Covid-19 Oral Medicine -- a Link to be focused on Against Epidemic

In the wake of the outbreak of the COVID-19, the globally cumulative infected population has capped 100 million, which poses a huge impact on human activities. Following the huge number of infected people and the mutating virus, the COVID-19 will probably evolve into a flu-like epidemic that couple with humans for a long time. 

In history, the substantial way to protect humans from the effects of influenza is the "prevention + cure" combination of "influenza vaccine + oral antiviral drugs". The presence of oral anti-flu drugs empowers people to take medicines at its own after being infected with influenza viruses. Simple protection is all required to take part in basic normal social activities. 

So far, oral drugs have been an unsolved urgent link in the prevention and control of the COVID-19. Yet, more challenges are associated with the R&D of small-molecule oral antiviral drugs. Currently certified antiviral drugs, including multiple neutralizing antibodies and Remdesivir, are administered by injection, and no oral small-molecule antiviral drugs have been endorsed. A variety of small molecule antiviral drug candidates have been placed in the clinical research stage across the globe. 

1. Molnupiravir

Molnupiravir is reported as a prodrug of the nucleoside analog N4-hydroxycytidine (NHC) under joint development by MSD and Ridgeback Biotherapeutics. 

At the CROI 2021 meeting dated March 10, the two companies exposed theclinical Phase IIa trial results of the medical supplies products: The positive rate of infectious virus isolation and culture in nasopharyngeal swabs was 0% (0/47) in 202 patients with mild COVID-19 (within 7 days after onset of symptoms) after taking Molnupiravir for 5 days, in contrast with 24% of patients in the placebo group (6/25). Nevertheless, data from the Phase II/III study provides an insight that the drug shows zero benefit in preventing death or shortening the length of stay in hospitalized patients. 

Thus, MSD has resolved to advance with full efforts the research of 800mg Molnupiravir in the treatment of patients with mild to moderate COVID-19. According to Dr. Roy Baynes, MSD's senior vice president and head of global clinical development, the data collected from previous studies has proved the consistency of the dose and the mechanism of action, and presented meaningful evidence for the 800mg dose. 

2. AT-527

AT-527 represents a small molecule inhibitor of viral RNA polymerase under joint efforts of Roche and Atea. It serves as an oral therapy to treat hospitalized COVID-19 patients, and reveals the potential for preventive treatment after exposure. 

Not long ago, the interim analysis results of a global randomized, double-blind, placebo-controlled, multicenter Phase II trial were made public, including data of 70 high-risk COVID-19 hospitalized patients, of which 62 patients' data were available for virological analysis and evaluation. It is indicated in the results of interim virological analysis that AT-527 can lead to quick reduction of viral load. In comparison to placebo, patients treated with AT-527 experienced a greater reduction in viral load than the baseline level on day 2, and the difference in viral load reduction continued until day 8. 

Furthermore, the potent antiviral activity of AT-527 was also suggested in patients with a baseline median viral load more than 5.26 log10, compared with the control group. In assessing whether the virus was cleared with RT-qPCR, COVID-19 was removed in some patients in the test group on day 2 (6% of patients), day 8 (7% of patients), day 10 (33% of patients), and on day 12 (31% of patients), while the ratio of patients with removed COVID-19 in the control group at the same time point was 0%. At day 14, 47% or so of patients in the test group revealed virus clearance, with 22% in the control group. 

Its safety is consistent with previous studies. AT-527 demonstrates ideal safety and tolerability, with no new safety problems or risks observed. No serious adverse events related to drug treatment appeared in this research. 

3. Proxalutamide 

Proxalutamide is an AR (androgen receptor) antagonist. The activated androgen receptor AR helps induce the expression of transmembrane serine protease (TMPRSS2). TMPRSS2 shows a shearing effect on the COVID-19 S protein and ACE2, so as to enhance the binding of viral spike protein (S protein) to ACE, thereby facilitating the virus to enter the host cell. Hence, the inhibited androgen receptor may inhibit the viral infection process, and AR antagonists are in sight to become drugs against COVID-19. 

Proxalutamide has formerly been associated with positive results in a multi-center, randomized, double-blind, placebo-controlled Phase III clinical trial in Brazil. According to data: Proxalutamide is related to a reduced risk of death in severely ill patients infected with COVID-19 by 92%, a lowered risk of new ventilator use by 92%, and the less length of hospital stay by 9 days. It indicates that Proxalutamide has a certain therapeutic effect for severe patients infected with COVID-19, as it can significantly reduce the mortality of patients, and substantially lower the use of new mechanical ventilation and shorten the patient's hospital stay. 

In view of the continuing COVID-19 on a global scale, and apart from vaccines and prevention and control measures, a multi-pronged program is required to control this disease. Oral antiviral therapy will beyond doubt provide a convenient treatment option. Its availability will allow people to recover normal daily life more quickly, in particular in areas where vaccines and antibody therapies are not easily accessible. 

References:

1.https://www.nytimes.com/2021/06/13/opinion/stimulus-unemployment-republicans-poverty.html；

2.Atea’s AT-527, an Oral Antiviral Drug Candidate, Reduces Viral Replication in Hospitalized Patients with COVID-19 in Phase 2 Interim Analysis. Retrieved June 30, 2021，from https://ir.ateapharma.com/news-releases/news-release-details/ateas-527-oral-antiviral-drug-candidate-reduces-viral；

3.Retrieved  Apr 25, 2021, from https://mp.weixin.qq.com/s/c1GBlYyr8LVwmJgJgveT8g.