“As always in life, people want a simple answer . . . and it’s always wrong.” Susan Greenfield, British neurochemist, writer, member of the House of Lords
“We need to create a much more cohesive clinical trial system in this country.” Esther Krofah, executive director, FasterCures
The Sars-CoV-2 Delta variant has caused an alarming uptick in COVID-19 cases and hospitalizations in America, as well as in other areas of the world. A striking feature of this variant is how readily it is transmitted. Dr. Rochelle Walensky, the director of the Center for Disease Control and Prevention (CDC), likened the Delta variant to varicella zoster virus, the cause of chickenpox, and warned that COVID-19 is “just a few mutations away” from becoming unstoppable by our current vaccines. As chinks in the vaccine armamentarium are beginning to appear, many people are asking how good is the arsenal of medications to treat COVID-19? This Germ Gems post addresses this important question.
The big picture. The topic of COVID-19 treatment was last featured in my February 10, 2021 Germ Gems post, “COVID-19 Treatment: A Roller Coaster Ride.” At that time, there were 179 active clinical treatment trials with 169,370 enrollees, but the U.S. Federal Drug Administration (FDA) had approved only one drug for the treatment of COVID-19—the antiviral remdesivir. Today, nearly six months later, we are still on the roller coaster and remdesivir remains the only FDA-approved agent
Despite an enormous effort on the part of dedicated clinical research teams, the treatment armamentarium for COVID-19 is disappointingly thin. The basis for the stark reality of such limited treatments is highlighted both in a July 26 Wall Street Journal article, “Covid Treatment Options Remain Elusive, Despite Months of Effort and Rising Delta Cases” and in a July 27 Science News report, “Why it’s still so hard to find treatments for early COVID-19.” Joseph Walker, the author of the WSJ article, summed it up this way, “A long list of factors played into the checkered development of drugs to treat Covid-19 cases—exposing flaws in the infrastructure of medical research and healthcare.” The simple fact is that the medical research enterprise has never dealt with a challenge as fast moving and complex as COVID-19. This global monster calls for a new clinical research paradigm.
My perspective is that of an “armchair quarterback.” I haven’t been involved in clinical research or medical care of COVID-19 patients. Nonetheless, my infectious diseases career spanned most of the 40 years of another devastating viral pandemic—HIV/AIDS. I find several striking differences in these two pandemics that may be helpful in explaining the relative paucity of treatments for COVID-19 at this juncture.
First, while a vaccine is still in the offing for prevention of HIV/AIDS, none exists. Yet, the FDA gave Emergency Use Authorization (EUA) to three remarkably safe and effective vaccines in less than a year after SARS-CoV-2 was identified as the cause of COVID-19. Benjamin Franklin’s adage, “An ounce of prevention is worth a pound of cure” still rings true. In fighting the war against COVID-19, putting most of the eggs in the prevention (vaccine) rather than in the treatment basket made sense more than a year ago, and it still makes sense today.
Second, HIV/AIDS is a chronic and, for most patients, a slowly evolving disease that takes on average nine to ten years before symptoms are manifest. This gives time for drug development and clinical trials. The first therapeutic agent for HIV/AIDS was an oral drug called zidovudine, released in 1987—six years after the first cases of HIV/AIDS were described in 1981. Very quickly, however, mutant HIV strains (variants) resistant to zidovudine emerged, and a strategy developed using multiple oral drug regimens. By 1994, highly active antiretroviral therapy (HAART) drug combinations were keeping HIV/AIDS patients alive. If these patients took their medicine, they could expect to live as long as people without HIV/AIDS.
In sharp contrast to HIV/AIDS, the COVID-19 pandemic came on like gangbusters. Millions of cases of COVID-19, hospitalizations, and deaths occurred worldwide in just the first year. The first treatments for COVID-19 used intravenous (IV) drugs given to acutely ill and dying patients. Doctors and their patients, as well as their families, were desperate for treatments that relieved suffering and staved off death. In hindsight, in the first year of COVID-19, the luxury of treating patients early in their illness with oral agents wasn’t a priority. We now realize, however, that what is needed most, perhaps, are oral drugs to treat COVID-19 patients early, preferably in an outpatient setting. The emergence of the Delta variant that makes patients sicker than the ancestral virus or other variants is making this abundantly clear.
COVID-19 treatments. An in-depth accounting of COVID-19 therapies is beyond the scope of this post. (For those readers who are interested, I recommend the on-line New York Times “Coronavirus Drug and Treatment Tracker.”) Nonetheless, below I provide an abbreviated list of therapeutic agents that keep cropping up in news. These agents work by targeting the replication of the virus (antivirals), or inhibiting the entry of SARS-CoV-2 into cells, or modulating the inflammatory response of the host’s immune system to SARS-CoV-2.
Antivirals. As mentioned earlier, the antiviral, remdesivir, is the only FDA approved drug for the treatment of COVID-19. It blocks the virus from copying itself and is active against a range of viruses including Ebola virus. In clinical trials, it shortened the recovery time for patients hospitalized with COVID-19. National Institutes of Health (NIH) guidelines recommended it initially for use in hospitalized patients who require supplemental oxygen, but in December 2020 the NIH limited its scope of use due to a “lack of data showing benefit at advanced stages of disease.”
Remdesivir captured everybody’s attention in 2020, however, it has one drawback—it must be administered IV. Thus, when molnupiravir, an oral antiviral that also works by inhibiting the replication of SARS-CoV-2, appeared in 2021 it was met with much enthusiasm. Produced by Merck in partnership with Ridgeback Biotherapuetics, early reports on molnupiravir have been promising (for example, consider these headlines, “Five-Day Course of Oral Antiviral Appears to Stop SARS-CoV-2 in Its Tracks” and “Merck’s Little Brown Pill Could Transform the Fight Against Covid”).
As pointed out by New York Times science writer, Carl Zimmer, in his June 17 article, “A Pill to Treat Covid-19? The U.S. Is Betting on It.,” molnupiravir is part of a new $3.2 billion program to support the development of antiviral pills. The announcement in late June that five Indian drug makers are jointly starting a trial of Merck’s drug is encouraging. But molnupiravir is still in an early stage of clinical trials and faces many hurdles. Nonetheless, according to a July 25 WSJ article, the COVID-19 pill race is heating up with recent entries from Pfizer and the Japanese company Shionogi. This is all good news.
Inhibitors of viral entry into cells. One strategy that the immune system uses to neutralize viruses is to block their entry into cells. It does so by producing antibodies against the virus. In the case of SARS-CoV-2, the most potent antibodies are aimed at its spike protein. Two therapeutic approaches of this strategy are to administer plasma containing these antibodies recovered from patients (convalescent plasma) or antibodies that are concocted in the laboratory (called monoclonal antibodies or mAbs).
Convalescent plasma has a FDA EUA to treat hospitalized COVID-19 patients. Although there is evidence that convalescent plasma with high antibody levels reduces the progression of COVID-19 from mild to severe disease in older adults, its overall role in treatment is at present unclear.
Monoclonal antibodies (mAbs) have captured much greater interest (and attention in the press) than has convalescent plasma. Two products (mAb “cocktails”) standout. One is from Eli Lilly (bamlanivimab/etesevimab) and the second from Regeneron (casirivimab/imdevimab). In late June, the U.S. government halted distribution of Lilly’s mAb cocktail because of its lack of efficacy against Gamma and Beta variants. On August 2, the FDA authorized Regeneron’s mAb cocktail for post-exposure prophylaxis. While Regeneron’s product appears to contain antibodies that target the Delta variant, the FDA stresses it should be no substitute for vaccination.
Anti-inflammatory agents. As I’ve mentioned before in various Germ Gems posts, while we can’t live without an immune system, mediators produced by cells of an activated immune system are responsible for most of the symptoms attributed to infections. And it is often these same mediators that when dysregulated kill infected patients. Armed with this knowledge and a long history of studies of corticosteroids with potent anti-inflammatory effects, a large randomized clinical trial (RCT) was coordinated last year by researchers in the UK using dexamethasone to treat patients with severe COVID-19. This trial demonstrated that administration of IV dexamethasone in hospitalized patients significantly reduced death. (The NIH recommends it for those who need supplemental oxygen or high flow or mechanical ventilation). Addition of dexamethasone, or a related corticosteroid, to the therapeutic armamentarium for severely ill patients remains a landmark development in the treatment of patients with severe COVID-19. (Currently, there is insufficient evidence to support the use of inhaled corticosteroids to treat early COVID-19.)
Patients with severe COVID-19 manifest a robust immune response with elevated levels of cytokines and other mediators in the blood and tissues. The first phase of COVID-19 treatment trials tested “repurposed” drugs that were already known to be effective and safe in the treatment of inflammatory diseases. One such agent, tocilizumab, used to treat rheumatoid arthritis, inhibits the cytokine interleukin-6. It has been shown to improve outcomes of patients with severe COVID-19. It is often used in combination with dexamethasone in critically ill patients.
RCTs of another class of immunomodulators called Janus kinase (JAK) inhibitors have been carried out in patients with severe COVID-19. Two of these agents, tofacitinib and baricitinib, improve outcomes of patients with severe disease. An advantage of these drugs is that they can be taken orally.
Other therapies. In addition to anti-inflammatory drugs, a number of other agents have been repurposed for potential use in COVID-19. Of these agents, the most promising is the anti-depressant fluvoxamine. This serotonin reuptake inhibitor also reduces the production of inflammatory cytokines. Because it is taken orally and can be given to outpatients with early COVID-19 it potentially could be used widely. But RCTs are needed to verify that it works.
A number of other repurposed drugs haven’t fared so well in clinical trials. The anti-malarial agent hydrocholoroquine is one such agent that failed to have any effect in properly controlled RCTs. And another anti-parasitic agent, ivermectin, has generated conflicting results. Both of these anti-parasitic drugs now appear to be relegated to the COVID-19 treatment dustbin, along with the antibiotic azithromycin.
Where do we go from here? According to data from the Milken Institute, current clinical trials are evaluating more than 225 new or repurposed drugs for treatment of COVID-19. Given the resurgence of cases, a shortage of potential patients for these trials shouldn’t be a problem. Nonetheless, it has become increasingly clear that a more cohesive clinical trial system is sorely needed.
The good news is that it looks like the NIH can provide such a coordinating role. The leadership of the NIH in supporting research on COVID-19 treatment was recently manifest in publication of the “Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit” in the Journal of Infectious Diseases. The NIH also recently launched a large trial called ACTIV-6 that is expected to enroll 13,500 people. ACTIV-6 will test a battery of existing drugs against a placebo to see if any of them can reduce the chance of people needing hospitalization. The goal is to potentially have up to eight “arms” of the trial with all the drugs being tested at the same time. Patients getting the placebo will serve as the comparison group for all drugs.
The war against SARS-CoV-2 is a World War and it’s not over. Vaccines remain our main weapon and they need to be distributed widely around the globe. This is certainly not the time to relax the all-out efforts to vaccinate everyone. But vaccines alone won’t defeat SARS-CoV-2. Development of antiviral drugs akin to the 20+ oral agents now available to treat HIV/AIDS patients could play an important complementary role. Plus, masking and social distancing, even after being vaccinated, are also vitally important measures to decrease the chances that the enemy (SARS-CoV-2) will find an unarmed (that is, unvaccinated) human target.
