Looking at the frontrunners

Three compounds are in the spotlight now as new and repurposed drug options are examined for COVID-19

The research into vaccines or therapeutics for SARS-CoV-2 infection and full-fledged COVID-19 disease continues to be fast and furious, both in terms of trying to find novel treatments for various pathways and also finding existing drugs that might have an impact.
 
And in spite of—or perhaps because of—the pushback against using the antimalarial drugs hydroxychloroquine and chloroquine for COVID-19, the enthusiasm for some of these potential therapeutics is high. At the same time, many are remembering the lesson of those malaria drugs as questions arose about efficacy and concerns spiked around potential adverse health effects on COVID-19 patients.
 
In the arena of therapeutics for the disease, three names are generating a lot of interest right now: remdesivir, dexamethasone and fluvoxamine.
 
Data and analytics company GlobalData anticipates that Gilead’s remdesivir will target a select severity group of COVID-19 patients, noting that it remains questionable as to how treatment with the drug will be initiated and optimized.
 
“Gilead’s remdesivir was trialled in a number of patients with varying severities, however, it was noted that the drug did not provide benefit to mild or critically ill COVID-19 patients who required ventilation or extracorporeal membrane oxygenation. Hospitals are therefore limited to targeting a select population of moderate to severe patients,” explained Angad Lotay, an infectious diseases analyst at GlobalData.
 
“Furthermore, the latest evidence did not provide guidance on how to optimize treatment or whether earlier initiation with remdesivir reduces mortality rates. With additional data from Gilead’s SIMPLE trial expected, patients with the highest unmet medical needs are still left without an optimal treatment option.”
 
Remdesivir has a broad spectrum antiviral activity and acts as a viral RNA polymerase inhibitor. However, it exerts minimal cytokine responses necessary to manage patients who are critically ill and require ventilatory support. In a bid to target this population, Gilead has been testing remdesivir with immune modulators to tackle the enormous immune reactions that strike patients in the latter stages of this disease.
 
Dexamethasone, for its part, was shown to save the lives of seriously ill patients with COVID-19. Dexamethasone is a corticosteroid used in a wide range of conditions for its anti-inflammatory and immunosuppressant effects.
 
As the World Health Organization (WHO) noted recently, “It was tested in hospitalized patients with COVID-19 in the United Kingdom’s national clinical trial RECOVERY and was found to have benefits for critically ill patients.”
 
 
 
According to preliminary findings shared with WHO, the treatment was shown to reduce mortality by about one-third for patients on ventilators; for patients requiring only oxygen, mortality was cut by about one-fifth.
 
Although June was when much of the buzz about dexamethasone emerged, AI VIVO—a company combining systems pharmacology and artificial intelligence (AI) to accelerate drug discovery—reported that its platform correctly identified dexamethasone as having high potential for the treatment of COVID-19 in April 2020.  While the company touted this as demonstrating the ability of AI VIVO’s platform to systematically and correctly identify candidates with the highest chance of therapeutic success, it also points to the importance of efforts overall to mine existing drugs for potential COVID-19 therapeutics.
 
“After receiving a world-first approval by the U.K. government, following groundbreaking data showing it can reduce COVID-19 deaths among hospitalized patients, the inexpensive and widely available corticosteroid dexamethasone has been getting significant attention,” noted Dr. Arafa Salam, an infectious diseases analyst at GlobalData. “While data supporting dexamethasone’s efficacy seem clear, the magnitude of its benefit remains modest. Further, additional studies are warranted so as to avoid the same roadblocks as hydroxychloroquine, where significant variations in results muddied the ability to determine its role in COVID-19 treatment.”
 
Although the data do identify an improvement in mortality with dexamethasone, its place in COVID-19 treatment modalities remains unclear, according to Salam, who pointed out that one of dexamethasone’s key competitors, remdesivir, saw clinical improvement in 36 of 53 patients (68 percent); however, with dexamethasone mortality was reduced by 17 percent—and while reductions in mortality with remdesivir trended downwards, the differences were not statistically significant.
 
“Something to consider is the combination of these two drugs, as they have differing mechanisms of actions, which could be complimentary, with remdesivir slowing damage due to the virus and dexamethasone slowing damage to a hyper-inflammatory state,” Salam continued. “This type of scheme is already being considered in trials with remdesivir and the anti-inflammatory IL-6 inhibitor tociluzimab, so the thought of the combination of remdesivir and dexamethasone isn’t too farfetched.”
 
Of the three compounds we’re looking at in this roundup, perhaps the most surprising is fluvoxamine, because it is used primarily to treat depression. But researchers from the drug as a potential treatment for the “cytokine storm” associated with COVID-19. If found effective, this selective serotonin reuptake inhibitor (SSRI) could be rapidly made available to patients as it is already globally marketed and has a known safety record, says GlobalData.
 
“Having a treatment for cytokine storm that is already so easily available will help reduce mortality and prevent progression from mild-to-severe COVID-19,” noted Johanna Swanson, a product manager at GlobalData.
 
Fluvoxamine is being investigated for COVID-19 treatment based on results from researchers at the University of Virginia School of Medicine, who found that the drug could prevent sepsis and reduced the generation of cytokines in mice.
 
“While it remains to be seen if fluvoxamine will have the same effect in humans as it does in mice for preventing sepsis, this would also indicate that the drug could be repurposed for treating other cytokine storm diseases in addition to COVID-19,” Swanson said.
 
As noted by Washington University, “Fluvoxamine, which is in the class of drugs called selective serotonin-reuptake inhibitors, also interacts with a protein important to the body’s inflammatory response. This effect may help relieve an overwhelming immune response, which is thought to occur in about one in seven COVID-19 patients, who then often end up hospitalized, and sometimes on ventilators, with a higher risk of death.”
 
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