Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques

Abstract

The periodic emergence of SARS-CoV-2 variants of concern (VOCs) with unpredictable clinical severity and ability to escape preexisting immunity emphasizes the continued need for antiviral interventions. Two small molecule inhibitors, molnupiravir (MK-4482), a nucleoside analog, and nirmatrelvir (PF-07321332), a 3C-like protease inhibitor, have recently been approved as monotherapy for use in high risk COVID-19 patients. As preclinical data are only available for rodent and ferret models, we here assessed the efficacy of MK-4482 and PF-07321332 alone and in combination against infection with the SARS-CoV-2 Delta VOC in the rhesus macaque COVID-19 model. Macaques were infected with the SARS-CoV-2 Delta variant and treated with either vehicle, MK-4482, PF-07321332 or a combination of MK-4482 and PF-07321332. Clinical exams were performed at 1, 2 and 4dpi to assess disease and virological parameters. Notably, use of MK-4482 and PF-07321332 in combination improved the individual inhibitory effect of both drugs resulting in milder disease progression, stronger reduction of virus shedding from mucosal tissues of the upper respiratory tract, stronger reduction of viral replication in the lower respiratory tract, and reduced lung pathology. Our data strongly indicate superiority of combined MK-4482 and PF-07321332 treatment of SARS-CoV-2 infections as demonstrated in the closest COVID-19 surrogate model.

Naturally Occurring Mutations of SARS-CoV-2 Main Protease Confer Drug Resistance to Nirmatrelvir

“…Overall, our study identified five hotspot residues located at the drug-binding site of nirmatrelvir that warrant close monitoring in the clinical setting. The results also call for the development of the next generation of M pro inhibitors with a high genetic barrier to drug resistance or combination therapy to reduce the incidence of resistance …”

Combination regimen of nirmatrelvir/ritonavir and molnupiravir for the treatment of persistent SARS-CoV-2 infection: A case report and a scoping review of the literature

“…In virtue of pre-clinical studies suggesting a synergistic effect of antiviral combinations [6] , [7] , [8] , [9] , an off-label combination regimen of molnupiravir (800 mg q 12 hours) and nirmatrelvir/ritonavir (300/100 mg q 12 hours) was started (day 64). Five days later (day 69), antigenic testing on NPS resulted negative, nonetheless, the treatment was still carried out until day 73.…”

“…Regarding in vivo models, the combination of molnupiravir plus nirmatrelvir was evaluated in two studies in mice and macaques, while one study evaluated molnupiravir in association with the parent nucleoside of remdesivir (GS-441524) in hamsters [ 6 , 7 , 14 ]. In macaques infected with the SARS-CoV-2 Delta variant, co-administration of molnupiravir and nirmatrelvir reduced viral shedding, virus replication in the lower respiratory tract, and viral antigen in respiratory tissues, but no definitive results were achieved regarding its safety and tolerability [6] .…”

Attention Mechanism-Based Graph Neural Network Model for Effective Activity Prediction of SARS-CoV-2 Main Protease Inhibitors: Application to Drug Repurposing as Potential COVID-19 Therapy

“…As reflected in Figure A, the attention weights highlight the nitrile group, dimethylcyclopropylproline (DMCP) group, tert-butyl group, and trifluoroacetyl group of PF-07321332, which is a second-generation orally available SARS-CoV-2 Mpro inhibitor developed by Pfizer and has been studied in vitro − and in the clinical phase (NCT04756531, NCT04960202, and NCT05011513). The substructures stressed by attention mechanism are highly in accordance with the inhibitory mechanism according to the crystal structure of SARS-CoV-2 Mpro in complex with PF-07321332 determined by Zhao and co-workers .…”