11 May 2020
With millions of people infected, and fatalities numbers growing alarmingly, an urgent search is underway for drugs to treat COVID-19 patients. Many treatments have been touted as potential cures, and now some are undergoing trials. Here’s an outline of the most talked about treatment options currently under study.
Convalescent plasma (CP) therapy was developed and used as a therapy in the flu pandemic of 1918-19, the concept is straightforward: take blood plasma containing neutralising antibodies from a person who has recovered, and transfuse it into patients with COVID-19.
Studies1 on patients in Wuhan, China, indicate the approach of preventing the SARS COV-2 virus from entering cells might work. Patients experiencing life-threatening respiratory distress showed some improvement, and the viral load levels in their bodies dropped. CP therapy was used to good effect in the previous SARS, MERS, and H1N1 outbreaks. A meta-analysis2 by John Mair-Jenkins and colleagues, published in 2014, showed that mortality rates were reduced after patients with severe acute respiratory infections received various doses of convalescent plasma, with no adverse events or complications after treatment.
There are a number of efforts to investigate CP. The most advanced is in the United States, a national COVID-19 Convalescent Plasma Project run by Michigan State University, and the Mayo Clinic. “The environment is conducive to moving the process forward,” said Priya Sampathkumar, a consultant at the Division of Infectious Diseases at the Mayo Clinic.
There are, however, problems with collecting sufficient quantities. A single donor yields only so many antibodies per draw, so a large pool of recovered donor patients is required. Further tests are then needed to establish what levels of antibodies are effective, so that dosage can be established. Work is progressing, and a neutralizing antibody test should soon be available onsite at the Mayo Clinic, Sampathkumar added.
There are several clinical trials underway, some due for completion by the end of this year, including a phase III trial in Paris due for completion in August, and another in Beijing due for completion in June. Johns Hopkins is also starting a trial to assess whether convalescent plasma could be used as a prophylactic measure to confer passive immunity against COVID-19.
In the United States, immunologist Arturo Casadevall from Johns Hopkins is spearheading a nationwide effort to encourage plasma donation from recovered COVID-19 patients spans 40 US institutions, including Johns Hopkins University, and the Mayo Clinic. The UK’s National Health System (NHS) Blood and Transplant is also leading a programme across 23 blood centres to collect convalescent plasma for clinical trials. Saudi Arabia has also launched its own study into using convalescent plasma to treat COVID-19.
Several industry players, including Takeda, CSL Behring, Biotest, Bio Products Laboratory, LFB, Octapharma and Microsoft have collaborated to develop an unbranded polyclonal antibody product from a pool of donors.
Using a familiar anti-viral drug may seem the quickest and safest approach, but scientists warn that this route is far from guaranteed.
Remdesivir is a nucleotide analogue anti-viral originally considered for Ebola. On April 29, Anthony Fauci, director of the US National Institute for Allergy and Infectious Diseases (NIAID) announced that a clinical trial in more than 1,000 people had showed that those taking remdesivir recovered in 11 days, compared with 15 days for those on a placebo. The U.S. Food and Drug Administration (USFDA) has now authorized the use of remdesivir to treat COVID-19.
Data from the trial referred to by Fauci has not been placed in the public domain, and scientists, clinicians, and those in public health have not been able to analyze efficacy. To add to the confusion, it follows the publication of a study in The Lancet3 from a randomised double-blind trial in 237 severely ill patients in China which concluded the drug failed to have any clinical benefits.
Gilead Sciences, the US company that makes the drug, began increasing its production for clinical use from the end of March, before trial results were available, so that stocks would be immediately ready. Even if remdesivir is effective, is not taken orally as is not available in a capsule or tablet form, and must be injected, making wide-scale population treatment more difficult.
Joint research is underway into the nucleoside analogue, EIDD-2801, at the University of North Carolina, Emory University, and Vanderbilt University Medical Center. EIDD-2801 is an experimental antiviral drug that works by blocking RNA polymerase. The orally bioavailable drug was developed in 2018 in the search for a universal influenza vaccine, and with the outbreak of COVID-19, research turned to the SARS-COV2 virus. Data published in Science of Translational Medicine4 in early April shows promising activity against SARS-COV-2 in cells and mice. But it’s a longer route to efficacy, and EIDD-2801 hasn’t gone through the safety screening that remdesivir has in human trials.
Another candidate that falls under the category of repurposed antivirals is chloroquine, the malaria drug, and its cousin, hydroxychloroquine, sometimes used in conjunction with the antibiotic azithromycin. Although sometimes touted as a potential treatment for COVID-19 , there has been no significant scientific evidence to back the claim.
The USFDA warned in a communication on April 24 that these drugs can cause dangerous abnormalities in heart rhythm in coronavirus patients. The caution is based on a review of adverse events reported from multiple hospital and outpatient settings for treating or preventing COVID-19, the agency said, including rapid, irregular heartbeats, abnormal heart rates, delayed recharge by the heart muscle between beats, and in some cases, death.
Kaletra, a lopinavir-ritonavir therapy developed for HIV was also considered, but it lacks supporting data for in-vitro activity against SARS-COV2. “Structurally, the HIV protease is quite different from the proteases, of which there’s more than one, in SARS-COV-2. It would be serendipity if it was active against the SARS-COV-2 protease,” says Nick Matheson, principal investigator at the Cambridge Institute of Therapeutic Immunology and Infectious Diseases (CITIID) and honorary consultant in infectious disease at Addenbrooke’s Hospital, Cambridge.
Existing anti-inflammatories are also being repurposed to potentially treat COVID-19.
There are also novel treatments such as tocilizumab, a humanised monoclonal antibody that works against the signalling chemical, interleukin-6, and has been used so far in the treatment of rheumatoid arthritis. Tocilizumab’s efficacy is being studied in phase III trials across sites in the United States, Europe and Canada, but no significant findings have been yet published.
- Duan, K. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proceedings of the National Academy of Sciences. 117 (2020) | article
- Mair-Jenkins, J. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: A systematic review and exploratory meta-analysis. The Journal of Infectious Diseases, 211 (201) | article
- Wang, Y. et al. Remdesivir in adults with severe COVID-19: a randomised double-blind, placebo-controlled multicentre trial. Lancet. (2020). | article
- Sheahan, T. An orally bioavailable broad-spectrum antibiral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Science Translational Medicine. 12 (2020) | article