From aspirin to Viagra, the remarkable success of several well-known drugs was only discovered by chance. Originally intended to treat other conditions, these drugs were found to have new therapeutic purposes that we know and use them for today. Now, years later, ‘old’ drugs are increasingly being trialled for different diseases, such as psychiatric medications for the treatment of cancers. How has this concept of drug repurposing been harnessed to treat poorly understood conditions or novel diseases like COVID-19?
“The most fruitful basis for the discovery of a new drug is to start with an old drug.”
Drug repurposing is the process of finding new therapeutic purposes for existing drugs. This relatively recent strategy offers a number of advantages for drug development. While the development of a new drug takes roughly 12 years, along with a small success rate and massive costs, repurposed drugs can take a fraction of that time to reach the market. Using a previously approved drug with a good clinical safety profile can fast-track early safety testing if the same drug delivery route is used. Less time means less money, and so the process is far cheaper overall.[1] Drug repurposing also provides an alternate approach for the treatment of novel or rare diseases, and conditions that lack effective treatments. As the Nobel laureate pharmacologist James Black once said, “The most fruitful basis for the discovery of a new drug is to start with an old drug.”
The first instances of successful drug repurposing were mainly the result of serendipitous discoveries. The oldest example is aspirin, which was initially marketed only as an analgesic (painkiller). Although aspirin is widely used for its pain relieving effects, in the 1980s it was also found to inhibit formation of blood clots when a group of patients who were having their tonsils removed experienced increased bleeding. Aspirin is now routinely used as a blood thinner.[2] Another example is Viagra, which was initially intended to treat angina but was reevaluated for the treatment of erectile dysfunction after several volunteers reported persistent erections upon taking the drug.[3] Similarly, the drug Minoxidil was developed to treat hypertension but caused hair growth among patients, leading to the drug’s repurposing for hair loss prevention.[4] Thus, some of the most lucrative discoveries for major pharmaceutical companies were actually discovered by chance.
Since then, drug repurposing has grown in popularity and technological advancements have allowed more systematic, computational approaches to be employed. One fascinating area of research is the repurposing of psychiatric drugs as anticancer agents. For example, a number of psychiatric medications have been shown to have suppressive action against malignant brain tumours, which are among the deadliest of all cancers. The antipsychotic drug chlorpromazine was shown to induce cancer cell death in human gliomas, brain tumours arising from non-neuronal cells called glia.[5] Valproic acid, primarily used for bipolar disorder, epilepsy and migraine, has also demonstrated antiproliferative effects on brain tumours, as have the antidepressants fluoxetine and escitalopram.[6] How these psychiatric drugs produce their antitumour effects is not fully understood but one suggested mechanism of the antipsychotic drugs is through their dopamine receptor blocking action.
Just as psychiatric drugs may have use in treating cancers, the reverse is also being investigated. Initially developed as an anticancer agent by AstraZeneca, the experimental drug Saracatinib is being assessed for its potential in treating the non-motor, psychiatric symptoms of Parkinson’s disease – in particular, the visual hallucinations, which are poorly treated at present and can significantly impact quality of life. While Parkinson’s disease is often characterised by motor dysfunction, such as tremor and rigidity, 40-50% of Parkinson’s
patients experience hallucinations. A phase 1 proof-of-concept study is currently being carried out at King’s College London and, if successful, this repurposed drug could be useful for reducing Parkinson’s disease psychosis as well as making sense of this debilitating and heterogeneous disease.[7] Drug repurposing may help to identify some common targets between certain cancers and psychiatric disorders, thus providing an opportunity to better understand underlying disease pathways. It has been stressed, however, that drug repurposing must not replace the search for novel drugs but rather work alongside and complement drug discovery.[2]
For novel diseases like COVID-19, drug repurposing is an important strategy to explore all therapeutic options. A range of different drug classes are being investigated as potential treatments for COVID-19, including existing antiviral, antiparasitic and antibiotic drugs. The antiviral drug Remdesivir, which was previously developed to treat Ebola virus, works by preventing viruses from replicating in the body and has shown some promise in treating patients with severe COVID-19.[8] Additionally, the Oxford University RECOVERY Trial reported in June 2020 that the steroid dexamethasone could reduce death by up to a third among patients with severe respiratory complications.[9] Martin Landray, Professor of Medicine and Epidemiology at the Nuffield Department of Population Health, University of Oxford, commented that, “COVID-19 is a global disease – it is fantastic that the first treatment demonstrated to reduce mortality is one that is instantly available and affordable worldwide.” These drugs have now been approved for treatment of severe COVID-19 cases in several countries. The urgent need to develop effective treatments quickly during this pandemic has been a reminder that sometimes in order to move forward we need to go back to basics.
Author: Carissa Drake, MSc Pharmacology, New College
References
[1] Pushpakom S., Iorio F., Eyers P.A. et al. Drug repurposing: progress, challenges and recommendations. Nature Reviews Drug Discovery, 2019, 18:41-58.
[2] Jourdan J., Bureau R., Rochais C. & Dallemagne P. Drug repositioning: a brief overview. Journal of Pharmacy and Pharmacology, 2020, 72:1145-1151.
[3] Renaud R. & Xuereb H. Erectile-dysfunction therapies. Nature Reviews Drug Discovery, 2002, 1:663-664.
[4] Ishida J., Konishi M., Ebner N. & Springer J. Repurposing of approved cardiovascular drugs. Journal of Translational Medicine, 2016, 14:1-15.
[5] Shin S.Y., Lee K.S., Choi Y. et al. The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/mTOR pathway in human U-87MG glioma cells. Carcinogenesis, 2013, 34(9):2080–2089.
[6] Z Zhuo C., Xun Z., Hou W., et al. Surprising anticancer activities of psychiatric medications: old drugs offer new hope for patients with brain cancer. Frontiers in Pharmacology, 2019, 10(1262).
[7] SRC Inhibition as a Potential Target for Parkinson's Disease Psychosis (SCRIPT), https://clinicaltrials.gov/ct2/show/NCT03661125; ClinicalTrials.gov Identifier: NCT03661125
[8] Low Z.Y., Farouk I.A. & Lal S.K. Drug repositioning: new approaches and future prospects for life-debilitating diseases and the COVID-19 pandemic outbreak. Viruses, 2020, 12(1058).
[9] The Recovery Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. The New England Journal of Medicine, 2020, NEJMoa2021436.