COVID-19 Tx Pipeline: Which drugs are showing early promise

The scramble to discover effective treatments for COVID-19 is in full swing. As the pandemic rages on—taking more lives in the United States than anywhere else in the world—researchers are busy conducting clinical trials of some promising treatments, hitting the SARS-CoV-2 virus and COVID-19 disease from many different therapeutic angles: from transmission to viral replication to symptomatology.

Here’s a look at what’s in the (shortened) pipeline thus far.

Remdesivir

Originally used for Ebola virus and other highly contagious diseases, the still-investigational drug remdesivir (Gilead Sciences) is thought to--by the WHO--to have the most potential to effectively treat patients infected with the novel coronavirus. Remdesivir is an investigational broad-spectrum antiviral treatment previously tested in humans with Ebola virus disease but found to be ineffective. In the past, remdesivir showed promise in animal models for the treatment of Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), both caused by other coronaviruses.

Remdesivir works to prevent human cells from infection with SARS-CoV-2. The WHO has started clinical trials of remdesivir in Spain and Norway. Clinical trials of remdesivir have also begun in China and, in the United States, five clinical trials are underway to assess the ability of remdesivir to shorten the disease course of COVID-19. In the United States, the study is being funded by the NIH, and is the first clinical trial to evaluate an experimental treatment for COVID-19.

Researchers at Gilead have published data on the outcomes of 53 patients with COVID-19 who were treated with remdesivir on a compassionate-use basis in The New England Journal of Medicine. After 10 days of treatment and a median of 18 days of follow-up, 68% showed improvements in oxygen-class support, and over half of those who had been mechanically ventilated were extubated. The lack of a control arm in this study, however, is problematic. 

In two phase 3 clinical trials also from Gilead, researchers at the University of Chicago Medicine included 125 participants, 113 of whom had severe disease. All received daily IV remdesivir. Unpublished, preliminary data show that only two patients died, and the rest have been discharged.

Many studies of remdesivir are also being conducted at other institutions, and although results are eagerly awaited, none are available as yet.

The FDA has approved the use of remdesivir for compassionate use in patients with severe COVID-19. On March 22, however, Gilead Sciences temporarily halted its compassionate use of the drug due to “overwhelming demand.”

Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine—long used as antimalarials, as well as for rheumatoid arthritis and lupus—have gotten a lot of press as potential treatments for COVID-19. Chloroquine confounds the ability of the SARS-CoV-2 virus to enter and replicate in human cells, and its derivative, hydroxychloroquine, does the same.

Researchers around the world are currently conducting clinical trials of these agents for both pre- and post-exposure prophylaxis of SARS-CoV-2 infection, and for treatment in patients with mild, moderate, and severe COVID-19.

For example, in China, seven clinical trials of hydroxychloroquine are underway. Researchers at the University of Minnesota, Minneapolis, MN, are also conducting a study to determine whether hydroxychloroquine can protect those living with COVID-19–positive patients from catching the virus.

In a study conducted by researchers in France, in which patients with COVID-19 received treatment with either hydroxychloroquine alone or in combination with the antibiotic azithromycin, detectable concentrations of SARS-CoV-2 decreased significantly faster than those who did not receive hydroxychloroquine. And, in those study participants who were also treated with azithromycin, this effect was even greater. The CDC stressed, however, that one small study was not enough to assess the clinical benefit of hydroxychloroquine, and advised caution on the part of clinicians in prescribing either drug.

In a collaboration between the University of Washington, and New York University, researchers plan an 8-week study—the COVID-19 PEP study—of the efficacy of hydroxychloroquine in preventing COVID-19 following viral exposure. The study is currently recruiting participants—with a goal of enrolling 2,000— and people who live in western Washington state or New York City who have had close contact with someone with COVID-19 may be eligible. Results are expected by the end of summer this year.

The FDA has issued an Emergency Use Authorization for the use of chloroquine and hydroxychloroquine from the Strategic National Stockpile for the treatment of hospitalized adults and adolescents with COVID-19 for whom a clinical trial isn’t available or participation is not possible.

Colchicine

Colchicine (Colcrys, Mitigare; Takeda Pharmaceuticals) is an inexpensive, FDA-approved, powerful anti-inflammatory drug used to treat gout and pericarditis. It’s currently being studied for its usefulness in mitigating the cytokine storm caused by the novel coronavirus. Researchers at the Montreal Heart Institute and the University of Montreal hope that colchicine can stop the body’s overproduction of immune cells and cytokines, which leads to a cytokine storm that damages lung tissue and leads to acute respiratory distress and multi-organ failure. Researchers are hoping to recruit 6,000 Canadians with the novel coronavirus for a clinical trial. They hope to determine the efficacy of colchicine against COVID-19 within the next 3 months. 

Combination lopinavir and ritonavir

The combination of the antivirals lopinavir and ritonavir (Kaletra; AbbVie) is an HIV medication that may be helpful in treating COVID-19. Although new data from a study done in China showed no mortality benefit in patients taking it, other studies are being done—including one from researchers at Oxford University—and the hope is that it may still prove efficacious against COVID-19, particularly if given early on in the disease course. Researchers are also studying this antiviral combination plus interferon-beta, an immune system messenger that may help combat the SARV-CoV-2 virus.

Immunosuppressants sarilumab and tocilizumab

Sarilumab (Kevzara, Regeneron and Sanofi) and tocilizumab (Actemra; Roche) are interleukin (IL)-6 inhibitors both being studied in patients for their ability to calm the cytokine storm caused by COVID-19. IL-6 is thought to play a role in driving the overactive inflammatory response that occurs in the lungs of patients who are critically ill with COVID-19, causing acute respiratory distress syndrome, as seen in a previous study in China of another IL-6 receptor antibody.

Sarilumab is a fully human monoclonal antibody currently approved for the treatment of adults with moderate-to-severe active rheumatoid arthritis who have not responded to one or more disease-modifying antirheumatic drugs. Regeneron and Sanofi have begun a phase 2/3 randomized, double-blind, placebo-controlled clinical trial to assess sarilumab in hospitalized patients with severe COVID-19.

Tocilizumab is currently approved to treat rheumatoid arthritis and juvenile rheumatoid arthritis. Roche has initiated a phase 3 clinical trial in hospitalized patients with severe COVID-19–related pneumonia. 

Losartan

Losartan is a generic anti-hypertensive medication that is being studied for the treatment of COVID-19. Researchers at the University of Minnesota have launched two clinical trials to assess not only whether losartan may prevent multi-organ failure in patients hospitalized with COVID-19–related pneumonia, but also whether losartan may prevent hospitalizations altogether in these patients. Losartan blocks the angiotensin-converting enzyme 2 (ACE2) receptor, to which SARS-CoV-2 binds. By blocking these receptors, losartan could prevent the virus from infecting cells.

Two recent studies, however, have poked holes in this hypothesis. In the first, researchers raised the possibility that antihypertensives, including losartan, could actually induce the body to make more ACE2, increasing the ability of SARS-CoV-2 to bind to and infiltrate cells. In the second study, Italian researchers found that three-quarters of patients with COVID-19 who died had hypertension. Antihypertensive treatment may have been the reason for their increased susceptibility.  

EIDD-2801

An investigational agent, EIDD-2801, has shown promise in in vitro experiments with human lung and airway cells from patients with COVID-19, according to a report in Science Translational Medicine. This drug works by introducing genetic mutations into coronavirus’ RNA. As the RNA makes copies of itself, replicating these mutations, the damaged mutations accumulate and render the virus unable to infect cells. One of the advantages of EIDD-2801 is that because it is an oral medication rather than an IV one, like remdesivir, it can be administered at home, shortly after a diagnosis of COVID-19. According to lead author Timothy Sheahan, PhD, Department of Epidemiology, University of North Carolina at Chapel Hill. “This has the potential to be as ubiquitous as Tamiflu in the future, as long as it proves to be safe and effective in people.”

EIDD-2801 is also effective against other RNA viruses and, thus, may have multiple uses. In preclinical studies, it has been shown to be effective against several strains of influenza, viruses for respiratory syncytial virus, and viruses for chikungunya, Venezuelan equine encephalitis, and Eastern equine encephalitis.

Human trials have not yet been done, but researchers are hopeful that EIDD-2801 may be beneficial as prophylactic treatment for healthcare workers, as well as uninfected nursing home residents and workers. Ultimately, EIDD-2801 is hoped to be available as an oral pill to be taken twice daily at home early on in the course of illness to prevent progression, hospitalization, mechanical ventilation, and death.

The FDA has granted Ridgeback Biotherapeutics—who licensed EIDD-2801—permission to begin human trials.

Vitamin C

The use of vitamin C to treat patients with COVID-19 is based on no evidence from clinical trials. Rather, it is supported by positive reports from China. Patients with COVID-19 in Shanghai who received large doses of vitamin C did significantly better than those who did not. New York-based pulmonologist and critical-care specialties Andrew Weber, MD, has been administering 1,500 mg of IV vitamin C to ICU patients with COVID-19 three to four times daily. A randomized, triple-blind clinical trial of IV vitamin C in patients with COVID-19 is currently underway and is expected to be completed shortly, on September 30, 2020.

Plasma-derived therapy

Plasma-derived therapy is comprised of searching for antibodies to COVID-19 using plasma from COVID-19 survivors and injecting that plasma into patients with active COVID-19. The FDA is currently expediting the use of this blood plasma treatment for seriously ill patients with COVID-19.