Highlights

Pfizer reported that the oral antiviral drug Paxlovid (nirmatrelvir + ritonavir) maintains its therapeutic activity against the Omicron (B.1.1.529) variant of SARS-CoV-2 coronavirus.

In any case, three in vitro studies have demonstrated that Paxlovid is able to maintain its own plasma concentration many times greater than that required to prevent Omicron replication in cells.

Paxlovid’s high antiviral activity is also true for other coronavirus variants of concern or interest, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Lambda (C.37), Delta (B.1.617.2), and Mu (B.1.621).

Nirmatrelvir (PF-07321332) is a reversible covalent inhibitor of 3C-like protease (3CLpro, Mpro), an enzyme required by coronavirus for replication. Ritonavir is a booster (enhancer) of nirmatrelvir.

Clinical trials have shown that prescribing Paxlovid within three to five days of COVID-19 symptom manifestation reduces the risk of hospitalization or death by 85%–89%.

Paxlovid (nirmatrelvir + ritonavir).

Paxlovid: New Cure for Coronavirus

Pfizer’s oral antiviral drug reduced the risk of hospitalization or death from COVID-19 by 85%–89%.

 

Details

The first study, which performed a biochemical enzymatic analysis, found that nirmatrelvir in Paxlovid is still a potent inhibitor of its target enzyme 3CLpro, despite the fact that this enzyme in Omicron contains a mutation at amino acid position 132 that changes proline to histidine (P132H). Thus, Ki inhibition constant, as a measure of the binding ability of nirmatrelvir to 3CLpro, was 0.635 nM (95% CI: 0.179–2.250) and 0.933 nM (95% CI: 0.471–1.850) for the Omicron and nonmutant coronavirus variants, respectively. According to the analysis of the crystal structure of the binding mode, the indicated mutation did not actually change it.

  • Structural basis for nirmatrelvir in vitro efficacy against the Omicron variant of SARS-CoV-2. bioRxiv, January 19, 2022. [PDF]

The second study evaluated EC50, the effective concentration of the drug required to suppress viral replication by 50%. The lower EC50, the more effective, i.e. at lower concentrations, the drug compound works. In a Vero E6 cell culture infected with the original SARS-CoV-2 coronavirus or its Alpha, Beta, Gamma, Lambda, Delta, Mu, or Omicron variants, EC50 for nirmatrelvir averaged 38.0, 41.0, 127.2, 24.9, 21.2, 15.9, 25.7, and 16.2 nmol. In other words, viral mutations did not affect the antiviral activity of Paxlovid.

  • Nirmatrelvir, an orally active Mpro inhibitor, is a potent inhibitor of SARS-CoV-2 variants of concern. bioRxiv, January 19, 2022. [PDF]

The third study established the half-maximal inhibitory concentration (IC50), the amount of drug required to inhibit a test reaction by 50%. In HeLa-ACE2 and Vero-TMPRSS2 cell cultures infected with the original SARS-CoV-2 coronavirus or its Alpha, Beta, Delta, or Omicron variants, nirmatrelvir maintained high antiviral activity: IC50 fell within the range of 0.02 to 0.21 μmol. Thus, Paxlovid has proper antiviral activity independent of the currently known viral mutations.

  • Nirmatrelvir, molnupiravir, and remdesivir maintain potent in vitro activity against the SARS-CoV-2 Omicron variant. bioRxiv, January 19, 2022. [PDF]
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Mark Gubar

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Mark has long been the most closely involved in the entire process of drug approval. His professional interests include phenotypic screening in vitro, sequencing technologies, predictors of clinical relevance, and patient compliance.

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