Last week, we began our two-part series on COVID-19 antiviral drugs by reviewing the stages of the Sars-Cov-2 (the virus that causes COVID-19) lifecycle that might be prone to attack by these drugs, and explained how hydroxychloroquine (HCQ) works and discussed the mixed results seen so far in clinical trials designed to test HCQ’s efficacy in COVID-19 patients. This week, guest author Kevin Curran discusses remdesivir, lopinavir/ritonavir, and favipiravir, and a brief look at plasma therapy.
Remdesivir
Remdesivir was developed by Gilead Sciences (Foster City, CA), a large biotechnology company with a history of developing successful antivirals. Remdesivir is an adenosine nucleotide analog that interferes with the action of viral RNA polymerase, resulting in reduced viral RNA production. Targeting viral RNA polymerase enzymes has proven to be a successful strategy for other viruses such as hepatitia C and influenza.
As of 2020, the FDA has not approved remdesivir for any disease, but it’s been in development as a broad-spectrum anti-viral, and was previously tested as a treatment for Ebola with limited success. Approximately 500 people were treated with the drug during the Ebola crisis and remdesivir was found to be generally safe for patients and healthy people.
Intriguingly, a 2017 study performed on human and bat cells grown in the lab showed remdesivir could stop different versions of coronavirus (SARS and MERS). Further encouragement is found in a February 2020 paper that demonstrates remdesivir can block the novel coronavirus (SARS-CoV-2) from replicating within human cells.
Despite the fact that remdesivir is not yet FDA-approved, patients in clinical trials have access to the drug. Emergency room patients can also provide this drug outside of trials through compassionate use programs, which allow patients to take unapproved, experimental drugs if they are in desperate circumstances and have no other options.
We saw our first glimpse of COVID-19 human patient data on 4/10/20, when Gilead published results from a compassionate use study. Clinical improvement was observed in 36 of 53 patients (68%). From this trial, we can conclude that remdesivir appears to be safe in these patients. However, it is challenging to learn much else from this study. We don’t know if remdesivir was the reason that 68% of this patient group improved. The only way to learn that valuable information is through large, controlled clinical trials. These are beginning to take place.
The National Institute of Allergy and Infectious Disease (Bethesda, MD) is currently testing remdesivir in a Phase 3 clinical study in adults with COVID-19. Four hundred and forty COVID-19 patients are being recruited for this adaptive, randomized, placebo-controlled study to assess the safety and efficacy of remdesivir. The trial will be conducted at 44 different hospitals.
A Chinese study is underway with results expected later this month.
Additionally, Gilead has launched a trial for moderate COVID-19 patients and another trial for severe COVID-19 patients.
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Lopinavir/Ritonavir
A fixed-dose combination of these two drug is sold under the brand name Kaletra. This drug is marketed by Abbvie (North Chicago, IL), and was FDA-approved in 2000 for the treatment of human immunodeficiency virus (HIV).
Lopinavir inhibits an HIV protease enzyme, which is required for the assembly of new viral particles. Ritonavir increases the bioavailability of lopinavir, thereby increasing its potency. Ritonavir accomplishes this task by inhibiting the liver enzyme that breaks down lopinavair.
Researchers realized that Kaletra also blocks other viruses, including SARS.
In 2004, a clinical trial tested the combination of lopinavir, ritonavir and ribavirin on 111 patients with SARS. This treatment combination performed better than ribavirin alone. This positive clinical result with SARS patients suggested a similar combination could work with COVID-19 patients.
Unfortunately, a clinical trial published in March 2020 reported negative results. Researchers at Jin Yin-Tan Hospital in Wuhan, China did not see any difference in outcome when comparing 99 lopinavir/ritonavir treated patients vs. 100 patients that received standard of care. It should noted, however, that it remains possible that treating patients at an earlier phase in COVID-19 symptoms could improve treatment outcome.
Favipiravir
Favipiravir is an antiviral drug marketed under the brand name Avigan by Fujifilm Toyama (Tokyo, Japan).
Avigan was previously approved in Japan and China as an influenza treatment.
Similar to remdesivir, favipiravir targets the viral RNA polymerase, making it a potential treatment for COVID-19. The hope here is that the SARS-CoV-2 RNA polymerase is similar in structure and function to the viral polymerase of influenza A.
Reason for optimism: In February 2020, China’s Science and Technology Ministry official Zhang Xinmin said that favipiravir helped patients recover in an 80-day participant trial conducted in Shenzhen city. When compared to Kaletra, favipiravir treatment shortened the recovery time from 11 days to 4 days in mild and moderate COVID-19 patients. It should be noted that the favipiravir treatment also included an additional agent, interferon-alpha. We need to see how favipiravir performs on its own.
Fujifilm is now conducting a larger, Phase III clinical trial to test favipiravir for COVID-19 patients.
Plasma Therapy
In addition to the possible antiviral treatments mentioned above, one topic that’s received a lot of attention lately is the possibility of using “convalescent plasma” as a COVID-19 treatment. This is based on the idea that when you survive a coronavirus infection, your blood becomes filled with antibody proteins that can attack the virus.
Is it possible to donate your blood and help patients currently hospitalized with Coivd-19?
The answer seems to be yes and this process is called plasma therapy.
Plasma, or serum, is the yellowish liquid component of our blood. This portion of blood is filled with antibody proteins. Once someone is fully recovered from COVID-19, they can make their way to a blood collection clinic and make a donation. After a screening process, a plasmapheresis step and an antibody check, the blood can be infused into recipients. New York City Blood Center is currently accepting plasma donations.
Scientists think this could be an effective treatment for patients hospitalized with COVID-19 or those who are at high risk of getting sick, like health care workers and people with weak immune systems. Plasma therapy seems to be most effective when administered early.
As researchers fight the clock to beat COVID-19, every possibility is being pursued.
This article is adapted from an article originally appearing at: https://www.risingtidebio.com/coronavirus-vaccine-treatment/#antiviral
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