beneficial for patients awaiting treatment, as it ensures the faster availability of medications on the market.

Examples of Repurposed Drugs

The term “drug repurposing” is relatively new and first came to light in the early 2000s (Ashburn and Thor 2004). Some repositioning ideas came from adverse reactions observed by researchers during clinical trials or physicians during clinical practice. Several examples of drug repurposing have been reported, and some of these examples are described below.

Aspirin

The first example of drug repositioning is Aspirin (acetylsalicylic acid), initially marketed in 1899 by Bayer (Sneader 2000) (Figure 3).

Figure 3. Aspirin-Bayer (1899). (Sneader 2000)

Aspirin is an analgesic (relieves pain) and anti‐inflammatory substance that inhibits cyclooxygenase 2 (COX‐2), a molecule involved in the generation of mediators of inflammation and pain. Additionally, aspirin inhibits cyclooxygenase 1 (COX-1), a molecule responsible for the formation of a powerful activator of platelet aggregation (Jourdan, Bureau et al. 2020). Platelets are small cell fragments in the blood that clump together and form a clot to stop bleeding. Platelet aggregation is part of the coagulation system and is an essential mechanism to stop bleeding, but many cardiovascular disorders are linked to abnormal and excessive activation of platelets. While the inhibition of COX‐2 reduces inflammation, the inhibition of COX‐1 has been associated with the adverse effects of Aspirin on the gastrointestinal tract, such as indigestion, stomach aches, and bleeding. However, Aspirin is well tolerated at low doses (<300 mg/day) and can exert its antiplatelet aggregation effect with mild negative side effects on the gastrointestinal tract. Aspirin was repositioned as an antiplatelet aggregation drug in the 1980s and it is still widely used today at low doses to prevent cardiovascular disorders, such as stroke and heart attack (Jourdan, Bureau et al. 2020).

Sildenafil

Sildenafil is a potential antihypertensive drug (reduces blood pressure) that was repurposed before it reached the market. Sildenafil's pharmacological potential as a vasodilator (relaxation of blood vessels) and platelet aggregation inhibitor was investigated in 1985 by Pfizer to treat hypertension (high blood pressure) and angina (chest pain usually caused by insufficient blood flow to the heart muscle). However, during clinical trials, an unexpected side effect emerged as a consequence of vasodilation: penile erections. Sildenafil was available on the market in 1998 under the brand name Viagra® to treat erectile dysfunction. Later, Sildenafil was subsequently repositioned in 2005 at one‐fifth of the dose used in erectile dysfunction to treat pulmonary arterial hypertension (Cruz-Burgos, Losada-Garcia et al. 2021).

Thalidomide

Thalidomide was released in the late 1950s as a nonaddictive, nonbarbiturate sedative (Figure 4). Shortly after, this medicine was prescribed for the treatment of nausea in pregnant women. However, in 1962, thalidomide was withdrawn from the market due to its teratogenicity (ability to cause birth defects or abnormalities), which affected thousands of victims worldwide. In 1964, its efficacy against erythema nodosum leprosum, an autoimmune complication of leprosy was described. Years later, in 1998, Thalidomide was repositioned for complications of leprosy. Its use is accompanied by rigorous contraceptive measures to prevent exposure to the drug during pregnancy (Raje and Anderson 1999, Vargesson 2015).

Figure 4. Structure of thalidomide (A) and packaging (B) marketed in the 1950s. (Vargesson 2015)

Challenges Associated with Drug Repurposing

Repurposing drugs may involve prescribing them for a condition that is not officially approved. This term is known as off-label use, and it refers to the practice of prescribing a drug for a different purpose than what the regulatory agencies (such as the FDA and EMA) approved. The most recent example of off-label use was during the COVID-19 pandemic when thousands of people used drugs that were still undergoing clinical testing for the treatment of COVID-19, resulting in a high risk of toxicity and adverse effects (Vaz, Vassiliades et al. 2023).

Another challenge associated with drug repurposing is the absence of intellectual property protection, which can deter potential investment in drug repurposing projects. Many drugs that are being considered for repurposing have had their patent protection expired. Due to the lack of intellectual property protection, the finances for new treatment use may be constrained for pharmaceutical companies to invest in clinical trials and the regulatory processes required, reducing their return on investment and discouraging companies from developing them (Krishnamurthy, Grimshaw et al. 2022).

As mentioned above, repurposed drugs may face additional regulatory challenges. The existing data on a certain drug collected during a clinical trial may not be sufficient to meet the regulatory standards for treating another disease. For instance, the safety profile required for a drug is based on balancing the desired effects, or 'benefits', against its undesired effects (adverse effects), or 'risks'. Thus, the adverse effect of a drug being acceptable or not is based on its gravity and the severity of the condition being treated (for instance, in the context of a life-threatening disease such as cancer). When a drug with severe side effects is repositioned for a disease that is less severe, the adverse effects will be proportionately less acceptable. Any modification in the formulation, dosage, or route of administration of a drug necessitates a thorough reassessment of its safety profile within the context of these new conditions. Even if the active substance remains the same, changes in formulation or administration can impact the drug's absorption, distribution, metabolization, and elimination by the body, and can favour potential interactions with other substances, thereby necessitating additional tests (Jourdan, Bureau et al. 2020). The requirement for additional clinical trials and data can lengthen the development process and increase costs.

Conclusions

Drug repurposing is a relatively new concept that holds significant value in the field of drug development. Repurposing "old" drugs to treat emerging, rare, or common diseases is becoming an increasingly attractive proposition as it reduces overall development costs and timelines, accelerating access to treatments. A number of repurposing drugs have been successfully used for therapeutic purposes, but the drug repositioning process must be rigorous and ensure patient safety as a fundamental principle to guarantee the best result with the maximum benefit for the population. Furthermore, most drug development is supported by the pharmaceutical industry for commercial reasons, which makes it more difficult to repurpose drugs due to financial and regulatory obstacles. Therefore, new specific funding programs for drug repurposing initiatives should be encouraged by the government, philanthropic organizations, and pharmaceutical companies to encourage research in this area.

References

Ashburn, T. T. and K. B. Thor (2004). "Drug repositioning: identifying and developing new uses for existing drugs." Nat Rev Drug Discov 3(8): 673-683. https://doi.org/10.1038/nrd1468

Cruz-Burgos, M., A. Losada-Garcia, C. D. Cruz-Hernandez, S. A. Cortes-Ramirez, I. Camacho-Arroyo, V. Gonzalez-Covarrubias, M. Morales-Pacheco, S. I. Trujillo-Bornios and M. Rodriguez-Dorantes (2021). "New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil." Front Oncol 11: 627229. https://doi.org/10.3389/fonc.2021.627229

Jourdan, J. P., R. Bureau, C. Rochais and P. Dallemagne (2020). "Drug repositioning: a brief overview." J Pharm Pharmacol 72(9): 1145-1151. https://doi.org/10.1111/jphp.13273

Krishnamurthy, N., A. A. Grimshaw, S. A. Axson, S. H. Choe and J. E. Miller (2022). "Drug repurposing: a systematic review on root causes, barriers and facilitators." BMC Health Serv Res 22(1): 970. https://doi.org/10.1186/s12913-022-08272-z

Pushpakom, S., F. Iorio, P. A. Eyers, K. J. Escott, S. Hopper, A. Wells, A. Doig, T. Guilliams, J. Latimer, C. McNamee, A. Norris, P. Sanseau, D. Cavalla and M. Pirmohamed (2019). "Drug repurposing: progress, challenges and recommendations." Nat Rev Drug Discov 18(1): 41-58.

Raje, N. and K. Anderson (1999). "Thalidomide--a revival story." N Engl J Med 341(21): 1606-1609. https://doi.org/10.1038/nrd.2018.168

Sneader, W. (2000). "The discovery of aspirin: a reappraisal." BMJ 321(7276): 1591-1594. https://doi.org/10.1136/bmj.321.7276.1591

Vargesson, N. (2015). "Thalidomide-induced teratogenesis: history and mechanisms." Birth Defects Res C Embryo Today 105(2): 140-156. https://doi.org/10.1002/bdrc.21096

Vaz, E. S., S. V. Vassiliades, J. Giarolla, M. C. Polli and R. Parise-Filho (2023). "Drug repositioning in the COVID-19 pandemic: fundamentals, synthetic routes, and overview of clinical studies." Eur J Clin Pharmacol 79(6): 723-751. https://doi.org/10.1007/s00228-023-03486-4

Zhang, Z., L. Zhou, N. Xie, E. C. Nice, T. Zhang, Y. Cui and C. Huang (2020). "Overcoming cancer therapeutic bottleneck by drug repurposing." Signal Transduct Target Ther 5(1): 113. https://doi.org/10.1038/s41392-020-00213-8

Visual Sources

Cover Image: Rose Wong (2021), Is drug repurposing worth the effort?, (Image), https://cen.acs.org/pharmaceuticals/drug-discovery/Is-drug-repurposing-worth-the-effort/99/i3

Figure 1: The MS Australia Clinical Trials Network (2023), What are clinical trials?, (Diagram), https://mstrials.org.au/what-are-clinical-trials/

Figure 2: Zhang et al. (2020), Overcoming cancer therapeutic bottleneck by drug repurposing, (Diagram), Signal Transduct Target Ther, https://doi.org/10.1038/s41392-020-00213-8

Figure 3: Sneader, W. (2000), The discovery of aspirin: a reappraisal (Image), BMJ, https://doi.org/10.1136/bmj.321.7276.1591

Figure 4: Vargesson, N. (2015), Thalidomide-induced teratogenesis: history and mechanisms (Image), Birth Defects Res C Embryo Today, https://doi.org/10.1002/bdrc.21096