COVID-19 Treatments in the Pipeline

Learn about the clinical evidence behind treatment modalities

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The novel coronavirus (COVID-19) has evolved into a pandemic that has infected more than a million people worldwide. Scientists and researchers are actively working to find treatments for the disease, and ideally, find a way to prevent infection in the first place.

There are hundreds of clinical trials underway evaluating the potential effectiveness of existing drugs and testing the viability of vaccines and blood products. As of May 1, only one treatment has received emergency use authorization from the Food and Drug Administration (FDA): remdesivir, which was initially developed as a treatment against Ebola.

Medications

Many existing medications indicated for other conditions are now being evaluated for potential effectiveness against COVID-19. A February 2020 study published in the journal Cell Research showed seven different drugs had some effect against the virus, but many require concentrations too high to be safely administered.

The following medications show promise for COVID-19, but study sizes are small and data is inconclusive. It is not safe to try to seek out these medications on your own.

Hydroxychloroquine and Chloroquine

Hydroxychloroquine and chloroquine are medications currently FDA-approved to treat malaria and autoimmune diseases such as lupus and rheumatoid arthritis. By interfering with protein glycosylation and other enzymatic processes, it is believed these medications could prevent COVID-19 from binding to, entering, and replicating in human cells.

A study comparing hydroxychloroquine to chloroquine found that hydroxychloroquine is slightly less potent, but still potentially effective against COVID-19 in vitro.

What the Research Says

A French study led the way in hydroxychloroquine and chloroquine research. It initially included 26 COVID-19 patients being treated with a hydroxychloroquine regimen and 16 untreated control patients. Six of the patients treated with hydroxychloroquine were also treated with azithromycin (also known as a Z-Pack, which is prescribed for several infections).

On paper, results look promising: By day six, the study authors noted that people treated with hydroxychloroquine had decreased their viral load—the amount of virus in their blood—by 57%, and those also treated with azithromycin had cleared the virus altogether.

While this was encouraging, the study did not address how the patients fared clinically, meaning whether or not their symptoms started getting better. Also, it was unclear if the treatment led to the medical issues that prevented study participants from following up with researchers (one died, three transferred to the intensive care unit, one stopped treatment due to medication side effects, one left the hospital).

Although the data was limited, it led to an acute shortage of these medications. The federal government has tried to stockpile the medications and some physicians have reportedly prescribed it for themselves and their families. This has left people who need these medications for their chronic conditions without treatment. Many states have had to put emergency orders in place to limit inappropriate prescriptions of these medications.

While the FDA granted emergency use authorization for both chloroquine phosphate and hydroxychloroquine sulfate products for COVID-19 in March, on June 15, it revoked the authorization, citing ineffectiveness and serious side effects.

While there is also anecdotal evidence to support their use, subsequent studies have not shown the same benefits. A second French study followed the same protocol as the original study but found that hydroxychloroquine did not significantly improve symptoms or decrease the clearance of the virus from the body. A Chinese study found no difference in outcomes between a treatment and a placebo group. A Brazilian study had to be discontinued early due to complications from high-doses of chloroquine. Another study shows that treatment with hydroxychloroquine prolongs the QT interval in more than 20% of COVID-19 patients. This finding on an electrocardiogram (ECG) can be associated with the development of life-threatening cardiac arrhythmias. A large study was published on May 22, 2020 in Lancet, including more than 96,000 patients hospitalized with COVD-19 from around the world. Compared with a non-treatment control group, patients treated with hydroxychloroquine or chloroquine with or without azithromycin had an increased risk for dangerous cardiac arrhythmias by as much as 4% to 8% and an increased risk of in-hospital mortality (16% to 23% in the treatment group compared to 9% in the control group). On June 4, 2020, three of the four authors retracted the Lancet study due to an inability to verify certain data sets.

A study has since been released that shows potential benefits for hydroxychloroquine in the treatment of COVID-19. Researchers studied over 2500 adults and found that people treated with the drug had a mortality of 14% compared to a 26% mortality without it. When hydroxychloroquine was combined with azithromycin, mortality was 20%. There is controversy over the study, however, because the number of people treated with the steroid dexamethasone was considerably higher in the treatment groups, suggesting that the benefit may derive from the steroid rather than hydroxychloroquine or azithromycin. While 68% of all study participants were treated with steroids, only 35% in the non-treatment group received dexamethasone. Approximately 79% in the hydroxychloroquine group and 74% in the combined hydroxychloroquine with azithromycin group had also received steroids.

Antivirals

There are a number of antiviral treatments—medications that prevent a virus's ability to reproduce—being investigated for COVID-19 at this time.

  • Remdesivir was initially developed as a treatment against Ebola. After in vitro studies showed it may be effective against COVID-19, compassionate use requests allowed hospitals to access the drug for the treatment of severely ill patients. Gilead Sciences, who produces the drug, began looking into expanding use to allow more people access to the medication. On May 1, it became the first treatment option for COVID-19 to receive emergency use authorization from the FDA. The FDA has permitted it to be used in adults and children hospitalized with severe cases of the disease.
  • What the research says: A study published in the New England Journal of Medicine looked at 61 compassionate use cases of remdesivir treatment among hospitalized COVID-19 patients. These patients were severely ill; at the start of the study, 30 were on mechanical ventilation and four were on extracorporeal membrane oxygenation (ECMO). Over an average of 18 days, 68% of patients had improved oxygenation and 57% of the people on ventilators were able to be extubated. However, as many as 60% had side effects, and 23% of people (all in the mechanical ventilation group) developed severe complications, including multiple-organ-dysfunction syndrome, septic shock, acute kidney injury, and hypotension. A clinical trial—the Adaptive COVID-19 Treatment Trial (ACTT)—by the National Institutes of Health (NIH) has shown promising results. People with severe COVID-19 infections that were treated with the drug had improvement in symptoms 4 days sooner (31% faster) than those who were not treated. Although there appeared to be an improvement in the overall survival rate, this was not statistically significant. Additional remdesivir studies are currently underway to assess effectiveness and clinical safety.
  • Favipiravir and arbidol are antiviral medications used to treat influenza. In high concentrations, they may be effective against COVID-19.
  • What the research says: In a study of 240 COVID-19 patients, researchers compared favipiravir effectiveness to arbidol. Symptoms of cough and fever improved much quicker with favipiravir than with arbidol, but there was no significant difference in the recovery rate by day seven. Both medications were well-tolerated with only mild side effects. Favipiravir continues to be investigated in other studies.
  • Lopinavir-ritonavir is a pair of antiviral medications used to treat HIV that may be effective against COVID-19.
  • What the research says: In a study of 199 people with pneumonia from COVID-19 and low oxygen levels, 94 were given lopinavir-ritonavir and the rest were given a placebo. Although more people treated with lopinavir-ritonavir had improved symptoms by day 14, (45.5% vs. 30%), there was no significant difference between the two groups when it came to the duration of oxygen therapy, the need for mechanical ventilation, the length of hospitalization, or mortality rate. Another study randomized 127 hospitalized adults with COVID-19 to either triple therapy with lopinavir-ritonavir, ribavirin, and interferon β-1b or to lopinavir-ritonavir alone. Patients in the triple therapy group stopped shedding the virus sooner (7 days vs. 12 days), had earlier improvement in symptoms (4 days vs. 8 days), and left the hospital sooner (9 days vs. 15 days). Other studies continue to explore the potential of this therapy.

Biologics

Severe cases of COVID-19 have been associated with what is called a cytokine storm. As part of the normal immune response, the body recruits cytokines—proteins secreted by immune system cells—to the site of infection. In some cases, however, that process becomes hyperresponsive and excess cytokines are released. Some of these cytokines are inflammatory in nature and can lead to worsening of respiratory symptoms or organ failure.

Biologic agents—pharmaceutical treatments created from biological sources—are now being considered to address this. Tocilizumab is a medication that blocks cell receptors from binding to interleukin-6 (IL-6), one of the pro-inflammatory cytokines. This, in theory, would help to decrease the severity of the cytokine storm and help people to recover faster.

What the Research Says

A case study of a patient with COVID-19 and underlying multiple myeloma noted high serum levels of IL-6. The patient was treated with conventional therapies (antivirals and steroids) and then received tocilizumab on day nine of his hospitalization. He had symptom improvement by day 12 and his IL-6 levels improved before he was discharged home. A study in Lancet Rheumatology found that there was a 39% decreased risk for ventilator use or death in COVID-19 pneumonia patients who were treated with tocilizumab when compared to those treated with standard therapy. However, tocilizumab acts as an immunosuppressant and the researchers found that those treated with the drug had a more than 3-fold increase in developing other new infections like invasive aspergillosis. Several other clinical trials are underway to assess the potential benefits of tocilizumab. There are also trials investigating another IL-6 inhibitor, sarilumab.

Dexamethasone

Dexamethasone is a steroid that is often used to treat inflammation. It comes in both oral and IV formulations. COVID-19 has been associated with a severe inflammatory reaction in many cases, and researchers looked to investigate the benefits of using this common anti-inflammatory drug.

What the Research Says

The RECOVERY trial (Randomised Evaluation of COVid-19 thERapY) trial) has found that treatment with once-daily dexamethasone over 10 days improved clinical outcomes when compared to placebo. Specifically, mortality rates decreased by 35% for patients who were placed on ventilators (8 patient would need to be treated prevent 1 death) and by 20% for people who required oxygen without ventilator therapy (25 patients would need to be treated to prevent 1 death). Patients who did not require oxygen or ventilator therapy did not see a clinical benefit from dexamethasone.

Antibodies and Plasma Exchange

Medications are one way to target COVID-19, but our own bodies may offer a way to combat the disease too. When we are exposed to a foreign substance like COVID-19, our immune system can develop antibodies against it. Blood that contains these antibodies is referred to as convalescent plasma.

Removing blood plasma from someone who is ill and replacing it with convalescent plasma from someone who has recovered from COVID-19 may help them fight the infection. This process is known as plasma exchange.

Convalescent plasma can be collected like a blood donation, and techniques are performed to assure the plasma is free of infection. It is currently recommended that someone be symptom-free for at least two weeks before donating plasma.

What the Research Says

Two small Chinese studies showed the potential benefit of using plasma exchange for treating severe cases of infection.

  1. One case series included five patients with severe pneumonia requiring mechanical ventilation
  2. A pilot study included 10 patients with severe COVID-19 infections

All patients underwent transfusion with convalescent plasma. Both studies noted improved symptoms within three days and decreased viral load within two weeks (12 days for the case series, seven days for the pilot study). The ability to wean off a ventilator was slow, however, and was not achieved for all patients. Most importantly, there seemed to be no harm caused by the treatment.

In April 2020, the FDA approved two randomized, placebo-controlled clinical trials at Johns Hopkins Medicine to see if blood plasma can help to prevent COVID-19 infection, not just treat those who are severely infected. A study in Mayo Clinic Proceedings noted that not only was convalescent generally safe when used to treat 20,000 hospitalized COVID-19 patients, it may be associated with decreased mortality, especially when administered earlier in the course of the illness.

The studies are complicated by the fact that all patients in these studies also received other therapies, like antiviral medications and steroids. Without standardized controls, it can be hard to know if the convalescent plasma or one of those other therapies led to the actual clinical improvements. More robust trials need to be performed to determine the optimal concentration of the convalescent plasma and timing of the plasma exchange to see if this can be a viable treatment for patients.

Dozens of U.S. hospitals are now a part of the National COVID-19 Convalescent Plasma Project, working together to investigate therapeutic plasma exchange.

Vaccines for COVID-19

The best hope for managing COVID-19 long-term is to develop a vaccine. Vaccines expose your body to an antigen—a substance that cause an immune response, in this case from a virus—and trigger antibody production from your immune system. The goal is to make antibodies against the virus without causing an infection. That way, if you are exposed to that antigen again (if, say, COVID-19 resurges in the fall), your body will remember how to make those antibodies against it. Hopefully, your immune response will be so strong you won't get sick at all. But if you do get sick, your symptoms will be milder than if you did not get the vaccine.

What the Research Says

An initial study looked to develop a vaccine by targeting the coronavirus spike (S) protein, a structural component of the virus. Researchers were able to generate an immune response to COVID-19 in rodents, and antibodies were produced within two weeks. This is promising as we turn to clinical trials in humans.

To date, the FDA has approved two Phase I clinical trials in humans for vaccines. It will be several months before we can expect to see results:

  1. The National Institute of Allergy and Infectious Diseases (NIAID) is funding a trial. It is based on a RNA vaccine co-developed by the NIAID and the biotechnology company Moderna Inc. The trial has enrolled 45 healthy study participants and the first injections were administered on March 16, 2020.
  2. The Coalition for Epidemic Preparedness Innovations and the Bill and Melinda Gates Foundation are among the multiple funding sources for the second clinical trial. A DNA vaccine developed by INOVIO Pharmaceuticals, Inc. will be given to 40 healthy study participants. The first injections were administered on April 6, 2020.

In the UK, Oxford University's Jenner Institute has surged ahead in vaccine research, planning to complete human trials of its COVID-19 vaccine in over 6,000 people by the end of May. Because its vaccine for a different type of coronavirus showed promise in smaller human trials last year, the Jenner Institute is able to move forward quickly. So far, the COVID-19 vaccine has been able to keep rhesus macaque monkeys exposed to the virus healthy.

A Word from Verywell

It is important to offer hope in this time of uncertainty, but it is also imperative that we find objective, scientifically-proven ways to protect ourselves. With hundreds of clinical trials in the works, we must stay vigilant when it comes to vetting what works and what does not. Treatments need to be proven safe and effective before we use them to treat large parts of the population.

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