A Fast Track for Testing Antiviral Treatments
Repurposing previously approved medicines could accelerate finding treatments for COVID-19.
Finding candidate treatments
Medicines and treatments must be both safe and efficacious (able to treat symptoms, reduce the duration of an illness, or cure the condition). A candidate drug can be identified in many different ways. To identify antiviral compounds, the compounds can be screened in a computer by modeling an interaction between compounds and a particular protein of the virus. This is one of the reasons so many researchers are trying to identify the molecular structures of the proteins of the new coronavirus SARS-CoV-2 and the structures of the proteins on the host cells that the virus uses to gain entry. Those structures can be used for in silico (virtual) drug design and screening.
Another approach is to take large collections of chemicals and screen them for antiviral activity in culture. A related approach is to take chemicals that have antiviral activity against other infections and test them for antiviral activity against the virus of interest. The chemicals are added to cells in culture to determine if they interfere with viral infection. This requires having a cell-based system that the virus can infect and a system to produce sufficient quantities virus for testing. It also requires laboratories to use special safety precautions. For the virus that causes COVID-19, this is done with the SARS-CoV-2 virus and one of several kidney-derived cell lines from monkey, called Vero cells. Some of the cell lines are highly infectable and produce large quantities of the virus, which is needed for performing the tests.
Compounds or chemicals that are predicted to interfere with the virus in the computer models or that interfere with infection in cell culture then must be tested for toxicity. Often those that pass the cell culture test will also be tested in animals before any testing in humans occurs.
The drugs in clinical trials for COVID-19 are one of two types. They are investigational, unapproved compounds that have antiviral activity against other viruses either in cell culture assays or animal models. Alternatively, they are approved for either viral infection or other uses in people. This difference impacts how quickly the treatment can advance through the testing process for the new use.
Finding candidates with a high therapeutic index
The ideal medicine has a high therapeutic index. This means that the dose that kills or causes toxicity in 50% of the samples (cells, animals, or test subjects) is very high and the dose that causes a beneficial effect in 50% of the samples (cells, animals, or test subjects) is low. Thus, the risk of toxicity when used in a large population will be very low; very rarely will anyone have an adverse effect. Drugs with a high therapeutic index result in a wide therapeutic window in which most of the population will be effectively treated without experiencing serious adverse effects.
For infections that have high mortality rates or that cause severe disability, a narrower therapeutic window may be acceptable because the risk of dying of the infection is so high. For infections with low mortality rates, a wide therapeutic window (high therapeutic index) is typically required. The benefit of treatment must outweigh the risk of toxicity or adverse effects.
Skipping steps by repurposing previously approved treatments
The figure below shows how testing a new molecule that has never been previously used in people takes more steps than does repurposing a drug that has been previously approved for use in humans.
Before testing in animals, testing in cultured cells is the starting point. Cultured cells are used to test both efficacy and toxicity of a new antiviral. To repurpose a previously tested and approved antiviral, only efficacy testing in cultured cells may be needed. The ability to skip toxicity testing in cultured cells does not save much, if any, time. It is easy to perform both toxicity and efficacy testing using high-throughput methods with cultured cells, so the time saved by skipping toxicity testing in cells is minimal.
New antiviral drugs that have never been approved for another use and that have a potentially useful therapeutic window in the cellular toxicity analysis will continue through the testing process. The next step is testing in animal models for toxicity, distribution throughout the body, persistence in the body, and routes of elimination. Drugs that do not have toxicity in animal studies or for which a wide potential therapeutic window is observed in animals can then proceed to efficacy studies.
Both efficacy and toxicity can be evaluated the same experiment in different animals. Toxicity in the absence of the pathogen must be tested. Thus, the same animal cannot be used for both efficacy and initial toxicity analysis. To avoid unnecessary cost and use of animals, many researchers will only perform toxicity testing first and then proceed to efficacy testing if a non-toxic dose can be identified.
The ability for a previously approved drug for other diseases to skip toxicity testing in animals is one of the big time-saving steps in the drug development process. This type of testing cannot be done in a high-throughput manner and is quite expensive. Thus, a drug that is a candidate for antiviral repurposing can proceed from the in vitro (cells in culture) studies or even from computational modeling analysis to animal efficacy studies without having to test for toxicity in cells or animals first.
A step where repurposing saves a lot of time is in the early phase clinical trials. These treatments already have established safety profiles, that is how they were approved for other uses. Thus, the Phase 0 and Phase I testing can be skipped or the Phase I and II testing can be performed together in a clinical trial with an adaptive design. This saves the most time, eliminating months of clinical testing time. In a pandemic situation with a virus that has severe or lethal outcomes, saving testing time is critical to saving the most lives.
Thus, researchers are investing major efforts in testing previously approved therapies for COVID-19. This will likely be the fastest path to effective treatment.
Chu, H., Chan, J. F.-W., Yuen, T. T.-T., et al., Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV and implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study. Lancet Microbe (published online 21 April 2020) DOI: 10.1016/S2666–5247(20)30004-5
Andersen P. I., Ianevski A., Lysvand H., et al. Discovery and development of safe-in-man broad-spectrum antiviral agents. Int. J. Infect. Dis. ;93:268‐276 (2020). DOI: 10.1016/j.ijid.2020.02.018
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