The World Health Organization (WHO) have launched SOLIDARITY, a giant trial, testing the potential of therapies, old and new, to beat the coronavirus that is causing the current pandemic.
The FDA have removed the Emergency Use Authorization (EUA) for hydroxychloroquine and chloroquine for the treatment of COVID-19. Based on a review of the latest research, the FDA determined that these drugs are not likely to be an effective treatment for COVID-19 and that the risks of using them for this purpose might outweigh any benefits.
In a press briefing last Friday, WHO director-general, Dr. Tedros Adhanom Ghebreyesus, announced the launch of SOLIDARITY, a giant multinational trial for testing therapies that researchers have suggested may be effective against COVID-19.
“That’s why WHO [have] launched the SOLIDARITY trial, to generate robust, high quality evidence as fast as possible,” Dr. Ghebreyesus said.
“I’m glad that many countries have joined the SOLIDARITY trial that will help us to move with speed and volume. The more countries that sign up to the SOLIDARITY trial and other large studies, the faster we will get results on which drugs work, and the more lives we will be able to save.”
– Dr. Tedros Adhanom Ghebreyesus
SOLIDARITY includes research looking at four possible therapeutics: remdesivir; chloroquine and hydroxychloroquine; lopinavir plus ritonavir; and lopinavir plus ritonavir and interferon-beta.
Scientists originally developed remdesivir as a drug to treat Ebola. However, clinical trials later indicated that the compound was insufficiently effective against the virus that causes that disease.
The drug relies on a mechanism that appears to be effective against other viruses, specifically coronaviruses, however.
So, more recently, investigators have started experimenting with the drug to fight SARS-CoV-2, the virus that causes COVID-19.
In one case study from earlier this month, doctors reported that a 35-year-old male from the United States, who received remdesivir after contracting the new coronavirus, started to recover soon after he began the drug. There have since been other reports of people recovering from COVID-19 thanks to this drug.
Remdesivir works by inhibiting a specific enzyme, RNA polymerase, which normally allows the virus to replicate. Without that enzyme, the virus becomes less able to maintain its hold on the body.
Commenting on a preliminary in vitro study, suggesting that remdesivir may be effective against SARS-CoV-2, Dr. Andrew Preston, from the University of Bath in the United Kingdom, explains that the drug “mimics one of the building blocks of the viral genome, but is nonfunctional, causing premature termination of virus genome replication.”
A WHO report from March 13 indicates that “chloroquine has received significant attention in [different] countries as a potentially useful prophylactic [preventive] and curative agent, prompting the need to examine emerging evidence to inform a decision on its potential role.”
The report weighed the results of different preliminary studies that tested the potential of chloroquine and hydroxychloroquine in the treatment of COVID-19, and it paved the way for larger trials due to verify the effectiveness of these drugs against the new disease.
In his independent comment, Dr. Preston notes that “[t]he anti-viral effects of chloroquine are thought to derive from two distinct functions.”
“In one,” he explains, “chloroquine blocks the synthesis of parts of the virus receptors on cells, by inhibiting the addition of certain sugar groups to the cell surface that are recognized by the virus.”
“In the second mechanism, following attachment of the virus to the cell surface, it is internalized within a membrane-enclosed compartment,” which may ultimately inhibit the virus’s replication.
The commentator further observes: “The virus escapes from this to reach the internal environment of the cell in a process that is triggered by a reduction in pH (making more acidic) of this compartment. Chloroquine can increase the intracellular pH (make it more alkaline), and this inhibits the escape of the virus into the cell where it replicates.”
Ritonavir and lopinavir are two compounds that doctors administer together as antiretroviral therapy — the therapy that treats HIV infections.
Research from The Lancet in January has suggested that this drug combo may be able to fight SARS-CoV-2 by targeting a specialized molecule that allows both HIV and coronaviruses, such as SARS-CoV and MERS-CoV, to replicate.
However, a trial whose results appeared in The New England Journal of Medicine earlier this month, cast a shadow of doubt upon this drug combo’s effectiveness.
In this trial, the researchers found that there was virtually no difference in outcome between patients with COVID-19 who received standard care, and those who received ritonavir and lopinavir.
However, the patients who agreed to join the trial had severe symptoms, which may mean that they received the intervention too late for it to be helpful.
To boost the potential effectiveness of ritonavir and lopinavir, one trial is testing a combination of those two drugs and interferon-beta, a compound doctors use as first-line therapy in the treatment of multiple sclerosis.
The trial — called MIRACLE — is currently testing this experimental treatment with the consent of MERS patients.
Yet another upcoming trial — supported by a U.K.-based pharmaceutical company and not part of the WHO effort — aims to use a specific formulation of interferon-beta on its own in the treatment of COVID-19.
“The idea behind the trial is that, by giving more of this molecule to the lung, this could help reduce the severity of infection with COVID-19, especially in those people who have reduced immune responses to the virus,” explains Prof. Ian Hall from the University of Nottingham in the U.K. Prof Hall is not associated with the upcoming trial.
The multinational WHO endeavor, as well as unrelated studies and trials taking place around the world, are all part of international efforts to bring SARS-CoV-2 definitively under control.
“We […] recognize that there is a desperate need for effective therapeutics. There is, currently, no treatment that has been proven to be effective against COVID-19,” emphasized Dr. Ghebreyesus in his press briefing.
Yet, he went on to add, “[i]t’s great to see the level of energy now being directed to research against COVID-19.”
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