The new COVID-19 pills are not a panacea for SARS-CoV-2

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Newly infected COVID-19 patients have two new treatment options that can be taken at home.

But that convenience comes with a catch: The pills have to be taken as soon as possible once symptoms appear.

The challenge is getting tested, getting a prescription and starting the pills in a short window.

U.S. regulators authorized Pfizer’s pill, Paxlovid, and Merck’s molnupiravir last week.

In high-risk patients, both were shown to reduce the chances of hospitalization or death from COVID-19, although Pfizer’s was much more effective.

A closer look:

WHO SHOULD TAKE THESE PILLS?

The antiviral pills aren’t for everyone who gets a positive test. The pills are intended for those with mild or moderate COVID-19 who are more likely to become seriously ill.

That includes older people and those with other health conditions like heart disease, cancer or diabetes that make them more vulnerable.

Both pills were OK’d for adults while Paxlovid is authorized for children ages 12 and older.

WHO SHOULDN’T TAKE THESE PILLS?

Merck’s molnupiravir is not authorized for children because it might interfere with bone growth. It also isn’t recommended for pregnant women because of the potential for birth defects. Pfizer’s pill isn’t recommended for patients with severe kidney or liver problems.

It also may not be the best option for some because it may interact with other prescriptions a patient is taking. The antiviral pills aren’t authorized for people hospitalized with COVID-19.

WHAT’S THE TREATMENT WINDOW?

The pills have to be started as soon as possible, within five days of the start of symptoms. Cough, headache, fever, the loss of taste or smell and muscle and body aches are among the more common signs. The Centers for Disease Control and Prevention offers a website to check your symptoms.

Dr. Cameron Wolfe, an infectious disease specialist at Duke University Hospital, advises getting a test as soon as you have symptoms of COVID-19.

“If you wait until you have started to get breathless, you have already to a large extent missed the window where these drugs will be helpful,” Wolfe said.

WHERE CAN I GET THE PILLS?

You’ll need a prescription first from a doctor or other authorized health worker. The U.S. government is buying the pills from Merck and Pfizer and providing them for free, but supplies will be limited initially. They’ll be shipped to states where they will be available at drugstores, community health centers and other places. Treatment lasts five days.

Some pharmacists may be able to administer a quick COVID-19 test and prescribe the pills all in one visit. They already do this in many states for flu or strep throat.

WILL THE PILLS WORK FOR THE OMICRON VARIANT?

The pills are expected to be effective against omicron because they don’t target the spike protein where most of the variant’s worrisome mutations reside. The two pills work in different ways to prevent the virus from reproducing.

ARE THERE OTHER OPTIONS FOR NEW COVID-19 PATIENTS?

Yes, but they aren’t as easy to use as a pill: They are given by IV or injection, typically at a hospital or clinic. Three drugs provide virus-fighting antibodies, although laboratory testing suggests the two aren’t effective against omicron. British drugmaker GlaxoSmithKline’s antibody drug appears to work, and officials say they are working to increase the U.S. supply. The only antiviral drug approved in the U.S., remdesivir, is for people hospitalized with COVID-19.

Covid-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company reports

Pfizer’s oral antiviral drug paxlovid significantly reduces hospital admissions and deaths among people with covid-19 who are at high risk of severe illness, when compared with placebo, the company has reported.

The interim analysis of the phase II-III data, outlined in a press release, included 1219 adults who were enrolled by 29 September 2021. It found that, among participants who received treatments within three days of covid-19 symptoms starting, the risk of covid related hospital admission or death from any cause was 89% lower in the paxlovid group than the placebo group.

The UK government has purchased 250 000 courses of paxlovid, which is a combination of PF-07321332 and ritonavir, alongside 480 000 courses of another antiviral for covid-19, molnupiravir, which has now been approved by the Medicines and Healthcare Products Regulatory Agency.1

Given these positive results, and after guidance from the trial’s independent data monitoring committee and the US Food and Drug Administration, study enrolment has ended. A total of 70% of the 3000 planned patients from clinical trial sites across North and South America, Europe, Africa, and Asia had been enrolled, with 45% of patients located in the US.

Pfizer said it will submit its data to the FDA as soon as possible as part of its ongoing rolling submission for emergency use authorisation. The UK’s MHRA will also review the drug for potential roll out this winter.

Commenting on the announcement, England’s health and social care secretary, Sajid Javid, said, “If approved, this could be another significant weapon in our armoury to fight the virus alongside our vaccines and other treatments, including molnupiravir, which the UK was the first country in the world to approve this week.”

In the study, trial participants were randomised 1:1, with half receiving paxlovid and the other half receiving a placebo orally every 12 hours for five days. Of those who were treated within three days of symptom onset, 0.8% (3/389) of patients who received paxlovid were admitted to hospital up to day 28 after randomisation, with no deaths. In comparison, 7% (27/385) of patients who received placebo were admitted, with seven deaths. The statistical significance of these results was reported as high (P<0.0001).

Similar reductions were seen in people treated within five days of symptom onset, with 1% (6/607) in the paxlovid group admitted up to day 28 (no deaths) and 6.7% (41/612) in the placebo group (10 deaths).

Overall, through to day 28, no deaths were reported among patients who received paxlovid, while 10 people (1.6%) in the placebo group died.

To look at safety data, the researchers included a larger group of 1881 patients in the analysis. The proportion of participants experiencing adverse events was similar, 19% in the paxlovid group and 21% in the placebo group, most of which were mild in intensity. People in the antiviral group were less likely to have a serious adverse event (1.7% versus 6.6% in the placebo group) or to have discontinued the study because of an adverse event (2.1% versus 4.1%).

reference link :https://www.bmj.com/content/375/bmj.n2713

Molnupiravir

Molnupiravir (Emory Institute of Drug Development-2801 [EIDD-2801]/MK-4482) is one upcoming oral drug which seems promising. This oral agent was developed by Drug Innovation Ventures at Emory University, later was acquired by Ridgeback therapeutics in partnership with Merck & Co, USA. In general, antiviral drugs tested so far usually terminate the elongation of RNA-chain by targeting the viral polymerases but such antivirals have not shown a very promising role in treatment of SARS-CoV-2 infections because of exonucleolytic proof-reading activity that can remove mis-incorporated nucleotides from the nascent RNA.

Both molnupiravir and remdesivir (GS-5734) targets RNA-dependent RNA-Polymerase (RdRp) enzyme used by the corona virus for transcription and replication of its viral RNA genome [1,2]. While remdesivir a nucleoside analog that stalls the RdRp and thus circumvents proof reading, molnupiravir has a unique mechanism of action pretty similar to favipiravir.

Notably, favipiravir was tried in the early part of pandemic without much success. Remdesivir was granted an EUA by the US Food Drug Administration (FDA), however in some studies it failed to show the expected efficacy, the reason as to why WHO did not recommend it. Moreover, it can only be administered via intravenous route in in-hospital settings which has its own limitations.

Molnupiravir initially emerged as a possible treatment of influenza viruses, encephalitic alphaviruses like Venezuelan, Eastern and Western equine encephalitic viruses due to its significant inhibitory effect in cell cultures [3,4]. It appears to work by the mechanism of “error catastrophe” which is essentially based on the concept that by increasing the rate of mutation in the viral genome beyond a biologically tolerable threshold it will become lethal to the virus and lead to its extinction [5,6].

The broad-spectrum antiviral activity of this drug is attributed to its 2-step mutagenesis mechanism. Molnupiravir is an isopropyl ester prodrug, which is cleaved in plasma by host esterases to an active nucleoside analog β-D-N4-hydroxycytidine (NHC) or EIDD-1931 [5]. This active form of the drug is distributed to various tissues and subsequently converted to its corresponding 5′-triphosphate (NHC triphosphate or MTP).

This then targets the RdRp which is virally encoded and competitively inhibits the cytidine and uridine triphosphates and incorporates M instead. The RdRp uses the NHC triphosphate as a substrate instead of the cytidine and uridine triphosphates and then incorporates either A or G in the RdRp active centers forming stable complexes and thus escaping proof reading by the synthesis of a mutated RNA [7,8].

Kabinger et al. [7] confirmed with structural studies about the formation of M-G and M-A base pairs in the active center of RdRp and after cryo-EM density interpretation assumed that one stable tautomer predominates in each case, that is, amino-M tautomer forms a base pair with G and the imino-M tautomer forms a base pair with A and do not impair the RdRp progression [6]. Thus, the 2-step mutagenesis can be summarized as follows- in the first step, RdRp synthesizes negative strand genomic RNA(-gRNA) by using positive strand genomic RNA(+gRNA) as a template.

Following this, in the second step, +gRNA or sub genomic RNA is synthesized using M-containing RNA as template. The M containing RNA in the -gRNA causes mutation in +gRNA and sub-genomic RNA subsequently formed resulting in mutagenesis which is lethal to the virus [5,6]. Fig. 1 illustrates the mechanism of action (schematic representation) of molnupiravir against SARS-CoV-2 and its comparison with remdesivir and favipiravir. These mutations are also produced in the host cell (mammalian DNA) which raises concerns regarding its interference with vacci

nation, and its potential carcinogenic and teratogenic effects which are theoretically possible with mutagenic drugs [9]. However, it might be less likely because of its proposed short-term use – twice daily for 5 days. It is also interesting to note that RNA synthesis in hepatitis C polymerase or RNA polymerase of respiratory syncytial virus is not seen with NHC triphosphate [10].

Fig. 1

Earlier, molnupiravir had illustrated in vitro activity in human airway epithelial cell culture against SARS-CoV-2. Improvement in pulmonary function and decline in viral titer were noted in mice infected with SARS-CoV-2 that were administered molnupiravir [6]. Wahl et al. [11] demonstrated via in vivo studies on human lung-only mice (LoM) that EIDD 2801 dramatically inhibited the replication of SARS-CoV-2.

Also, the drug demonstrated reduced viral shedding and inflammatory infiltrates in nasal lavages and adequate humoral antiviral response in ferret model of influenza [12]. Additionally, molnupiravir demonstrated an inhibitory effect on the replication of SARS-CoV-2 in Syrian hamster model when it was commenced 12 h before or after experimental infection [13]. Thus, further trials in humans were conducted for SARS-COV-2 infections. In this systematic review, we aimed to provide clinical data with molnupiravir through phase 1 to 3 studies conducted in patients with COVID-19.

reference link : https://www.sciencedirect.com/science/article/pii/S1871402121003490?via%3Dihub

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