The COVID-19 pandemic has been cataclysmic for much of the planet, and the SARS-CoV-2 virus, which causes it, is far from finished with us.
After earlier good control of the pandemic, Taiwan, Singapore and other countries are experiencing a surge, and India is facing a catastrophe, with millions of deaths counted already and the nation's healthcare system devastated.
In spite of the progress in suppressing the spread of COVID-19 in the U.S., U.K. and some other countries, primarily through remarkably effective vaccines and non-pharmaceutical interventions, such as masking, social distancing, and good hygiene, it seems likely that COVID-19 will not in the foreseeable future completely disappear but will become endemic, with seasonal variation, similar to influenza.
Because people will continue to fall ill, there will be an ongoing need for treatments, which are currently in short supply. Although some moderately effective drugs are already being used, new treatments are needed to treat severe COVID-19 infections.
The anti-viral drug remdesivir, which binds to the virus's RNA-dependent RNA polymerase and inhibits viral replication, is currently the only drug that is approved by the FDA for the treatment of COVID-19. It is recommended for use in hospitalized patients who require supplemental oxygen.
The corticosteroid dexamethasone has been found to improve survival in hospitalized patients who require supplemental oxygen, with the greatest benefit observed in patients who are on ventilators. Adding the monoclonal antibody tocilizumab to dexamethasone therapy was found to improve survival among patients who were exhibiting rapid respiratory deterioration due to COVID-19.
In outpatients with mild to moderate COVID-19 who are at high risk for disease progression, anti-SARS-CoV-2 antibody-based therapies may have the greatest potential for a clinical benefit during the earliest stages of infection. For these patients, a panel of NIH experts recommends administering monoclonal antibodies bamlanivimab plus etesevimab or casirivimab plus imdevimab, both of which are available through Emergency Use Authorizations (EUAs) from the Food and Drug Administration (FDA).
Other analogous approaches that via various mechanisms blunt the activity of the immune response are promising.
One of these attempts to therapeutically modulate the activity of an often-overlooked system called the lectin pathway, a part of the body's complement system that helps the immune system respond to infection. When over-activated, as happens with severe COVID-19, it can lead to an uncontrolled cascade of inflammation, endothelial damage, dangerous blood clots, and "cytokine storm," which can, in turn, lead to severe respiratory distress, organ failure, and death.
Once the coronavirus reaches the lungs, it soon infects the surrounding blood vessels, damaging the endothelial cells lining the vessels. This endothelial damage results in a triad of inflammation, complement activation, and excessive clotting responsible for the pathophysiology of COVID-19.
At the nexus of these three pathways sits MASP-2, the key enzyme in the lectin pathway. Endothelial injury activates MASP-2 and the lectin pathway, driving inflammation and hypercoagulation, which leads to organ-damaging thrombi or clots. In COVID-19, activation of the lectin pathway is a very early event, occurring prior to hyperinflammation and the innate antibody response. Lectin pathway activation causes further endothelial damage, initiating a positive feedback loop with further activation of systemic inflammation and clotting.
A monoclonal antibody called narsoplimab blocks the MASP-2 enzyme and is, thus, an inhibitor of the lectin-pathway. Narsoplimab has shown impressive responses in advanced clinical trials for several illnesses marked by endothelial cell injury, and because similar pathophysiology is found in COVID-19 infections, it has been tested in a small number of infected patients, with promising results.
The largest study, conducted in Italy in six severely ill COVID-19 patients, concluded: (1) "[n]arsoplimab down-modulates SARS-CoV-2-induced activation of the lectin pathway and endothelial cell damage"; (2) "[n]arsoplimab can reduce the thrombotic risk of Covid-19 patients"; and (3) [a]ll patients treated with narsoplimab improved and survived without any drug-related adverse events," a far better result than would have been expected, based on retrospective control groups.
Narsoplimab is only one example of the frenzy of clinical research on various treatment protocols for COVID-19, including the use of drugs, new and repurposed. This is critical, especially if new variants of SARS-CoV-2 emerge that are not effectively combated by existing vaccines.
Henry I. Miller is a physician, molecular biologist and senior fellow at the Pacific Research Institute. He was the founding director of the FDA's Office of Biotechnology.
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