Viral Load Rebound in Placebo and Nirmatrelvir-Ritonavir Treated COVID-19 Patients is not Associated with Recurrence of Severe Disease or Mutations (preprint)

Nirmatrelvir-ritonavir was developed for the treatment of COVID-19 and has shown efficacy in a Phase 2/3 study of high risk patients (EPIC-HR1). Monitoring for the emergence of viral resistance and recurrence of symptoms is a critical component of any antiviral drug development. As part of the study of viral resistance, a sub-analysis was conducted to examine viral load rebound (VLR) following nirmatrelvir-ritonavir treatment in the EPIC-HR study. Nasopharyngeal or nasal swabs were collected from all study participants at Day 1, Day 3, Day 5, Day 10, and Day 14, and analyzed for viral RNA load and next generation viral sequencing. Two categories of viral load rebound were considered including present/persistent and transient. In EPIC-HR, the proportion of present/persistent VLR was low, occurring at 1.73% (17/980) vs 2.32% (23/990) and for transient VLR 2.35% (23/980) vs 4.65% (46/990) in placebo vs nirmatrelvir-ritonavir participants, respectively. VLR occurred in both treatment arms and was not associated with low nirmatrelvir exposure, hospitalization or death, severe symptom relapse, serological status, or Mpro gene/cleavage treatment emergent mutations. In summary, viral load rebounds are likely a phenomena COVID-19 disease course and nirmatrelvir-ritonavir continue to be an important treatment option for high risk COVID-19 patients.

An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19 (preprint)

The worldwide outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become an established global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to counter 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 I clinical trial in healthy human participants. Clinical Trial Registration ID #: NCT04756531

Comparative study of a 3CLpro inhibitor and remdesivir against both major SARS-CoV-2 clades in human airway models (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of Coronavirus Disease 2019 (COVID-19), a pandemic that has claimed over 700,000 human lives. The only SARS-CoV-2 antiviral, for emergency use, is remdesivir, targeting the viral polymerase complex. PF-00835231 is a pre-clinical lead compound with an alternate target, the main SARS-CoV-2 protease 3CLpro (Mpro). Here, we perform a comparative analysis of PF-00835231 and remdesivir in A549+ACE2 cells, using isolates of two major SARS-CoV-2 clades. PF-00835231 is antiviral for both clades, and, in this assay, statistically more potent than remdesivir. A time-of-drug-addition approach delineates the timing of early SARS-CoV-2 life cycle steps and validates PF-00835231s time of action. Both PF-00835231 and remdesivir potently inhibit SARS-CoV-2 in human polarized airway epithelial cultures. Thus, our study provides in vitro evidence for the potential of PF-00835231 as an effective antiviral for SARS-CoV-2, addresses concerns from non-human in vitro models, and supports further studies with this compound.