Discovering new ways to use existing drugs can happen intentionally or by chance.
Sometimes doctors or patients notice an unexpected beneficial effect of a drug. An example is sildenafil, a drug originally developed to treat severe chest pain caused by coronary heart disease. Although sildenafil failed in clinical trials, researchers noticed that one of its side effects was the induction of erections. This led to its successful rebranding as erectile dysfunction drug Viagra.
Most of the time, when drugs are reused for diseases or conditions for which they were not originally intended, it is done deliberately. As scientists raced to develop treatments for COVID-19, drug redirection has come into the spotlight for good and bad reasons.
As a researcher focused on drug discovery and development, I have seen the potential for redirection and the challenges it faces. Although finding new uses for drugs that have already been tested and approved for safety by the FDA can dramatically reduce development time and cost, financial and logistical hurdles can make it difficult to get to market.
The success of thalidomide
When the redirection is successful, a drug that is ineffective or harmful for one condition can save the life of others.
One such drug is thalidomide, first approved as a treatment for morning sickness. It gained notoriety in the late 1950s when it caused birth defects in an estimated 10,000 infants worldwide, leading to regulatory and drug development changes that included increased developmental toxicity testing . Thalidomide was banned globally in the late 1960s.
In the 1990s, however, researchers discovered that thalidomide inhibits angiogenesis, or the growth of new blood vessels that supply nutrients and oxygen to tumors. Its new use as a treatment for a blood cancer called multiple myeloma has finally achieved clinical and commercial success. This has led to the development of improved versions of the drug that treat cancer with reduced side effects.
Scientists continued to find other therapeutic uses for thalidomide.
When researchers discovered that thalidomide targets a molecule in the body that marks other proteins for destruction, they exploited this feature in an emerging technology called PROTAC. Many drugs work in the body by inhibiting a particular target that produces an adverse effect, usually reversibly and temporarily. PROTACs, on the other hand, are a type of drug that can completely destroy the target. This potentially increases the effectiveness of the drug and reduces the risk of drug resistance.
An example is bavdegalutamide, a PROTAC that combines thalidomide with an inhibitor typically used to treat prostate cancer. This inhibitor works by blocking a target that supplies the tumor with hormones that help it grow. An ongoing phase 2 clinical trial of bavdegalutamide is based on the idea that killing the target would cut off the hormone supply to tumors and stop their growth more effectively than conventional inhibitors.
Researchers currently produce PROTACS often by repurposing existing drugs. With promising results underway, 2021 has seen the launch of a wave of clinical trials testing PROTACs as a treatment for a number of different cancers.
Reassignment for COVID-19
Researchers have used a myriad of drug redirection approaches during the COVID-19 pandemic, ranging from educated guesses to large-scale drug screening and data mining from millions of electronic health records. Regardless of how researchers decide which drugs to reuse, all candidates must demonstrate strong clinical benefit in people before they can be cleared or approved for any proposed new use by the FDA.
My research team and I tested 1,425 FDA-approved drugs in human cells infected with COVID-19 and found 17 candidates for redirection for further investigation. Several of the leads we identified have since entered early clinical trials, including drugs originally intended to treat leprosy and prostate cancer, as well as a milk-derived supplement.
Researchers launched hundreds of clinical studies early in the pandemic to test drug redirection candidates for COVID-19. There have been some notable successes, including the generic antidepressant fluvoxamine, which reduced the risk of hospitalization by 32% in a clinical study. A meta-analysis of fluvoxamine and two other COVID-19 antiviral drugs, molnupiravir and Paxlovid, found that they all provided protective benefits against COVID-19 with comparable safety profiles.
Unlike these newer COVID-19 antivirals, however, fluvoxamine has a 40-year track record of safely treating depression and obsessive-compulsive disorder. Despite this, fluvoxamine has not been cleared for emergency use by the FDA, and the National Institutes of Health says there is insufficient evidence for its use against COVID-19.
The Challenges of Drug Discovery
Successful drug repurposing highlights the difficulty of predicting the off-target effects of new treatments.
Eflornithine, for example, is a drug that has been shown to be ineffective against cancer – but it turns out to inhibit facial hair growth in women and cure a parasitic infection called trypanosomiasis or sleeping sickness. It’s often not immediately obvious why a drug would effectively treat two seemingly different health conditions like these.
There are approximately 2,500 drugs approved by the FDA, and an average of 46 new drugs are approved each year. However, more than 90% of drugs that enter clinical trials fail. This percentage rises to 97% for cancer drugs. Although many shots are needed to produce a viable drug, each failed drug is a candidate for reuse. Researchers like me collected these “failed” compounds for further testing, combing through research papers, patents, and clinical trial databases to find candidates for reuse. Some labs have used artificial intelligence to automate this process.
But it can be difficult to determine which drugs are available for reuse. While a drug development database suggests that there are 47,000 compounds already tested ready for re-use, there is no central repository for this information.
Drug reuse comes up against an intellectual property barrier. Reuse is more accessible with generic drugs that do not have patents limiting their use for other conditions. But there are fewer opportunities for profit with generics than with new drugs.
Patents allow drug suppliers to have a sales monopoly for a period of time. Repurposed drugs typically receive “use patents” that protect the use of an existing drug for a particular new disease. But companies see this kind of protection as less valuable than a “composition of matter” patent that restricts drug sales to patent holders only. An FDA analysis found that a drug with two drug suppliers resulted in an average price reduction of 39%, and six or more suppliers resulted in a 95% reduction. With less patent protection on a drug, more competitors can enter the market and manufacturers make less money.
Because of this perceived lack of market potential, drug repurposing is typically left to academic institutions that lack the resources to obtain new or repurposed drugs through the costly approval process.
It’s possible that if fluvoxamine was a new drug in development with patent protection at a major pharmaceutical company, it would have already obtained FDA approval to treat COVID-19. But as it stands, fluvoxamine is a widely available generic that any doctor can prescribe “off-label” to treat conditions that haven’t been approved by the FDA, such as COVID-19.
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This leads to a tragedy of the commons in which no company will invest in the clinical trials needed to bring a repurposed drug to market, because the resulting benefits would be immediately shared with all competitors.
Bringing a new drug to market is a long and expensive process with a high failure rate. When the pharmaceutical industry cannot justify the development of a new drug due to low return on investment, drug repurposing can fill the void. Federal support could make repurposing more commercially attractive, enticing companies to enter the market and boosting this cost-effective way to meet unmet medical needs.