Clinical trials for drugs targeting IL-6 to slow the immune system are underway in the fight against Covid-19

One of the most perplexing aspects of Covid-19 is its seemingly random pattern of severity. Coronavirus infections induce severe acute respiratory syndrome (SARS) in some people, but as of yet there is no clear pattern for who will come down with this acute form of the disease. Researchers are now turning to the human immune system rather than the virus itself to find targets that may lower the chances of this acute form of coronavirus. One clinical trial is underway for an existing drug that targets a cytokine responsible for the acute immune response in hopes that they will stop Covid-19 infections from progressing into SARS. But, is lowering the activity of the human immune system a wise move during an active infection? The results of these trials may reveal a key mechanisms in fighting Covid-19.

Regeneron, in collaboration with Sanofi, are currently running clinical trials on Kevzara (sarulimab), a drug that blocks the activity of interleukin-6 (IL-6). IL-6 is an immune modulating compound that is responsible for the acute reaction to infection. Kevzara is a monoclonal antibody therapy that targets the IL-6 receptor on cells, effectively lowering the activity of IL-6. Drugs of this kind are currently prescribed for acute inflammatory or autoimmune conditions such as rheumatoid arthritis, which has been shown to damped the acute inflammation induced by IL-6 signaling.

The rapid inflammatory state caused by coronavirus, modulated in part through IL-6 activity, may be involved in the deterioration of lung function seen in SARS.

IL-6 is a class of proteins called cytokines (cyto = cell, kine = movement) that are released by cells as a sort of intercellular message. Once cytokines are released, they go on to bind to the outside of adjacent cells. Once IL-6 binds to its target receptor, it induces the symptoms we associate with acute illness, namely a high fever. During coronavirus infection in the respiratory system, the high rate of viral replication induces acute inflammation within those tissues. The rapid inflammatory state caused by coronavirus, modulated in part through IL-6 activity, may be involved in the deterioration of lung function seen in SARS.

This acute immune reaction as seen in coronavirus infections is known as a cytokine storm. As the name implies, the sudden release of cytokines like IL-6 and a number of others churns the immune system into a frenzy of activity. While the immune system ramps up in this way to respond as rapidly as possible to invading pathogens, it does so at the expense of the surrounding tissues. A cytokine storm can be vigorous enough to be life threatening in itself.

Kevzara works by targeting not IL-6 itself, but the IL-6 receptor on cells. The antibodies in the drug are designed to bind specifically to this receptor, and once there they block IL-6 from binding and thus stop IL-6 from initiating its acute response. This drug would be used to treat those who have an acute form of Covid-19, and would not serve as a prophylactic treatment against infection. The phase II/III clinical trials are currently enrolling 400 participants with acute Covid-19. These trials seek to demonstrate the safety and efficacy of this drug.

The first patients enrolled in this trail outside of the US received injections of Kevzara on March 30th.

Tamping down the immune system during an active infection has its risks. The function of IL-6 is multifaceted and complex. We simply do not have enough understanding of its role in Covid-19 to be sure this is a safe and effective therapy. These trials should shed light on any negative outcomes from this treatment approach. However, successful treatment of the acute immune response to Covid-19 may be key to easing the number of people acutely ill. Reducing the number of acute cases of Covid-19 means easing the burden on health care workers, less crowding of hospitals and a potentially lower death toll.

Reference

Sanofi Press Release: https://www.sanofi.com/en/media-room/press-releases/2020/2020-03-30-07-00-00

NIH Trial Info: https://clinicaltrials.gov/ct2/show/NCT04315298

US Department of Health and Human Services Info: https://www.hhs.gov/about/news/2020/03/21/hhs-funds-phase-2-3-clinical-trial-for-potential-treatment-for-covid-19.html

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