COVID-19 Treatment: A Roller Coaster Ride

“Clinically, a lot of things are better about COVID now. I feel much more confident that we’re providing good standard of care, and we know that certain things help our patients.” - Angela Rogers, MD, MPH, Pulmonary and Critical Care, Stanford University Medical Center

“When a lot of remedies are suggested for a disease, that means it cannot be cured.” - Anton Chekhov, Physician, Playwright, and Short Story Writer

Most of the recent public health attention has been laser-focused on the development and delivery of COVID-19 vaccines. Nationwide, vaccine rollouts are now finally showing signs of improvement. And the current wave of coronavirus infections is trending downward in almost every part of the United States. Nonetheless, we still face enormous challenges in the battle against SARS-CoV-2, the virus responsible for this pandemic.

Many patients are struggling with severe COVID-19. They need a life-saving treatment to help fight this devastating disease. In this post, I provide an update on COVID-19 treatment, a topic I last reviewed on November 18, 2020 in my Germ Gems post: “COVID-19: Updates on Treatment and Prevention.” But, before you read further, as Bette Davis said in “All About Eve,” “Fasten your seat belts. It’s going to be a bumpy [ride].”

Why is the development of treatments for COVID-19 so slow? To date, the federal government has poured $18.5 billion into vaccine development but only $8.2 billion into investments for drugs for the treatment of COVID-19. In his article in the January 30, 2021 New York Times “How the search for Covid-19 treatments faltered while vaccines sped ahead,” Carl Zimmer identifies the lack of centralized coordination of the many COVID-19 clinical trials as a major stumbling block to finding effective treatments.

Zimmer mentions 179 active COVID-19 clinical treatment trials with 169,370 enrollees. In addition, the Clinical Trials.gov registry website lists 607 trials that are currently recruiting patients. In my opinion, these clinical trials should be coordinated to help accelerate substantial improvement in the discovery of more effective treatments. And based on my experience, I believe that the National Institutes of Health (NIH) is in the best position to coordinate this effort.

Several decades ago, I witnessed what the NIH achieved in coordinating the clinical trials for drugs to treat HIV/AIDS. At that time, there were many researchers across the country conducting trials, much like today. And while various researchers were obtaining promising results, there was a lack of coordination that was impeding progress overall. The NIH stepped in and took the lead by directing the antiviral drug candidates coming out of pharmaceutical company labs and entered them into randomized clinical trials. The NIH was credited for accomplishing what looked impossible—finding, in a very timely manner, effective antiviral drugs to defeat HIV. Today there are 26 HIV antivirals on the market. Eventually, the use of combinations of antiretroviral drugs transformed HIV/AIDS from a uniformly fatal disease into a chronic illness. (Despite an intensive effort on the part of many brilliant investigators, however, a vaccine against HIV still doesn’t exist.)

Antiviral drugs to treat SARS-CoV-2 infection. Remdesivir, a nucleoside analogue given by intravenous infusion (IV) in the hospital, is an antiviral drug that was developed to treat Ebola infection. On October 22, 2020, the Federal Drug Administration (FDA) approved remdesivir for treatment of COVID-19 in patients 12 years or older requiring hospitalization. In other words, with the help of the FDA remdesivir was repurposed for the treatment of SARS-CoV-2. The FDA based its approval on studies showing that this antiviral drug decreased the number of days of hospitalization. To date, remdesivir is the only antiviral that has been found to be useful in the treatment of SARS-CoV-2.

Nonetheless, not everyone agrees about the impact of remdesivir on the course of SARS-CoV-2 infection. While the NIH recommends using remdesivir for certain hospitalized patients, the World Health Organization, citing the lack of convincing data, doesn’t recommend it for any COVID-19 patients.

Remdesivir is also under study in combination with other medications, in particular with baricitinib, a JAK1/JAK2 inhibitor approved for treatment of rheumatoid arthritis. One study reported that hospitalized COVID-19 patients who were treated with both remdesivir plus baricitinib recovered about 1 day faster than those who only received remdesivir. In addition, patients who received both medications were less likely to need ventilation or die at day 29 compared to those who only received remdesivir (23% vs. 28%). On November 19, the FDA granted an Emergency Use Authorization (EUA) for baricitinib in combination with remdesivir for patients hospitalized with COVID-19 who need extra oxygen or breathing support.

Antibodies to treat SARS-CoV-2 infection. Our immune system is our first line of defense against any invasive infection. Some of the most promising COVID-19 treatments, therefore, aim at bolstering the patient’s own immune system to defeat SARS-CoV-2.

As you may recall from previous Germ Gems posts, SARS-CoV-2 is encased in a protein shell that is studded with spike (S) proteins that it uses to gain entry into human cells via their ACE2 receptors. Antibodies directed at S proteins can, however, block cell entry and thereby help neutralize the infection. One approach of using anti-SARS-CoV-2 antibodies to inhibit viral entry is by taking plasma from people who have recovered from COVID-19 infection (referred to as convalescent plasma) and infusing it into ill patients.

On January 6, 2021, the New England Journal of Medicine published the results of a recent Argentinian clinical trial. This study showed that if treatment with convalescent plasma containing high anti-SARS-CoV-2 antibody levels is given within 72 hours after the onset of mild symptoms, the treatment prevented severe COVID-19 in older adults.

A second approach to using antibodies to neutralize SARS-CoV-2 is to supercharge the immune system with lab-made SARS-CoV-2 antibodies, called monoclonal antibodies. Two companies, Eli Lilly and Regeneron, are pioneering this approach. The FDA granted EUAs to both Lilly and Regeneron for their monoclonal antibody cocktails—bamlanivimab plus etesevimab in the case of Lilly, and casirivimab plus imdevimab, for Regeneron—for the treatment of outpatients with mild to moderate COVID-19 disease. While the clinical results and laboratory responses (reductions in viral load) are promising, practical hurdles are stalling their use (prolonged IV administration times of the monoclonal antibodies ties up outpatient facilities and personnel). Nevertheless, federal health leaders are urging greater use of these monoclonal antibodies, arguing that the therapy is extremely beneficial in that it prevents patients from becoming sicker and needing hospitalization.

Additionally, wider spread vaccination and the emergence of SARS-CoV-2 variants are likely to further reduce the enthusiasm for using monoclonal antibody treatment. Vaccines give the revved up immune system a chance to make its own protective antibodies thereby obviating the need for monoclonal antibody treatment. And antiviral antibodies either in convalescent plasma or those made in the laboratory (i.e., monoclonal antibodies) may not recognize the SARS-CoV-2 variants thereby rendering the treatment ineffective.

Anti-inflammatory agents for treating COVID-19 and status of the cytokine storm hypothesis. Both the antiviral drug, remdesivir, and antibody treatment strategies mentioned above aim at the virus either by inhibiting its replication or binding to its S protein. But many researchers believe that certain patients become extremely sick or die because of the damage inflicted by an overactive immune response in COVID-19. While no one is sure what is going on (yet), one hypothesis that has been offered is that a dysregulated release of inflammatory mediators called cytokines by activated immune cells (a condition referred to as a cytokine storm) is responsible.

At the time of the last Germ Gem post reviewing COVID-19 treatments in November 2020, the New England Journal of Medicine had published the results of the large Oxford University-led multicenter RECOVERY trial. This randomized, placebo-controlled trial demonstrated that the potent anti-inflammatory steroid dexamethasone (a corticosteroid) significantly reduced mortality of patients with severe COVID-19 who were receiving supplemental oxygen or on mechanical ventilation. Using this corticosteroid to fight COVID-19 appeared to be a landmark treatment discovery that was widely hailed by intensive care clinicians and researchers.

Nonetheless, the benefits of dexamethasone in the treatment of severe COVID-19 did not hold up upon re-examination. In the January 21, 2021 issue of Nature Scientific Reports, investigators in Brescia Northern Italy published the results of a study involving 1,444 COVID-19 patients titled: “Corticosteroid treatment has no effect on hospital mortality in COVID-19 patients.” This study suggested that while corticosteroid treatment reduced admissions to an intensive care unit, there was no impact on mortality (30.6% of those exposed to corticosteroids died vs. 21.7% of those who didn’t receive corticosteroids).

To date, no one seems to have reconciled the differences in the findings of the RECOVERY trial with those in the Italian study. It is possible, however, that over time the management of severe COVID-19 has improved even without the use of corticosteroids. It is also possible that the cytokine storm hypothesis is not correct.

In September 2020 the Journal of the American Medical Association published a study that compared the cytokine levels in critically ill COVID-19 patients versus those with other causes of acute respiratory distress syndrome. The findings suggested that COVID-19 may not be characterized by a cytokine storm after all. Therefore, anti-cytokine therapies in COVID-19 may not be expected to be beneficial.

The conflicting results of trials of dexamethasone raises a fundamental question, “Just how important are cytokines in the pathogenesis of severe COVID-19?” This question may also be relevant to studies of monoclonal antibodies that inhibit the receptor for the cytokine interleukin-6, called IL-6 receptor antagonists. The preliminary results of REMAP-CAP, a large, on-going international clinical trial of two IL-6 receptor antagonists, tocilizumab and sarilumab, suggest that these agents improve the outcome of critically ill patients with COVID-19. Yet, an extensive review by the NIH Panel of experts (published on-line at covid19treatmentguidelines.nih.gov) of the REMAP-CAP study findings and those of multiple other trials of IL-6 receptor antagonists for COVID-19 suggest that the evidence for benefit is equivocal at best.

Other treatments for COVID-19. The search for game-changing treatment of COVID-19 is still on. Ideally, of course, treatment should be simple (oral therapy beats IV infusions) and safe (at the very least, the side effects shouldn’t be worse than the symptoms of COVID-19 itself). As mentioned earlier, in these early days of treatment discovery, the strategy has been to test repurposed drugs (agents that are already on the market for other diseases, like Ebola virus infection, rheumatoid arthritis, etc.). This makes sense because the safety of these agents is already established. Some of the other drugs that have been tested are:

· Ivermectin. Ivermectin is an antiparasitic drug that has been shown to inhibit the replication of SARS-CoV-2 in cell culture. The NIH COVID-19 Treatment Guidelines Panel, however, recently determined that currently there are insufficient data either for or against the use of ivermectin for the treatment of COVID-19.

· Fluvoxamine. Another drug that fits this repurposed drug safety profile that looks promising is the antidepressant fluvoxamine, a selective serotonin reuptake inhibitor. As mentioned in the recent Germ Gems post reviewing COVID-19 treatments, a study published in the Journal of the American Medical Association in November 2020 reported the results of a randomized, double-blind, placebo-controlled trial showing that fluvoxamine significantly reduced clinical deterioration in outpatients with COVID-19. Recently, a nonrandomized study of California racetrack workers with COVID-19 was completed. On February 1, 2021 Science News reported that 65 workers who took a 2-week course of fluvoxamine didn’t have serious COVID-19 symptoms or need to be hospitalized, whereas six of the 48 workers who turned down fluvoxamine had to be hospitalized and two required treatment in the intensive care unit.

The results of these early trials of oral fluvoxamine treatment of COVID-19 are encouraging. Washington University and other academic institutions both here and abroad are now conducting randomized clinical trials of fluvoxamine. Hopefully, these trials will confirm this drug’s effectiveness against COVID-19. We will just have to wait and see.

The most exciting news for me regarding COVID-19 treatments occurred in December 2020 when Merck & Co. entered into a $356 million agreement with the U.S. Government for 100,000 doses of Merck’s experimental COVID-19 treatment. This funding will support advanced development and large-scale manufacturing of an investigational therapeutic, MK-7110, to treat hospitalized patients with severe or critical COVID-19. I am hopeful that other ‘Big Pharma’ companies have strategies similar to Merck’s. And, I am optimistic that it won’t be long before we have a therapeutic armamentarium against COVID-19 to rival that of HIV/AIDS.