Along with vaccines, comes a new hope in the form of Remdesivir to help us out of the COVID-19 pandemic.
Remdesivir marketed as Veklury was first developed to combat Hepatitis C infection by Gilead Science. Despite being drug ineffective against the Hepatitis C virus, the drug did help in abating the Ebola outbreak. Remdesivir is a broad-spectrum antiviral drug that is administered through the intravenous route. FDA issued an emergency use authorization in October 2020 for this drug to tackle the rapidly rising SARS-CoV-2 infections as a possible treatment. The World Health Organisation (WHO) released guidelines recommending against the use of remdesivir stating that the therapeutic effects of the drug are not conclusive and further studies need to be conducted.
How does Veklury work?
Remdesivir is a prodrug having a nucleotide monophosphate analogue (GS-441524). Nucleotides being charged cannot enter the cell through the lipid membrane on their own needing a carrier. It is in a biologically inactive form and allows the drug to be transported into the cell. Once the drug enters the cell, it is converted to an active nucleotide monophosphate form. The adenosine nucleotide monophosphate is converted to a triphosphate form which can then be used by RNA-dependent RNA polymerase (RdRp) involved in the formation of the viral RNA. The GS-441524 analogue can then get integrated into the viral RNA and interfere with the action of RdRp by arresting the addition of nucleotides (delayed chain termination). This prevents further elongation, thereby halting the formation of new viral particles. The analogues do not get incorporated into the host genome as they are immediately removed by the proofreading mechanism.
Many scientists have proposed the targeted delivery of the GS-441524 analogue. However, the phosphorylation rate on this analogue inside the cell is very slow, reducing its antiviral nature. Using chloroquine or hydroxychloroquine along with Remdesavir can reduce its antiviral property as well.
A set of randomised double-blind placebo trials was conducted on 1026 patients across 17 countries. The participants were hospitalised with mild to severe forms of the SARS-CoV-2 infection. Some of the participants received remdesivir and the rest placebo. The outcome was to evaluate the time to recovery within 29 days of being treated. The patients who received remdesivir showed reduced symptoms within ten days as compared to the placebo control group who took 15 days to recover.
Another set of open-label clinical trials were conducted to test the safety and efficacy of remdesivir which involved administering the drug for 5 days and for 10 days along with usual standard care. Not much of a difference was seen in either of the groups with regards to recovery rates and mortality rates.
Remdesivir may not be the only nucleotide candidate being considered for possible treatment against SARS-CoV-2 infection, but it is the most clinically advanced. Other nucleoside/nucleotide analogues, such as the hepatitis C drug sofosbuvir and HIV drugs alovudine and zidovudine, have been effective in arresting the activity of SARS-CoV-2 RdRp activity in several in-vitro assays and can be potential therapeutic agents.
The WHO guidelines advise against using the antiviral remdesivir for hospitalized patients, saying there’s no evidence it improves survival or avoids the need for breathing machines. This is based heavily on a WHO-sponsored study that involved a larger cohort and less rigorous than the US-led one. The ineffectiveness of remdesivir was also supported by scientists at British Medical Journal stating that it may reduce the recovery time which still needs evidence. The ambiguity involving effectiveness has created a lot of confusion.
In India, the second wave of the pandemic has brought a surge in SARS-CoV-2 cases like never before. The production of remdesivir is not taking place at a quicker pace leading to a shortage. The lesser availability of the drug has given rise to its illegal purchasing and marketing via several scams. The high cost of manufacturing as well as the associated side effects, especially elevated levels of liver enzymes has augmented the controversial profile of remdesivir.
Remdesivir is the first investigational drug to obtain FDA authorization for treating SARS-CoV-2. This drug may be one of the first compounds to help mitigate the severity of the pandemic, additional research will help in providing more insight into the repurposing of drugs against SARS-CoV-2 infections.