Pfizer has shared results from several studies that reportedly show in vitro efficacy of nirmatrelvir, the active main protease (Mpro) inhibitor of Paxlovid (nirmatrelvir [PF-07321332] tablets and ritonavir tablets), is maintained in use against omicron, the variant of the SARS-CoV-2 currently dominating around the globe. The company reports that taken in combination, the in vitro studies suggest Paxlovid possesses the potential to maintain plasma concentrations several times higher than the amount required to prevent omicron from replicating.
Mikael Dolsten—chief scientific officer and president of worldwide research, development, and medical of Pfizer—said the company designed Paxlovid specifically to “retain its activity across coronaviruses, as well as current variants of concern with predominantly spike protein mutations.” He added that the company is heartened by the early results.
“Following the clinical findings – showing Paxlovid reduced risk of hospitalization or death by nearly 90% compared to placebo for high-risk patients when treated within five days of symptom onset – we are encouraged by these initial laboratory findings,” Dolsten commented. “These data suggest that our oral COVID-19 therapy can be an important and effective tool in our continued battle against this devastating virus and current variants of concern, including the highly transmissible omicron."
Dolsten added that the company plans to keep monitoring the treatment’s activity in real-world settings, and they are confident the in vitro findings will keep holding up.
In the first in vitro study of Paxlovid conducted by the company, researchers tested nirmatrelvir tested against the Mpro (an enzyme necessary for the virus to replicate) – from several SARS-CoV-2 variants of concern (VoCs), including omicron, in a biochemical assay. Pfizer reported the results showed in all cases that nirmatrelvir was a potent inhibitor of its target.
Nirmatrelvir’s Ki – a measure of its ability to bind to an enzyme – was approximately 1 nanomolar (nM) (or Ki fold change <1) for both the omicron and the original Washington variant (USA-WA1/2020) in this assay, indicating its continued ability to prevent in vitro viral replication, according to Pfizer. These results (along with a crystal structure reportedly demonstrating how nirmatrelvir binds to the omicron variant) have been submitted to the online preprint server bioRxiv.
In Pfizer’s second in vitro study, nirmatrelvir was tested against several SARS-CoV-2 VoCs, including omicron, in an antiviral, cell-based assay. Researchers measured reduction in viral load through polymerase chain reaction (PCR) analysis, a test designed to detect the virus.
Nirmatrelvir’s EC50 (a measure of drug potency showing a concentration that is effective in producing 50% of the maximal response) was 16 nM for the omicron variant, compared to 38 nM for the USA-WA1/2020 variant, reaffirming its robust in vitro antiviral activity. These results reportedly are in line with the values that have been observed for other VoCs (Alpha, Beta, Gamma, Delta, Lambda, and Mu) in this assay, with EC50 measures ranging from 16 to 127 nM compared to USA-WA1/2020, where EC50 was 37 nM. Results from this study have been submitted to the online preprint server bioRxiv and will be submitted to a peer-reviewed journal.
Another study conducted by the Icahn School of Medicine at Mount Sinai (Icahn Mount Sinai) in collaboration with Pfizer used a SARS-CoV-2-specific immunofluorescence-based assay to similarly detect the virus and measure the in vitro potency of nirmatrelvir, as well as some other authorized/approved COVID-19 therapeutics, against VoCs. Treatments were tested against the alpha, beta, delta, and omicron variants in two cell lines. IC50 values – a measure of drug efficacy indicating the concentration needed to inhibit infection by half – ranging from 22 to 225 nM for nirmatrelvir compared to USA-WA1/2020, where the IC50 was 38 to 207 nM, were observed. Results from this study have been submitted to the online preprint server bioRxiv and will be submitted to a peer-reviewed journal.
“Omicron is proving itself to be a formidable and highly transmissible variant of an already detrimental virus,” said Kris White, assistant professor in the Department of Microbiology at Icahn Mount Sinai. “We are heartened to see early data showing that this oral treatment is maintaining robust in vitro antiviral activity against it, as well as other variants of concern.”
Paxlovid is currently authorized for conditional or emergency use in several countries across the globe. Pfizer has submitted applications for regulatory approval or authorization to multiple regulatory agencies and anticipates further regulatory decisions to follow.