AsianScientist (Apr. 14, 2020) – A killer combo against HIV. A potential Ebola treatment that had fallen from grace. A “game-changing” antimalarial drug. What do these three seemingly distinct drugs have in common?
They are among the many therapeutics being given a second shot in the ongoing fight against coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus. Typically, it takes over a decade for a new drug to receive regulatory approval, but with the death toll rising by day, there’s no time left to lose.
To fast track treatments for COVID-19, pharmaceutical companies are turning to a practice known as ‘drug repurposing,’ where off-label uses are found for FDA-approved medicines. Given that the viruses causing SARS, MERS and COVID-19 all belong to the same Coronaviridae family, treatments found effective against one disease may prove useful for another. In fact, even blood serum from survivors may represent a possible antidote.
What are these treatments, then, and which one has the best chance of beating COVID-19? Find out in our roundup of seven potential treatments below.
- Lopinavir/ritonavir: unsuccessful to date
- Remdesivir: in clinical trials
- Favipiravir: in clinical trials
- Chloroquine and hydroxychloroquine: in clinical trials
- Actemra and Kevzara: in clinical trials
- Convalescent plasma
- Monoclonal antibodies
One of the first treatments explored early on in the outbreak was an HIV cocktail developed by Abbott Laboratories. Commercially known as Kaletra, the combination drug is composed of two antivirals, namely lopinavir and ritonavir. Both components work by inhibiting the action of HIV’s protease—when blocked, immature and non-infectious viral particles are subsequently produced.
In a 2015 study, the same combination was observed to improve MERS outcomes in marmosets, giving scientists reason to believe that it may also work for the novel coronavirus. Alas, a recent clinical trial involving 199 COVID-19 patients in Wuhan, China, found that lopinavir/ritonavir offered no additional benefit beyond typical hospital care.
Another therapeutic currently making the rounds in the spotlight is remdesivir from Gilead Sciences. Remdesivir works by crippling RNA polymerase, an enzyme required by viruses to multiply. Originally developed to treat Ebola, remdesivir fizzled out in mid-2019 after clinical trials in the Democratic Republic of Congo found that it was significantly less effective than two other treatments.
Even though remdesivir may have faltered against Ebola, it has shown some success in treating coronaviruses. In a study published in January 2020, researchers from the University of North Carolina at Chapel Hill demonstrated that remdesivir worked better than lopinavir/ritonavir in inhibiting the MERS virus in cell culture and mouse models.
Considering its potential, six trials testing the drug against different COVID-19 disease severity and dosing regimens are now underway at various locations around the globe, including China, France and the US.
Slowly gaining traction as another potential COVID-19 treatment is favipiravir, an anti-influenza drug from Fujifilm’s Toyama Chemical. Also known as Avigan, favipiravir shuts down viral replication by inhibiting RNA polymerase, similar to remdesivir.
On March 17, 2020, Chinese medical authorities announced that the drug was found effective in two clinical trials collectively involving 320 individuals in Wuhan and Shenzhen. In the Shenzhen trial, patients who were given favipiravir cleared the virus after just four days instead of 11 days for those who had received lopinavir/ritonavir.
While this information sounds encouraging, it’s still too early to pin all of our hopes on favipiravir. Case in point: Japanese health ministry officials have suggested that the drug may not be as effective in patients showing more severe symptoms. Therefore, use of favipiravir may be limited to mild and moderate cases of COVID-19.
The antimalarial drug chloroquine and its derivative hydroxychloroquine burst into the public imagination after US President Donald Trump praised the latter as potentially “one of the biggest game changers in the history of medicine.” His remarks appear to be based on the results of a tiny French study, in which 20 COVID-19 patients were treated with hydroxychloroquine. However, the results are dubious at best, as six patients dropped out of the treatment arm, and the measure of efficacy was viral load, which is not a clinical endpoint.
In malaria, chloroquine makes hemoglobin increasingly toxic for the parasite to digest, leading to its eventual death. With COVID-19, it may work by elevating the pH of endosomes, membrane-bound compartments within cells that play a crucial role in viral entry. This impairs the virus’ ability to hijack and fuse with host cells.
Although a hydroxychloroquine clinical trial is actively enrolling research volunteers, chloroquine’s reputation has been tainted by its association with chloroquine poisoning and at least one death. Other concerns include worse outcomes in COVID-19 patients with underlying cardiovascular disease.
Counterintuitively enough, an overactive immune response to COVID-19 has been linked to higher mortality rates. This is attributed to a phenomenon known as a cytokine storm, where an excess of inflammatory molecules called cytokines overwhelms healthy lung tissue, causing acute respiratory distress and multi-organ failure.
To keep the immune system at bay and avoid triggering a cytokine storm, clinicians are turning to immunosuppressants like Roche’s Actemra and Sanofi’s Kevzara. Both drugs work by inhibiting a specific cytokine, namely interleukin-6 (IL-6). Interestingly enough, although clinical trials for Actemra are still ongoing in China, the country’s National Health Commission has already given the green light for its usage on patients with serious lung damage and elevated IL-6 levels.
In early April 2020, a large-scale clinical trial evaluating the efficacy of Actemra in adults with severe COVID-19 pneumonia is set to begin recruitment. Similarly, Sanofi and Regeneron Pharmaceuticals have also already launched Phase III clinical trials for Kevzara as a treatment for critically-ill COVID-19 patients.
The use of convalescent plasma originates back to the 20th century, when it was first used to treat diphtheria. It has since been applied to a whole gamut of infectious diseases, from measles to chickenpox, H1N1, SARS, MERS and even Ebola.
The logic is simple: when we recover from a viral illness, our body naturally forms antibodies against the virus. These antibodies can be found in plasma, the liquid portion of our blood. By infusing patients with so-called convalescent plasma, the donated antibodies can fight off the virus in the recipient’s blood, akin to vaccination.
In a preliminary Chinese study involving five critically ill COVID-19 patients, this approach reportedly resulted in improved clinical outcomes. But just like any therapy, using convalescent plasma carries certain risks. For example, there’s a chance it can exacerbate the disease through a response known as antibody-dependent enhancement, where antibodies facilitate viral entry instead of having a neutralizing effect.
Yet, it’s promising enough that the US FDA has already approved its use in patients “with serious or immediately life threatening covid-19 infections.” Only time can tell if this age-old approach will finally work.
Despite the promise offered by convalescent plasma, one major drawback of the approach lies in its scalability. Not all recovered COVID-19 patients have antibody-laden blood. According to Prof. Arturo Casadevall, a microbiologist and immunologist at the Johns Hopkins Bloomberg School of Public Health, even donors with the highest activity plasma can likely only treat two people.
To overcome these constraints, drug makers are racing to engineer antibody therapies based on the antibodies found in the convalescent plasma of COVID-19 survivors. Within a week of receiving blood from one of the first US survivors of COVID-19, Canada’s AbCellera Biologics was able to identify over 500 unique antibodies that could potentially be scaled up in the laboratory.
Other companies are also working to develop monoclonal antibodies (mAbs) that hone in on specific pieces of the novel coronavirus. Regeneron Pharmaceuticals, for instance, intends to produce mAbs targeted towards the virus’ spike protein, which helps it bind to host cells. Unlike convalescent plasma, however, mAbs take considerably longer to engineer and purify, meaning that the outbreak could long be over before such therapeutics are ready for release.
As countries worldwide scramble to contain the pandemic, it’s worth remembering that the battle has just begun. Most of the seven therapeutics have been available for a while now, but it will still take time to prove their mettle against COVID-19. Until then, the best that many of us can do is stay at home and let science lead the way.
Copyright: Asian Scientist Magazine; Illustration: Oi Keat Lam/Asian Scientist Magazine.
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