In the desperate search for effective antiviral drugs against SARS-CoV2 two existing drugs, hydroxychloroquine and remdesivir, have become household names. Hydroxychloroquine is a drug that was first approved in 1994 and prescribed for rheumatoid and psoriatic arthritis, lupus and as an antimalarial; while remdesevir is a drug developed for the fight against Ebola. So how did these drugs come to be used for the treatment of COVID-19?
In scientific and medical communities this is called “drug repurposing.” Drug repurposing refers to the identification of alternative therapeutic applications for existing or investigational drugs. From a research perspective, exploring repurposing is a common and necessary practice in the fight against emerging and re-emerging infectious diseases, and in the lab both of these drugs demonstrated promising effects against SARS-CoV-2, the virus that causes COVID-19.
Why is drug repurposing so important for infectious diseases?
For more than half a century, our ability to synthesize new drugs has improved rapidly due to technological advancements, such as computational approaches to drug discovery. While there are many efforts directed to finding new therapeutics for communicable and non-communicable diseases, they have faced significant challenges. These include the increasing time lengths in moving newly discovered drugs from the lab bench to bedside (which can take 13-15 years), greater regulatory requirements for approvals, and the resulting cost from both factors (it’s now estimated at $2-3 billion per new drug). Consequently, the number of newly approved drugs per year has been largely flat from the 1950s onwards.
In 2012, researcher Scannell and his colleagues coined the term Eroom’s Law to describe the finding that the number of new drugs approved by the US Food and Drug Administration per billion dollars spent on drug research and development was halved every nine years from 1950 onwards. By contrast, from an infectious diseases standpoint, it is estimated that antimicrobial resistance will result in more than 10 million deaths worldwide and cost more than $100 trillion USD by 2050. This does not account for outbreaks of emerging or re-emerging infectious diseases.
In March 2020, the United Nations Conference on Trade and Development estimated that COVID-19 could repress global annual growth in 2020 to below 2.5% and an estimated $2 trillion in global income. The massive global human health and economic tolls of emerging infectious diseases preclude our ability to rely solely on new drugs to combat disease.
This is where repurposing existing drugs comes in. This strategy helps reduce the time lag and total cost of finding treatments for disease. Licensed drugs also offer the advantage of having been assessed for safety in pre-clinical trials. Both of these factors reduce costs: it is estimated that moving a repurposed drug to market is around $300 million compared to $2-3 billion for a new drug.
Does drug repurposing actually work in the clinic?
Sudeep Pushpakom and colleagues recently reviewed drug repurposing and highlighted multiple successes from this approach. Famously, Sildenafil, originally developed as an antihypertensive drug, was repurposed as Viagra by Pfizer for the treatment of erectile dysfunction. Similarly, the hair loss treatment drug Minoxidil was also originally indicated for treatment of hypertension. Thalidomide, which was originally indicated for morning sickness in 1957 prior to being withdrawn due to links with birth defects, has recently been approved for treatment of Erythema nodosum leprosum and multiple myeloma.
Nonetheless, the use of drug repurposing for combating emerging infectious diseases is still in its relative infancy. While there has been an array of testing, we have seen relatively few successes thus far for infectious disease applications and these have primarily been for parasitic and protozoal diseases. For example, Doxycycline, a tetracycline antibiotic, has found alternative life as an antimalarial drug.
Are repurposed drugs, such as hydroxychloroquine and remdesivir, magic bullets in the fight against COVID-19?
We, and others, have utilized technological advances, including high-throughput drug screening and characterizations of how our cells respond to infection, to identify potential targets for repurposed drugs, including coronaviruses. Considering the concerns raised for new drug development and deployment, for combatting infectious diseases, drug repurposing represents an alternative and viable option. However, what happens in the lab doesn’t always translate well to the clinic. As is the case for hydroxychloroquine and remdesivir, preliminary data out of a number of ongoing clinical trials suggests they are not likely to be our saviors in the fight against COVID-19.
The use of hydroxychloroquine has always remained controversial as it is known to have a high potential for severe side effects. Furthermore, in the rush to get these drugs to the clinic there was little time to conduct animal [JK1] studies on effective dosing, including when and how much to administer, which further complicates the interpretation of the data coming out of the initial trials. For example, if a clinical trial of a high dose of a drug fails because patients are getting sicker from the drug, such was the case for chloroquine in Brazil, can we conclude that there is no potential effective use for the drug against COVID-19? Unfortunately, we cannot make any useful conclusions, but the risks of rushing to any further trials begin to outweigh any potential benefit.
If hydroxychloroquine and remedsivir fail where does this leave us?
There are currently several promising drugs under development in the pipeline. Given the increasing frequency of emerging infectious disease outbreaks, and the devastating human and economic toll that they continue to entail, it is imperative that we identify new approaches that ultimately reduce the time for potentially life-saving drugs to reach the most vulnerable. Drug repurposing for combatting infectious diseases has become a critically important area of biomedical research, and presents a potentially fruitful area for combatting growing global health problems. But even as we search for the fastest way to find a cure for this pandemic and future diseases, we still cannot lose sight of the importance of conducting carefully controlled studies for evaluating new drugs.