Today, Gilead Sciences announced that the European Commission has granted Veklury (remdesivir) a conditional listing permit for the treatment of adult and adolescent patients with new coronary pneumonia who require supplementary oxygen caused by the new coronavirus infection. Conditional listing permits in Europe are initially valid for one year, but can be extended or converted to unconditional listing licenses after other corroborative data have been submitted and evaluated. Previously, Redsewee has received an emergency use authorization from the U.S. FDA, as well as special approval from Japan.
From a paper published in the New England Journal of Medicine in February for the treatment of the first confirmed patient of new crown pneumonia in the United States, to the world’s many countries and regions approved, Redseywe can say that in the “spotlight” through this development process. Although it has shown promising results in the treatment of severely ill patients, has the currentapproved indications, as an antiviral therapy, reach its greatest potential? Today, the Potion Conde Content team will review Redsewe’s development and look ahead to its next steps with the reader.
Broad-spectrum antiviral therapy holds promise
With increased human contact with livestock and wildlife and increased global travel, the emergence and even prevalence of new diseases is no longer uncommon. The WHO’s “Emergency Health Challenge for the Next 10 Years” released earlier this year says it is hard to avoid a new, highly contagious, airborne pandemic, most of which is immune to the virus. We need to be better prepared for a potential pandemic. In the National Institutes of Health’s (NIH) strategy on emerging infectious diseases, it proposes “the development of a single-bug, one-drug for each disease.” “It is not enough, but broad-spectrum therapy is needed to improve the preparedness of all infectious threats.
Redsewe is a drug with broad-spectrum anti-RNA viral potential. The proliferation of RNA viruses depends on the replication of RNA strands that carry the viral genome, and THE replication of RNA strands relies on a class called RNA-dependent RNA polymerase (RdRp), which can be used as a template for a single RNA strand, using nucleotides in cells as raw materials to synthesize another RNA strand. The use of nucleotides or nucleotide analogues to inhibit RNA replication is one of the important research and development strategies of antiviral therapy. These analogies are similar to the nucleotide structure of the raw material that builds the viral RNA chain, so they can be synthesized by the virus’s RdRp, but because their structure is different from natural nucleotides, after binding to the RNA chain, like a misplaced link on the bicycle chain, the RdR is always “falling the chain” when it continues to synthesize the RNA chain, resulting in the premature termination of RNA chain synthesis.
Redsewe’s structure (Photo: Meodipt (Public Domain))
Redsewe is a precursor to a nucleotide analogue. Its design first enhances the ability of the drug precursor to be absorbed by cells, thereby increasing the concentration of triphosphate (TP) metabolites in the cells (bottom left below), giving nucleotide analogues more opportunities to be integrated into the RNA chain. At the same time, Redsewe triphosphate metabolites are highly specific to RNA polymerases in viruses, and are very low in the activity of mitochondrial polymerases and DNA polymerases in cells, which guarantees its safety. What’s more, RdRp is widespread in RNA viruses, which also include coronaviruses. Redsiwe, which has the potential to inhibit RdRp activity, has potential inhibition effects on a variety of RNA viruses, including coronaviruses.
The Mechanism of Action of Redsewe (aka GS-5734)
In addition, Redsiwe is different from other nucleotides or nucleotide analogues in that it overcomes the error-generated modifications in RNA replication by the new coronavirus’s own repair mechanism. The new coronavirus itself contains a mechanism for repairing errors in RNA replication, which makes the new coronavirus less mutated than other viruses, such as influenza viruses, but also makes it more difficult to introduce replication errors with nucleotideors or nucleotide analogues. Previous studies have shown that Redsewe can still effectively inhibit the proliferation of the virus in this case.
Key clinical studies pave the way
Redsewe was able to be used quickly in clinical trials during the outbreak of the New Crown outbreak, thanks to its clinical tests and key findings on MERS and SARS.
Prior to this, Redsewe’s in-patient in-patient disease was primarily a treatment for Ebola virus infection, and phase 2 clinical trials have been completed. After the 2018 Ebola outbreak in Congo, who conducted a multi-arm clinical trial comparing the safety and efficacy of four drugs in nearly 700 patients, 175 of whom received Redsiwe. Although Redsivir’s mortality rate from Ebola virus infection improved less than other drugs in the trial, the safety of its use in humans was confirmed to some extent. The trial, published in the New England Journal of Medicine, noted that the overall safety of the four experimental drugs, including Redsewe, was good, similar to what it had previously observed in Ebola patients or healthy subjects.
Today’s EU conditional listing of Redseve is supported by the results of Phase 3 clinical trials sponsored by the American Institute of Allergy and Infectious Diseases (NIAID). In this trial, preliminary findings showed that Redsewe significantly reduced the recovery time of adult patients admitted to COVID-19, with potential benefits of improving the risk of death. Preliminary results of the trial were published in the New England Journal of Medicine in May. A clinical study conducted by Gilead Sciences has shown that using a five-day Redsiwe course is comparable to a 10-day Redsiwe course, meaning that the same number of Redsiwels may benefit more patients.
The next step in harnessing Redsewe’s maximum potential
Current studies on COVID-19 show that severe symptoms such as acute respiratory distress syndrome occur in patients with severe illness, in addition to the proliferation of viruses in tissues, the “cytokine storm” caused by the overreaction of the human immune system is also an important factor in the exacerbation of the patient’s condition. As an antiviral therapy, Redsewe’s main role is to inhibit the proliferation of the virus, therefore, earlier treatment of COVID-19 patients, before the virus stimulates a severe immune response to reduce the level of the virus in the patient, not only can prevent the occurrence of severe symptoms, but may reduce the level of the virus in the patient, delay the spread of COVID-19.
Previous experience with the use of antiviral therapy, such as Tamiflu for influenza, suggests that the “window” for effective treatment of patients with antiviral therapy may be located in the early stages of the patient’s illness. Data from Redsewe’s clinical trials also show signs that early use may be more effective.
However, because Redseve is a drug that requires intravenous fluids, it is usually only used to treat inpatients, who have a higher proportion of the disease for longer periods of time. How to get early COVID-19 patients to use Redsivir will be one of the most important factors in the treatment’s full potential.
Currently, Gilead Sciences plans to conduct clinical trials to test the efficacy of inhaled Redseve in the treatment of patients with COVID-19. This new dosage form, administered through aneizer, bypasses the barrier sway that patients need intravenous fluids to receive treatment. At the same time, Gilead Sciences will explore the possibility of treating patients in medical settings outside hospitals, such as infusion centers and nursing homes. In an open letter, Daniel O’Day, the company’s chief executive, said it was more important for patients at higher risk of disease progression to start treatment before they were admitted to hospital. This may allow these patients to avoid hospitalization altogether.
In addition, the company is exploring the effects of Redsivir’s combination with other therapies, including the JAK1 inhibitor baricitinib and the IL-6 inhibitor tocilizumab, which inhibits the immune response of patients.
Mr. Daniel O’Day noted that while developing Redsewe’s greatest potential to treat as many COVID-19 patients as possible, Gilead will continue its research on other emerging viruses, in keeping with its tradition of focusing on emerging viruses. Redsewe’s success was due to the company’s extensive work on Redsewe before the new crown outbreak. “Continuous research, iteration, persistence is a necessary element of scientific progress.” He said. Gilead Sciences will not only do everything in its power to help end the new crown outbreak, but will also work to prepare for the next outbreak.