First-in-class Pharmaceutical Design Series: Prospects for the First Batch of Anti-COVID-19 Oral Drugs to Be Marketed in 2022

At the start of 2022, the U.
S.
Food and Drug Administration (FDA) has considered approval of two oral anti-COVID-19 drugs, Pfizer’s paxlovid and Merck & Co.
molnupiravir, the launch of oral drugs will greatly improve the treatment plan for patients after positive infection, what impact will this have on the trend of the epidemic in 2022, and whether it will be affected by the potential mutation of the virus, these are all countries around the world expect that the epidemic will gradually subside in 2022.
The important consideration of , let us discuss some of these two molecules with you today
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The COVID-19 virus has been raging around the world for more than 2 years, and major pharmaceutical companies and research units have been working on developing their treatment options
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With the launch of multiple vaccines in 2019, its spread has been slowed to some extent
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Due to the emergence of various mutant strains of COVID-19, vaccines have reduced their effects to varying degrees, and have failed to fundamentally reduce their global prevalence and harm
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Small molecule drugs have always been the main treatments for various diseases.
In early 2022, Pfizer and Merck demonstrated their leadership in innovative drug development in the face of this pandemic crisis, with unprecedented development speed.
In less than 20 months, it has promoted its related oral drug molecules to enter the clinical approval stage, and will soon launch a convenient treatment plan for small molecule drugs for COVID-19
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Preliminary clinical data show that both drugs are superior to Gilead's remdesivir (an intravenous antiviral drug for hospitalized patients) and to varying degrees as an oral antiviral drug for non-hospitalized patients , bringing new hope for a fundamental quell of the global COVID-19 fight in 2022
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Based on existing research and development experience, oral antiviral drugs have several significant potential advantages: (1) they are cheaper and easier to use than antibodies already approved for non-hospitalized patients; (2) resistance to resistance-causing mutations may not be too sensitive
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As we all know, antibodies target the Spike protein used by the sars-cov-2 virus when it enters human cells.
From previous virus research, the Spike protein is relatively easy to mutate, which is the weaker part of the virus replication process
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For example, the recently discovered Omicron has more than 30 mutations in Spike, but only 1 mutation in each of the proteins targeted by paxlovid and molnupiravir; (3) it can complement existing vaccines or inpatient treatments to prevent COVID-19-related deaths provide unprecedented opportunities
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1.
Research engine and target selection After the outbreak of COVID-19, once its SARS-CoV-2 genome was published, researchers from various countries began to analyze the weaknesses of 29 proteins contained in the virus
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Combined with studies of other viral diseases, the researchers began to focus on the replication mechanism of the virus
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Pfizer's choice is the main protease (Main protease, Mpro)
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During viral replication, SARS-CoV-2 synthesizes long polypeptides that must be cleaved by Mpro into its component viral proteins
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Inhibiting Mpro stops the virus from making the proteins it needs to replicate
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Rolf Hilgenfeld of the University of Lübeck in Germany said Mpro is a good target because it is the Achilles heel of the virus
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Pfizer researchers started from an existing lead molecule (review of the development of Pfizer's oral anti-new crown drug Paxlovid), and obtained a covalent molecule PF-07321332 that inhibits Mpro enzyme activity after rapid optimization, and ritonavir (ritonavir, An HIV drug that inhibits cytochrome p450 and slows the metabolism of protease inhibitors) in combination to form paxlovid, advanced from lab idea to submission to the FDA in just 20 months
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Pfizer started a Phase I clinical trial of paxlovid in March 2021 and a Phase II/III clinical trial in July, which will end in early 2022
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In an interim analysis of 1,219 patients, paxlovid treatment within 3 days of symptom onset was associated with an 89% reduction in hospitalization or mortality
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"It's a rapid process, which would take 8-10 years during normal small molecule program development," said Mikael Dolsten, Pfizer's chief scientific officer
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In addition to Pfizer, other Mpro-targeted SARS-CoVs -2 compounds are also under development.
Like Pfizer's compounds, most of them are peptides that mimic Mpro cleavage and covalently bind to the active site to inhibit Mpro's enzymatic activity
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Merck's research focuses on viral RNA replicase (RNA-dependent RNA polymerase, RdRp)
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Viral RdRp is an enzyme that synthesizes RNA, which can be converted into viral protein and self-replicating.
Its structure is relatively conserved in different virus categories, and its function provides more opportunities for broad-spectrum antiviral drugs
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Gilead's remdesivir is also an RdRp inhibitor
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It capitalized on this broad-spectrum potential, first entering clinical trials for Ebola in 2015, but it failed and was not approved for use outside the U.
S.
in the treatment of COVID-19
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It is important to point out that not all RdRp inhibitors work in the same way
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In most cases (including remdesivir) the virus incorporates the drug into the extended RNA, stopping the elongation process; the mechanism of molnupiravir is different, when it is incorporated into the viral RNA, the elongation does not stop
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Instead, the virus re-uses the molnupirvir-containing RNA as a template strand and incorporates the wrong base into the new viral RNA when it encounters molnupirvir again
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Mutations accumulate in the loop, leading to "mismutation" and virus death
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Molnupiravir itself originated in the laboratory of George Painter at Emory University
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In 2013, when Painter was developing a drug to treat Venezuelan equine encephalitis virus (VEEV), he hoped to develop a broad-acting RNA-encoded antiviral drug by targeting RdRp
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He chose to study nucleoside analogs as chemical backbones because they are generally potent, highly resistant, and generally available orally
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With the onset of COVID-19, Painter et al.
found that molnupiravir had broad antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV-1, and influenza in preclinical models, followed by Emory ) licensed the drug to Ridgeback Biotherapeutics, and two months later, Merck acquired exclusive global development and commercialization rights to the drug, entered Phase I trials in April 2020, and began Phase II/III MOVe in October 2020 -OUT trial and submitted interim results from the EUA trial to FDA in October 2021
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Interim results of molnupiravir in 1,433 patients showed a 30% reduction in hospitalization or mortality when the drug was used within 5 days of symptom onset, however, molnupiravir showed no further benefit in the second half of the trial
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Experts narrowly voted for approval at an FDA advisory committee meeting on the drug
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But 10 panelists argued that the drug's benefits did not justify its risks
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Because molnupiravir induces errors in viral RNA, it could theoretically accelerate the evolution of this virus
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This risk is further increased in immunocompromised patients, and molnupiravir may be incorporated into human DNA, causing mutations in rapidly dividing human tissues, including the fetus
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FDA advisory committee member David Eastmond suggested that the FDA should not approve the drug for pregnant women
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2.
Antiviral therapy requiring early intervention For both vaccinated and unvaccinated non-hospitalized patients, both drugs are available in outpatient clinics after approval, and each course of treatment costs about $530 to $700, respectively
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The U.
S.
government has committed to buy 10 million courses of Pfizer and 1.
7 million courses of Merck
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However, in hospitalized patients with more severe disease, these drugs may be less effective, and the earlier the better, the better
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Once infected patients become so ill that they require hospitalization, all current research evidence suggests that most disease is no longer caused by viral replication, and the inflammatory response will dominate
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As a result, Merck stopped its trial of molnupiravir in hospitalized patients after treating only about 300 patients
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The need for early treatment of the virus may also partly explain the ineffectiveness of Roche's use of oseltamivir to treat influenza
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The flu patient felt bad for a few days before going to the doctor and prescribing Tamiflu (oseltamivir), but by then it was too late
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Early intervention in the first 3-7 days - depends on access to early detection
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Therefore, rapid testing for COVID-19 provides an important aid for the use of oral antiviral drugs
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3.
Facing the future At the beginning of the COVID-19 pandemic, British clinical trial expert Horby presided over the screening of antiviral drugs that could directly enter the clinical phase III, including the possibility of new use of remdesivir and other FDA drugs, all of which were unsuccessful.
Molecular effects on viruses are too weak.
He pointed out that in COVID-19, there is no confidence in using old drugs to be used successfully.
New antiviral drugs are definitely needed, and the community needs to fully evaluate these new drugs in large-scale trials
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Judging by target conservation, molnupiravir will be a broad-spectrum virus drug that plays a role in ending this pandemic and may play an important role in future zoonotic diseases transmitted by other coronaviruses
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Due to the large structural differences between Mpros of different viruses, although paxlovid is more active, its use may be limited to SARS-CoV-2
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However, the Mpro inhibitor discovered by Pfizer is optimized on the basis of candidate antiviral drugs with similar targets, which can also provide a good research idea for other antiviral drugs in the future
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