SARS-CoV-2 viral dynamics in a placebo-controlled phase 2 study of patients infected with the SARS-CoV-2 Omicron variant and treated with pomotrelvir
Katyna Borroto-Esoda, David Wilfret, Xiao Tong, Andrew Plummer, Brian Kearney, Ann D Kwong
Microbiology Spectrum, doi:10.1128/spectrum.02980-23
Current guidelines recommend that individuals with moderate COVID-19 disease isolate for 5 days after the first appearance of symptoms or a positive SARS-CoV-2 test. It would be useful to understand the time course of infectious virus production and its correlation with virus detection using a rapid antigen test (RAT) or quantitative reverse transcriptase (qRT)-PCR. In a phase 2 study, 242 vaccinated patients with COVID-19 and at low risk for progression to severe disease initiated 5 days of treatment with pomotrelvir (PBI-0451, a SARS-CoV-2 main protease inhibitor) or placebo within 5 days after symptom onset. The primary endpoint, the proportion of subjects with SARS-CoV-2 viral titers below the limit of detection on Day 3 of treatment in the pomotrelvir versus placebo groups, was not met. No between-group differences in SARS-CoV-2 clearance or symptom resolution or alleviation were observed. Additional analyses evaluated the dynamics of SARS-CoV-2 replication in mid-turbinate nasal swabs and saliva samples using infectious virus assay (IVA), RAT, and qRT-PCR. SARS-CoV-2 cleared rapidly, with negative results first determined by IVA (TCID 50 below the limit of detection), followed by the RAT (negative for SARS-CoV-2 N antigen), and qRT-PCR (RNA below the limit of detection), which suggests that delayed initiation of treatment (up to 5 days after symptom onset) may have contributed to the lack of treatment response. Symptom resolution lagged behind viral clearance assessed by IVA and RAT. These data support reliance on a negative RAT to determine when an individual is no longer producing infectious virus and may end isolation. IMPORTANCE A phase 2 double-blind, placebo-controlled study was performed evaluating pomotrelvir, a SARS-CoV-2 Mpro inhibitor, compared with placebo in 242 non-hospitalized, vaccinated, symptomatic adults with COVID-19 (Omicron). No improvement in the decrease of viral replication or relief of symptoms was observed between the two groups when treatment was initiated ≥3 days after symptom onset. These results suggest that future COVID-19 antiviral studies using a similar patient population may need to initiate treatment earlier, like influenza studies. This is the first study to prospectively evaluate SARS-CoV-2 viral dynamics and the time to viral clearance in a significant number of patients using concurrently obtained results from an infectious virus assay, a rapid antigen test (RAT), and a qRT-PCR assay over a 15-day time course. These results suggest that a negative RAT assay is a good indicator of loss of infectious virus and the ability to return to normal activities.
MATERIALS AND METHODS
Study design A phase multicenter, randomized, double-blind, placebo-controlled study that the antiviral activity, clinical efficacy, and safety of orally administered pomotrelvir compared with placebo.
Patients Patients were non-hospitalized, symptomatic males and females from 18 to <65 years old with COVID-19, who were not at high risk of progressing to severe disease, with onset of COVID-19 symptoms within 5 days prior to randomization, a positive SARS-CoV-2 test within 24 hours prior to randomization, and at least two symptoms of acute SARS-CoV-2 infection at randomization. Patients had a primary COVID-19 vaccination series (and any booster) at least 3 months prior to randomization.
Randomization and blinding Patients were randomized 2:1 to the pomotrelvir or placebo treatment group and assigned a unique subject number via an interactive voice and web response system. Randomization was stratified based on SARS-CoV-2 positive direct test diagnosis ≤3 days versus >3-5 days from the first onset of COVID-19 symptom(s) and if patients received primary vaccination series alone versus any COVID-19 booster doses. Patients, investigators, and all internal and external personnel directly involved in the conduct of the study were blinded to treatment assignment.
Treatment and procedures Following randomization on Day 1, subjects initiated dosing with either pomotrelvir 700 mg (2× 350 mg tablets twice daily for a total daily dose of 1,400 mg) or..
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'correlation with virus detection using a rapid antigen test (RAT) or quantitative reverse '
'transcriptase (qRT)-PCR. In a phase 2 study, 242 vaccinated patients with COVID-19 and at low '
'risk for progression to severe disease initiated 5 days of treatment with pomotrelvir '
'(PBI-0451, a SARS-CoV-2 main protease inhibitor) or placebo within 5 days after symptom '
'onset. The primary endpoint, the proportion of subjects with SARS-CoV-2 viral titers below '
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'concurrently obtained results from an infectious virus assay, a rapid antigen test (RAT), and '
'a qRT-PCR assay over a 15-day time course. These results suggest that a negative RAT assay is '
'a good indicator of loss of infectious virus and the ability to return to normal '
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