The difficulties with repurposing approved drugs to treat coronavirus infection; or why we aren’t yet ready to give everyone chloroquine!

Executive Summary

• Many drugs approved to treat other diseases have been proposed to treat coronavirus infection.
• Some of these drugs block similar viral infections, while others treat inflammation from any cause which could reduce symptoms. 
• Repositioning approved drugs may allow shortening of the development cycle; however, there is no assurance they will work or be entirely safe if used in coronavirus infections.
• Rigorously controlled trials will need to be conducted to determine if a drug truly provides benefits to patients with coronavirus, especially given the emotions that surround this disease.

There has been much discussion about using drugs that have been approved for other human diseases to treat coronavirus infection. This is a very complex topic and cannot be easily reviewed. To understand why there is a push to consider using already approved drugs to treat coronavirus, one needs to understand; 1) the reasons why these drugs might work in coronavirus infection, 2) why there is value to repurpose drugs that are approved for human use rather than developing new drugs, and 3) how might this approach deliver a therapy faster than traditional drug development.

People have two main reasons why they think a drug that was developed for another disease might work in coronavirus infection. The most rational reason is that the drug was developed to treat another viral disease that’s similar to coronavirus and targets a common mechanisms of viral replication. Since Coronaviruses are RNA viruses, the focus is on drugs developed for other RNA viruses including influenza or HIV. In particular, a number of anti-viral drugs that block specific enzymes that produce the virus have gained attention. Favilavir, a drug developed for many RNA viruses, is the first drug approved by the Chinese government to treat coronavirus. It works by inhibiting the RNA-dependent RNA polymerase enzyme, which is crucial to the production of the virus. In contrast, Kaletra, a combination of antiviral HIV drugs, has been recently tried but failed in Coronavirus despite the well conceived approach. So even with the best scientific rationale repurposing can fail.

In contrast, there’s been talk about other types of drugs that are more generally effective against inflammatory diseases. These drugs would block inflammation related to the viral infection. They work more generally and would function in the same manner that they would for a disease like lupus or arthritis. A prominent example of this type of drug is chloroquine. This drug has been touted for use in coronavirus infection with little data to support its action. Interestingly, the actual mechanism of action of this drug in suppressing inflammation isn’t really clear.

It interferes with lysosomal activity and cell death, stabilized cell membranes and alters signaling pathways and transcriptional to reduce activity in inflammatory cells. This drug has been touted for coronavirus infection by Elon Musk, who was treated with it for malaria. However, the action of the drug on malaria infection does not involve inflammation. Therefore, this type of drug does not provide a sure way to treat coronavirus infection.

If success is not assured with repurposing a drug why do it rather than design a new drug for coronavirus infection? The major reason is that the safety and the target dose of these drugs in humans is defined through many years of studies (preclinical studies in animals and early studies in humans) and could be skipped for coronavirus. This could shorten the development timeline of a drug for coronavirus from decades to months (see timeline figure). However there are limitations. A drug that is safe in one situation, such as chronic arthritis, might not be equally safe in an acute viral infection. In addition, while the exact dose required in coronavirus infection may actually be higher or lower than in other diseases. Therefore, while repurposing provides good starting points they may not exactly identify what would be necessary for coronavirus infection.

Finally, it’s important to understand standard drug development and how repurposing could shorten development. In the normal drug development process:

• Phase I (1) clinical trials are where human safety is evaluated.
• Phase II (2) human studies look at both the safety of a drug and pinpointing the exact dose to use to prove efficacy.
• Phase III (3) trials are efficacy studies that involve large numbers of patients and have both blinding (to not bias the investigator) and control groups to show that the drugs is truly effective.

While repositioning an old drug for a coronavirus might allow skipping the first step or two of drug development, high quality Phase III human efficacy testing will have to be performed.

Blinding of a clinical trial is important because emotions run high with coronavirus. It is difficult not to be overcome with enthusiasm for any drug that one thinks will help people. Even a drug that shortens hospitalizations by a few days could turn the tide at this time. However, this emotion certainly would bias any observer. The worst thing that could happen is to call a drug effective when it truly isn’t. This could prevent effective drugs from being developed. In addition, potential toxicity from any drug might outweigh the benefit of the drug. The list of toxicities from chloroquine is great and too much of the drug could easily kill you.

We must use scientific rigor to make sure that any drug is effective and we don’t waste the effort of many volunteers. There are an incredible number of candidates proposed to treat corona virus, including promising drugs like Remdesivir. Let’s not rush off and put everyone on chloroquine quite yet!!!