Remdesivir - a possible treatment for COVID-19?

[Andrew Mason]

It was announced today that five Indian pharmaceutical companies will be conducting trials for molnupiravir/EIDD-2801.

India has a strong pharmaceutical manufacturing base and has a large non-vaccinated population. So attacking the virus at early stages of infection using an oral anti-viral could be very effective in limiting the terrible human toll that the virus is taking in India.

AM

 

[artis]

I guess there are two questions left, first is the final overall efficiency of the drug/s and then comes the availability and price.
For medication that is most effective at the very early onset of symptoms it would seem it would need to be purchased preemptively and kept at "arm's length" much like other drugs for people who have to take them regularly.

 

[pinball1970]

On the same subject.

https://www.news-medical.net/news/20210628/Study-suggests-vitamin-B12-as-a-SARS-CoV-2-antiviral.aspx

 

[Andrew Mason]

On the same subject.

https://www.news-medical.net/news/20210628/Study-suggests-vitamin-B12-as-a-SARS-CoV-2-antiviral.aspx

They don't explain much about how their "quantum inspired device" works. But it should be pointed out that there was also this in silico analysis by researchers in India reported in October of last year that also suggested vitamin B12 might be a good anti-viral candidate.

There was a paper published just today that may be of interest:

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp12/7/8 RNA-dependent RNA polymerase ​

The RdRp is one of the key druggable targets for CoVs due to its essential role in viral replication, high degree of sequence and structural conservation and the lack of homologues in human cells. Here, we have expressed, purified and biochemically characterised active SARS-CoV-2 RdRp complexes. We developed a novel fluorescence resonance energy transfer-based strand displacement assay for monitoring SARS-CoV-2 RdRp activity suitable for a high-throughput format. As part of a larger research project to identify inhibitors for all the enzymatic activities encoded by SARS-CoV-2, we used this assay to screen a custom chemical library of over 5000 approved and investigational compounds for novel SARS-CoV-2 RdRp inhibitors. We identified three novel compounds (GSK-650394, C646 and BH3I-1) and confirmed suramin and suramin-like compounds as in vitro SARS-CoV-2 RdRp activity inhibitors. We also characterised the antiviral efficacy of these drugs in cell-based assays that we developed to monitor SARS-CoV-2 growth.

 

[Andrew Mason]

Gilead has https://www.gilead.com/news-and-press/press-room/press-releases/2021/9/veklury-remdesivir-significantly-reduced-risk-of-hospitalization-in-highrisk-patients-with-covid19 from its phase 3 trial for Veklury (remdesivir) for high risk patients with Covid19 who were treated early.

In an analysis of 562 participants randomly assigned in a 1:1 ratio to receive Veklury or placebo, Veklury demonstrated a statistically significant 87% reduction in risk for the composite primary endpoint of COVID-19 related hospitalization or all-cause death by Day 28 (0.7% [2/279]) compared with placebo (5.3% [15/283]) p=0.008.

AM

 

[Andrew Mason]

Merck, which is running Phase III trials for its anti-viral drug molnupiravir (EIDD-2801) has just announced some promising preliminary results showing effectiveness against the delta variant of SarsCoV-2:

Laboratory studies show that Merck & Co's (MRK.N) experimental oral COVID-19 antiviral drug, molnupiravir, is likely to be effective against known variants of the coronavirus, including the dominant, highly transmissible Delta, the company said on Wednesday.

Earlier results showed that the drug was generally effective against the virus:

"Merck said earlier this year that a small, mid-stage trial found that after five days of molnupiravir treatment, none of the patients taking various doses of the drug tested positive for infectious virus, while 24% of placebo patients did have detectable levels.

Merck is currently conducting two Phase III trials of the antiviral it is developing with Ridgeback Biotherapeutics - one for treatment of COVID-19 and another as a preventive."

The "preventative" aspect is interesting. Since molnupiravir is delivered in pill form, it would be much more practical as a preventative treatment for health-care professionals who are at high-risk of exposure to the SarsCov-2 virus than remdesivir, which must be administered intravenously.

AM

 

[Ygggdrasil]

Merck announced today results from its Phase 3 clinical trial of molnupiravir. The trial was a study of non-hospitalized adult patients with laboratory-confirmed mild to moderate COVID-19, at least one risk factor associated with poor disease outcomes, and symptom onset within five days prior to treatment.

An investigational antiviral pill reduced the chances that patients newly diagnosed with Covid-19 would be hospitalized by about 50%, a finding that could give doctors a desperately needed new way to treat the sick, the drug maker Merck announced Friday.

A five-day course of molnupiravir, developed by Merck and Ridgeback Biotherapeutics, reduced both hospitalization and death compared to a placebo. In the placebo group, 53 patients, or 14.1%, were hospitalized or died. For those who received the drug, 28, or 7.3%, were hospitalized or died.

https://www.statnews.com/2021/10/01...tients-a-possible-game-changer-for-treatment/

As mentioned previously in the thread, treatment of already hospitalized patients showed no benefit, so early treatment is key for the efficacy of the drug.

See also the Merck press release: https://www.merck.com/news/merck-an...to-placebo-for-patients-with-mild-or-moderat/

 

[Ygggdrasil]

Analysis of the full dataset from the Phase 3 molnupiravir trial appears to show that the drug is much less effective than initially thought:

On Tuesday, throughout the hearing of the advisory committee, panelists asked pointed questions of both Merck and the FDA, whose scientists had seemed to back the approval of the medicine in briefing documents released Friday. Among them was how to interpret the change in the results around the drug’s effectiveness. The early results released Oct. 1 showed a 50% reduction in hospitalization, or an absolute decrease of 7%. In the final results, the result shrank to a 30% decrease, or a 3% absolute difference in hospitalization in the full population.

Lindsey Baden of the Brigham and Women’s Hospital, the panel chair, asked early on how this could be. “Help me understand,” he said.

Nicholas Kartsonis, a Merck researcher, explained that the interim analysis was the primary analysis, but also said, at length, that Merck’s scientists had not been able to come up with clear reasons for the result. “I don’t have a satisfying answer to your question but at least that’s the totality of the data we have.”

https://www.statnews.com/2021/11/30...rck-covid-pill-after-day-of-tense-discussion/

Despite the results, an FDA advisory panel voted 13-10 to recommend an EUA for molnupiravir.

Popular press summaries:
https://www.statnews.com/2021/11/30...rck-covid-pill-after-day-of-tense-discussion/
https://www.science.org/content/blog-post/rethinking-molnupiravir

 

[artis]

@Ygggdrasil Maybe I have gotten something wrong here but it seems to me that Molnupiravir is expensive and in the end not better than already existing cheap drugs like Fluvoxamine which as we now see have shown their usefulness despite being originally dismissed in a somewhat arrogant way by many.

https://www.nature.com/articles/d41586-021-02988-4
https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext

 

[Andrew Mason]

@Ygggdrasil Maybe I have gotten something wrong here but it seems to me that Molnupiravir is expensive and in the end not better than already existing cheap drugs like Fluvoxamine which as we now see have shown their usefulness despite being originally dismissed in a somewhat arrogant way by many.

https://www.nature.com/articles/d41586-021-02988-4
https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext

re: Cost: Molnupiravir is about $700 per dose which compares favourably to remdesivir which costs $2300.

Re: the comparison to fluvoxamine. Fluvoxamine appears to act as an anti-inflammatory so its usefulness is not in fighting infection but in countering the body's inflammatory response to the viral damage. Anti-virals such as molnupiravir and remdesivir and Pfizer's new pill, ritonavir, can prevent or limit infection. The effect of both types is to limit the damage to the body triggered by the virus. The advantage of fluvoxamine is that it is about 1/40th the cost of molnupiravir and about 1/150th the cost of remdesivir.

AM

 

[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).