Remdesivir - a possible treatment for COVID-19?

[Ygggdrasil]

Molnupiravir has received an EUA from the US FDA for use in treating COVID-19, though given that Pfizer's protease inhibitor drug seems much more effective, the FDA says its use should be limited to situations where other FDA-authorized treatments are not accessible or appropriate:

The Food and Drug Administration on Thursday granted emergency authorization to Merck’s molnupiravir, an antiviral pill shown to reduce hospitalization and death in cases of Covid-19, but only in cases where other FDA-authorized Covid treatments are not accessible or clinically appropriate.

The approval comes a day after the FDA authorized an antiviral pill from Pfizer for much broader use in patients as young as 12.

“Today’s authorization provides an additional treatment option against the COVID-19 virus in the form of a pill that can be taken orally. Molnupiravir is limited to situations where other FDA-authorized treatments for COVID-19 are inaccessible or are not clinically appropriate and will be a useful treatment option for some patients with COVID-19 at high risk of hospitalization or death,” Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, said in a statement.

https://www.statnews.com/2021/12/23...-pill-but-stresses-its-use-should-be-limited/

The protease inhibitor drug showed 89% reduction in hospitalizations in phase 3 clinical trials versus a 30% reduction in hospitalizations for molnupiravir. The clinical trial for fluvoxamine cited by @artis above showed a 32% decrease in hospitalizations, similar to the efficacy of molnupiravir.

Another candidate antiviral drug showed some promising pre-clinical results against COVID-19 recently:

4′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication
https://www.science.org/doi/10.1126/science.abj5508
Abstract:

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and the elderly. We describe 4′-fluorouridine (4′-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and SARS-CoV-2 with high selectivity index in cells and human airway epithelia organoids. Polymerase inhibition within in vitro RdRP assays established for RSV and SARS-CoV-2 revealed transcriptional stalling after incorporation. Once-daily oral treatment was highly efficacious at 5 mg/kg in RSV-infected mice or 20 mg/kg in ferrets infected with different SARS-CoV-2 variants-of-concern, initiated 24 or 12 hours after infection, respectively. These properties define 4′-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2, and related RNA virus infections.

Popular press summary from the NIH: https://www.nih.gov/news-events/nih...viral-drug-shows-promise-against-covid-19-rsv

Like molnupiravir, 4'-fluorouridine is a nucleoside analog that targets the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), the enzyme responsible for copying the virus's genetic information.

 

[Andrew Mason]

Molnupiravir has received an EUA from the US FDA for use in treating COVID-19, though given that Pfizer's protease inhibitor drug seems much more effective, the FDA says its use should be limited to situations where other FDA-authorized treatments are not accessible or appropriate:

https://www.statnews.com/2021/12/23...-pill-but-stresses-its-use-should-be-limited/

The protease inhibitor drug showed 89% reduction in hospitalizations in phase 3 clinical trials versus a 30% reduction in hospitalizations for molnupiravir. The clinical trial for fluvoxamine cited by @artis above showed a 32% decrease in hospitalizations, similar to the efficacy of molnupiravir.

I would really like to see how effective the two drugs, molnupiravir and ritonavir, would work in combination -- one disrupting RNA replication and the protease inhibitor interfering with the protein translation. What would be the reasons for the FDA not allowing both to be given to a patient?

AM

 

[Astronuc]

What would be the reasons for the FDA not allowing both to be given to a patient?

I would expect that the combination has to be tested to ensure no severe side-effects, in addition to an efficacious treatment.

Most recently, according to AP News, "Pfizer pill becomes 1st US-authorized home COVID treatment"
https://apnews.com/article/coronavirus-pandemic-pfizer-medication-f5f65e7e61d6aa9c7dfa193053e8878a
https://www.cnn.com/2021/12/22/health/pfizer-antiviral-pill-authorized/index.html
https://www.nytimes.com/2021/12/23/health/covid-pill-merck.html

From FDA regarding Paxlovid (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use)

Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for Pfizer’s Paxlovid (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use) for the treatment of mild-to-moderate Coronavirus disease (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kilograms or about 88 pounds) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. Paxlovid is available by prescription only and should be initiated as soon as possible after diagnosis of COVID-19 and within five days of symptom onset.

https://www.fda.gov/news-events/pre...rizes-first-oral-antiviral-treatment-covid-19

So in theory Merck's molnupiravir could be co-packaged with ritonavir, however, the FDA has expressed "concerns that Merck’s pill is only modestly effective and carries possible safety risks, including for pregnant women." From NY Times article.

 

[Ygggdrasil]

I would really like to see how effective the two drugs, molnupiravir and ritonavir, would work in combination -- one disrupting RNA replication and the protease inhibitor interfering with the protein translation. What would be the reasons for the FDA not allowing both to be given to a patient?

AM

The protease inhibitor drug (nirmatrelvir) already seems very effective at preventing hospitalizations (89%), so it would be difficult to assess whether the combination helps to improve efficacy. One potential benefit from combining them would be to help evade drug resistance (as in the case of antiretroviral drug cocktails used for anti-HIV therapy). However, molnupiravir acts to increase the mutation rate of the virus, so it's possible that the drug could accelerate resistance to nirmatrelvir. While unlikely, this issue should at least be studies before clinical trials of the combination therapy begin. Similarly, clinical trials of the combination should be performed to see if the combination has any unexpected adverse effects (esp. because we have very little data on the use of these drugs in the real world versus more established drugs where real world data might have already provided information on interactions with other types of medications).

 

[sysprog]

The protease inhibitor drug (nirmatrelvir) already seems very effective at preventing hospitalizations (89%), so it would be difficult to assess whether the combination helps to improve efficacy. One potential benefit from combining them would be to help evade drug resistance (as in the case of antiretroviral drug cocktails used for anti-HIV therapy). However, molnupiravir acts to increase the mutation rate of the virus, so it's possible that the drug could accelerate resistance to nirmatrelvir. While unlikely, this issue should at least be studies before clinical trials of the combination therapy begin. Similarly, clinical trials of the combination should be performed to see if the combination has any unexpected adverse effects (esp. because we have very little data on the use of these drugs in the real world versus more established drugs where real world data might have already provided information on interactions with other types of medications).

In my inexpert opinion, MCAs are probably a good post-vaccination temporary enhancement for persons at risk of encountering mutated versions of SARS-CoV-2, and may be beneficial for persons using protease inhibitors (I don't know whether any PIs are in clinical trial yet).