As of Friday, May 8, 2020 (the latest data available as of this writing), the Johns Hopkins Coronavirus Resource Center (Johns Hopkins) estimates that, worldwide, there are over 3.9 million cases of coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2, and there have been over 270,000 deaths. The comparable Johns Hopkins estimates for the US are over 1.27 million cases and over 76,000 deaths. Currently, there is no approved targeted therapy for patients with COVID-19. Since the disease was first identified in Wuhan, China, in December 2019, various antiviral therapies have been studied; this report examines therapies being tested in the US and elsewhere, whether in the lab or in clinical practice. The data is current as of Friday, May 8, 2020; we will continue to monitor this rapidly changing area; please contact the authors or your DLA Piper relationship attorney for the most current information.
The CDC states: “An array of drugs approved for other indications as well as several investigational drugs are being studied in several hundred clinical trials that are under way across the globe” (retrieved from: www.CDC.gov). Most researchers think that the fastest route to developing new treatments is to repurpose existing compounds that have been already approved for human use by the FDA or by corresponding health agencies in other countries. The consensus in the scientific community is that compounds that have shown promise in treating other diseases -- such as Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) caused by related types of coronaviruses have the best chance of success in treating patients with COVID-19. However, a lesson learned from efforts to find effective therapies for MERS and SARS is that, while numerous compounds tested in vitro or in animal models have been found to inhibit the entry of virus particles into cells and/or replication of the virus once inside a cell, these results do not necessarily translate into efficacy in humans (Zumla et al., 2016).
While some of these investigational compounds have been administered to patients in the context of clinical trials, access to these compounds outside of the clinical trial setting is limited. Clinical trials provide a controlled setting where patients can be randomly assigned to groups that receive either the treatment in question (the “experimental” group) or a placebo; this model is designed to create groups that are similar in all respects other than their experimental/placebo status, so that any observed difference in health outcome between the groups is likely attributable to the treatment. Further, clinical trials are closely monitored by safety boards. A safety board can halt a trial before its scheduled conclusion under two circumstances: (1) a treatment clearly shows a harmful effect or, in some cases, clearly shows no effect at all; and (2) a treatment shows a clear benefit. In this latter circumstance, it may be recommended that all comparable patients receive the treatment in question. Because no other treatment options are available, in areas without clinical trials, some patients in the US and other countries have been treated with some of these medications on an uncontrolled, “compassionate use” basis.
As of May 8, 2020, there are over 1,300 clinical trials investigating potential therapies for COVID-19, of which nearly 800 are interventional trials. Below is a summary of some compounds and medications that are currently being evaluated as therapies. It is important to understand that all of these compounds are investigational. As of the date of this publication, none of these compounds and medications have been approved for the treatment of COVID-19. These compounds and medications can be grouped into three broad categories: antivirals, immune-system based therapies, and vaccines (to prevent the disease in healthy people).
Darunavir is part of a class of drugs known as protease inhibitors; these drugs inhibit viral replication. Darunavir has been shown to inhibit replication of the human immunodeficiency virus 1 (HIV-1). On February 4, 2020, researchers in China announced that darunavir inhibited SARS-CoV-2 infection in vitro (Dong et al., 2020).
Favipiravir is a drug thought to act by interfering with enzymes necessary for viral replication and was approved in China for treatment of COVID-19 in February 2020. The drug is currently undergoing clinical trials as a treatment for COVID-19. The preliminary results from a study of 80 patients (including both the experimental group and the control group) indicated that favipiravir had more potent antiviral action than that of lopinavir/ritonavir (discussed below) (Dong et al., 2020).
Hydroxychloroquine and chloroquine are oral prescription drugs that have been used to treat malaria and some inflammatory conditions such as rheumatoid arthritis. The mechanism of action of these related compounds in combatting viral infections is not well understood, but, based on in vitro studies, they are thought to decrease intracellular acidity, thereby inhibiting viral propagation. On March 30, 2020, the FDA issued an EUA for both hydroxychloroquine and chloroquine. An EUA is not a full approval of a drug, and it is separate from the use of a product under an investigational drug application. The FDA can issue an EUA if it determines (a) that the known and potential benefits of the product, when used to diagnose, prevent, or treat the identified disease or condition, outweigh the known and potential risks of the product; and (b) that there are no adequate, approved, available alternatives. 21 U.S.C. § 360bbb-3 (c)(2)(B), (3). On April 4, 2020, the CDC took the unusual step of posting dosing information for hydroxychloroquine and chloroquine, despite there being an absence of peer-reviewed studies on the subject. Three days later, the CDC removed the extended guidance; the website now states “Hydroxychloroquine and chloroquine are under investigation in clinical trials” for use on COVID-19 patients. (retrieved from: www.CDC.gov). A combination of chloroquine with remdesivir, a novel compound (described further below), has been found to inhibit the growth of SARS-CoV-2 in vitro. However, as with any in vitro data, this information needs to be verified in clinical trials translated into patient therapy (Guo et al., 2020). One small study reported that hydroxychloroquine, either alone or in combination with the antibiotic azithromycin, reduced detection of SARS-CoV-2 RNA in the upper respiratory tract compared to controls. This study, however, did not evaluate whether this treatment resulted in clinical benefit (Gautret et al., 2020). The most recently published study found no evidence of a strong antiviral activity or clinical benefit of the combination of hydroxychloroquine and azithromycin for the treatment of hospitalized patients with severe COVID-19 (Molina et al., 2020). On April 24, 2020, the FDA issued a Drug Safety Communication entitled “FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems” (FDA 2020). The Communication states:
The FDA is aware of reports of serious heart rhythm problems in patients with COVID-19 treated with hydroxychloroquine or chloroquine, often in combination with azithromycin and other QT prolonging medicines. We are also aware of increased use of these medicines through outpatient prescriptions. Therefore, we would like to remind health care professionals and patients of the known risks associated with both hydroxychloroquine and chloroquine….
Hydroxychloroquine and chloroquine have not been shown to be safe and effective for treating or preventing COVID-19. They are being studied in clinical trials for COVID-19, and we authorized their temporary use during the COVID-19 pandemic for treatment of the virus in hospitalized patients when clinical trials are not available, or participation is not feasible, through an Emergency Use Authorization (EUA).
Hydroxychloroquine and chloroquine can cause abnormal heart rhythms such as QT interval prolongation and a dangerously rapid heart rate called ventricular tachycardia. These risks may increase when these medicines are combined with other medicines known to prolong the QT interval, including the antibiotic azithromycin, which is also being used in some COVID-19 patients without FDA approval for this condition. Patients who also have other health issues such as heart and kidney disease are likely to be at increased risk of these heart problems when receiving these medicines….
To decrease the risk of these heart problems that can be life-threatening, we are warning the public that hydroxychloroquine and chloroquine, either alone or combined with azithromycin, when used for COVID-19 should be limited to clinical trial settings or for treating certain hospitalized patients under the EUA….
Further, in a clinical trial in Brazil, COVID-19 patients receiving high doses of hydroxychloroquine were found to have a greater incidence of heart issues and mortality. As a result, the high-dose arm of the study was halted. The study continues with a low-dose arm, but, as the study lacks a control group, any interpretation of the data will be difficult if not impossible (Borba et al., 2020).
Lopinavir is another protease inhibitor; like darunavir, it has been found to inhibit replication of the HIV-1 virus. It is being tested in combination with ritonavir, a compound that increases the half life of lopinavir. The combination (lopinavir/ritonavir) has been approved for treating SARS, MERS, and HIV-1 infections, but has not shown a benefit beyond standard care for COVID-19 patients in the most recently published clinical study (Cao et al., 2020). Further, a study from Taiwan reported that it also did not shorten the duration of SARS CoV-2 shedding (Cheng et al 2020). Lopinavir is continued to be evaluated in clinical trials.
Remdesivir (GS-5734) is a novel compound in development. Remdesivir has shown broad-spectrum antiviral activity against several RNA viruses, including coronaviruses like SARS-CoV and MERS-CoV, and is currently in clinical trials for the treatment of Ebola virus infections. In a study of mice infected with SARS-CoV virus, it was found to improve clinical signs of disease and respiratory function compared to untreated control mice. Remdesivir was used to successfully treat the first US case of COVID-19 (Holshue et al., 2020). In March 2020, the National Institutes of Health initiated several global phase III trials on the efficacy of remdesivir in COVID-19 patients with up to 75 sites in multiple countries, including sites in the US (see https://clinicaltrials.gov/). A randomized, placebo-controlled, double-blind, multicenter, phase III clinical trial of efficacy and safety of remdesivir in COVID-19 patients, initiated in China in February 2020, was expected to conclude by the end of April 2020, but was terminated early. Gilead Sciences, the main sponsor of the study, issued the following statement with regard to the study:
The study was terminated early due to low enrollment and, as a result, it was underpowered to enable statistically meaningful conclusions. As such, the study results are inconclusive, though trends in the data suggest a potential benefit for remdesivir, particularly among patients treated early in disease” (Parsey, 2020).
On April 29, 2020, Gilead released the results of its phase II clinical trial tracking two groups of patients who were hospitalized with COVID-19. One group received a five-day treatment of remdesivir, while the other group received a ten-day treatment. Of those receiving a five-day treatment, 64.5 percent were discharged within 14 days; of those receiving a ten-day treatment, 53.8 percent were discharged within 14 days. There was no statistically significant difference in the outcome between the five- and ten-day treatments. There was no control group (ie, no group receiving only “usual care” for the condition), so it was not possible to determine whether the medicine improved the overall course of the illness (retrieved from www.gilead.com).
The same day, the National Institutes of Health - National Institute of Allergy and Infectious Diseases (NIAID) released a statement describing the results of its trial of remdesivir (known as the Adaptive COVID-19 Treatment Trial, or ACTT). NIAID reported that the time to recovery was statistically-significantly shorter in patients treated with remdesivir than those on placebo. Patients receiving remdesivir had a median time to recovery of 11 days, compared to 15 days in those who were on placebo. The statement also noted a reduction in mortality, with a death rate of 8 percent in the treatment group compared to 11.6 percent in the placebo group, though this difference fell just short of statistical significance (retrieved from www.nih.gov). The full article describing the results of the ACTT study has not yet been published.
Also on the same day, a group from China published the results of a randomized double-blind placebo-controlled clinical trial conducted at ten hospitals in Hubei, China. The authors reported that the drug did not result in statistically significant clinical improvement. More adverse events were reported in the patients who received remdesivir (12 percent of patients) than in those who received the placebo (5 percent of patients) (Wang et al., 2020).
The FDA issued an emergency use authorization for remdesivir on May 1, 2020.
Immune system-related therapies
Sarilumab (trade name Kevzara) is a drug that works by damping down an overactive immune system. It has been used to treat certain autoimmune conditions, such as rheumatoid arthritis. The drug is an antibody for the pro-inflammatory cytokine IL-6. Following positive preliminary results reported from a small 21-patient study in China, a randomized placebo-controlled trial, in hospitalized patients with “severe” or “critical” respiratory illness caused by COVID-19, has been initiated at various hospitals in the US. Among those collaborating on the trial are the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services, and the Food and Drug Administration (FDA). On April 27, 2020, the preliminary results from a portion of the trial, Sarilumab showed negative trends for most outcomes in the “severe” group, but positive trends for all outcomes in the “critical” group. Following a review by the Independent Data Monitoring Committee (IDMC) of all available data, the arm of the trial that included “severe” patients was halted, but “critical” patients continued to receive treatment (Sanofi, 2020). As of May 8, 2020, there were 11 interventional clinical trials investigating Kevzara in COVID-19 patients.
Tocilizumab (trade name Actemra/RoActemra) is also an antibody targeting IL-6. Tocilizumab has been approved by the US FDA for the treatment of cytokine release syndrome, sometimes referred to as a “cytokine storm.” “Cytokine storms” can follow infections and are believed to be a factor in many critical and fatal cases of COVID-19. As of May 8, 2020, there were 35 interventional clinical trials investigating the use of Tocilizumab in COVID-19 patients. One trial of 25 critically ill COVID-19 patients reported that the mortality rate of patients treated with tocilizumab was significantly lower than the rate seen in hospitalized patients generally. However, the trial did not include a control group of patients who were not treated with the drug. Further, all patients in this study received concomitant investigational anti-SARS-CoV-2 therapies. Finally, the trial did not measure levels of interleukin-6 before and after the treatment with tocilizumab, thus preventing an assessment of its inhibitory effect on IL-6 (Alattar et al., 2020).
Convalescent plasma is purified plasma from the blood of persons who have recovered from COVID-19 infection; it has been examined as a therapy on the theory that, during the course of viral infection, most patients produce specific antibodies against the SARS-Cov-2 virus. Purified blood plasma contains these antibodies and, when injected into critically ill patients, may act to stimulate the body’s immune response to the virus. The success of this approach will depend in part on finding enough potential donors with sufficiently high levels of SARS-Cov-2 antibodies in their blood.
Using convalescent plasma as a treatment had been investigated during the SARS, Ebola, MERS and influenza A H1N1 outbreaks with some promising results, including reduced mortality and shorter hospital stays (Chen et al., 2020). Some patients have been treated with convalescent plasma in China during the current COVID-19 outbreak, and the reported results are encouraging. As of May 8, 2020, there are 61 clinical trials of convalescent plasma as a therapy for COVID-19, of which 48 are interventional trials (see https://clinicaltrials.gov/), and further trials are getting under way. One recently published study from China, involving 10 patients, reported that all patients treated with convalescent plasma had diminution or elimination of symptoms after convalescent plasma treatment (Duan et al., 2020). On April 13, 2020, the FDA stated: “Although promising, convalescent plasma has not yet been shown to be safe and effective as a treatment for COVID-19” (FDA, 2020b).
In the US, the Johns Hopkins Institute is leading the effort to develop plasma-based treatment, and researchers at the Mayo Clinic in Minnesota, the Stanford University Medical Center in California and the Albert Einstein College of Medicine in New York have joined that effort. If proven safe and effective, this therapy may see clinical use in a comparatively short time, as the process of plasma isolation is well-established.
Vitamin C has drawn media attention due to the claim of a pulmonologist with the Northwell Health system in New York, Dr. Andrew G. Weber, that COVID-19 patients in China who received Vitamin C “did significantly better that those who did not” (retrieved from: https://nypost.com/2020/03/24/new-york-hospitals-treating-coronavirus-patients-with-vitamin-c/). Some New York City hospitals have begun infusing certain COVID-19 patients with high doses of Vitamin C (more than 16 times the recommended daily intake) (Mongelli and Golding, 2020). The results of such aggressive Vitamin C treatment remain to be seen. Clinical trials for administration of Vitamin C to COVID-19 patients have begun in the US, China, Italy and Canada. As of May 8, 2020, there were 19 interventional trials investigating Vitamin C in COVID-19 patients.
A joint research team of the Shanghai Institute of Materia Medica and Shanghai Tech University examined a number of compounds, and on January 25, 2020, they reported 30 agents with potential activity against SARS-CoV-2 (Dong et al., 2020). Using a similar in silico approach, the US team of researchers screened FDA approved drugs with established safety profiles and identified over 100 medications with potential inhibitory effects on SARS-CoV-2 virus (Farag et al., 2020). These agents included the compounds darunavir, lopinavir, ritonavir, and remdesivir, described above. However, they also included other antivirals, anti-cancer medications, cholesterol-lowering compounds, antioxidants, and even drugs used to treat alcohol dependence (Dong et al., 2020; Farag et al., 2020).
There are currently 100 candidate vaccines in pre-clinical development and 8 candidate vaccines in clinical trials, according to the May 5, 2020 update from the WHO (www.who.int). This effort is at preliminary stage, and has not yet yielded scientific publications. Researchers and public health officials have stated that it is unlikely that such a vaccine will be ready for general use any earlier than 11 to 17 months from now.
For further reference on ongoing clinical trials, please visit this page.
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This information does not, and is not intended to, constitute legal advice. All information, content, and materials are for general informational purposes only. No reader should act, or refrain from acting, with respect to any particular legal matter on the basis of this information without first seeking legal advice from counsel in the relevant jurisdiction.
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