ABSTRACT
There is an urgent need for potent and selective antivirals against SARS-CoV-2. Pfizer developed PF-07321332 (PF-332), a potent inhibitor of the viral main protease (Mpro, 3CLpro) that can be dosed orally and that is in clinical development. We here report that PF-332 exerts equipotent in vitro activity against the four SARS-CoV-2 variants of concerns (VoC) and that it can completely arrest replication of the alpha variant in primary human airway epithelial cells grown at the air-liquid interface. Treatment of Syrian Golden hamsters with PF-332 (250 mg/kg, twice daily) completely protected the animals against intranasal infection with the beta (B.1.351) and delta (B.1.617.2) SARS-CoV-2 variants. Moreover, treatment of SARS-CoV-2 (B.1.617.2) infected animals with PF-332 completely prevented transmission to untreated co-housed sentinels.
Subject(s)
COVID-19 Drug Treatment , Disease Models, Animal , Lactams/administration & dosage , Leucine/administration & dosage , Nitriles/administration & dosage , Proline/administration & dosage , SARS-CoV-2/drug effects , Viral Protease Inhibitors/administration & dosage , A549 Cells , Administration, Oral , Animals , COVID-19/prevention & control , COVID-19/transmission , COVID-19/virology , Chlorocebus aethiops , Coronavirus 3C Proteases/antagonists & inhibitors , Cricetinae , Humans , Lactams/pharmacokinetics , Leucine/pharmacokinetics , Mesocricetus , Nitriles/pharmacokinetics , Proline/pharmacokinetics , Respiratory Mucosa/drug effects , Respiratory Mucosa/virology , SARS-CoV-2/enzymology , SARS-CoV-2/physiology , Vero Cells , Viral Protease Inhibitors/pharmacokinetics , Virus Replication/drug effectsABSTRACT
BACKGROUND: Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro. METHODS: We conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. RESULTS: A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of -5.81 percentage points (95% CI, -7.78 to -3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. CONCLUSIONS: Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).
Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Lactams , Leucine , Nitriles , Proline , Ritonavir , Administration, Oral , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Disease Progression , Double-Blind Method , Hospitalization , Humans , Lactams/administration & dosage , Lactams/adverse effects , Lactams/therapeutic use , Leucine/administration & dosage , Leucine/adverse effects , Leucine/therapeutic use , Nitriles/administration & dosage , Nitriles/adverse effects , Nitriles/therapeutic use , Proline/administration & dosage , Proline/adverse effects , Proline/therapeutic use , Ritonavir/administration & dosage , Ritonavir/adverse effects , Ritonavir/therapeutic use , SARS-CoV-2 , Treatment Outcome , Vaccination , Viral Load/drug effects , Viral Protease Inhibitors/administration & dosage , Viral Protease Inhibitors/adverse effects , Viral Protease Inhibitors/therapeutic useABSTRACT
The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.