Daily Respiratory Research Analysis
An adaptive randomized trial showed that oral ensitrelvir accelerates SARS-CoV-2 viral clearance versus no treatment, though modestly less than ritonavir-boosted nirmatrelvir. A mechanistic study identified the host factor UBXN7 as a pan-coronavirus promoter by stabilizing the viral nucleocapsid protein. A phase 2 single-arm study suggests a radiotherapy-free pembrolizumab plus chemotherapy strategy may be feasible for unresectable, locally advanced NSCLC with high PD-L1.
Summary
An adaptive randomized trial showed that oral ensitrelvir accelerates SARS-CoV-2 viral clearance versus no treatment, though modestly less than ritonavir-boosted nirmatrelvir. A mechanistic study identified the host factor UBXN7 as a pan-coronavirus promoter by stabilizing the viral nucleocapsid protein. A phase 2 single-arm study suggests a radiotherapy-free pembrolizumab plus chemotherapy strategy may be feasible for unresectable, locally advanced NSCLC with high PD-L1.
Research Themes
- Antiviral therapeutics and pharmacometric endpoints
- Host–virus interaction and ubiquitin-mediated protein stability
- Radiation de-escalation strategies in locally advanced lung cancer
Selected Articles
1. Antiviral efficacy of oral ensitrelvir versus oral ritonavir-boosted nirmatrelvir in COVID-19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial.
In 604 concurrently randomized participants, both ensitrelvir and nirmatrelvir significantly accelerated oropharyngeal SARS-CoV-2 clearance versus no treatment. Median half-lives were 5.9 h (ensitrelvir), 5.2 h (nirmatrelvir), and 11.6 h (no drug); ensitrelvir was 82% faster than no drug but 16% slower than nirmatrelvir. Viral rebound rates were low and similar (5–7%).
Impact: This adaptive RCT provides head-to-head pharmacometric evidence positioning ensitrelvir as an effective oral antiviral alternative to nirmatrelvir and quantifies relative antiviral potency using rigorous serial sampling and Bayesian modeling.
Clinical Implications: Ensitrelvir may serve as an alternative when nirmatrelvir-ritonavir is contraindicated or unavailable, with the caveat that clinical outcomes were not primary endpoints. Results support rapid viral suppression strategies and inform prioritization for high-risk patients.
Key Findings
- Median viral clearance half-life: 5.2 h (nirmatrelvir), 5.9 h (ensitrelvir), 11.6 h (no drug).
- Ensitrelvir accelerated clearance by 82% versus no drug but was 16% slower than nirmatrelvir (95% CrI 5–25%).
- Viral rebound occurred in 7% (nirmatrelvir) and 5% (ensitrelvir) with no significant difference.
- Meta-analysis within the platform found nirmatrelvir and ensitrelvir had the largest antiviral effects among small-molecule agents tested.
Methodological Strengths
- Adaptive randomized platform design with concurrent controls and head-to-head comparison.
- High-frequency serial oropharyngeal sampling and Bayesian hierarchical modeling of viral kinetics.
Limitations
- Open-label design and low-risk outpatient population; clinical outcomes were not primary endpoints.
- Generalizability to high-risk, older, or hospitalized patients is uncertain.
Future Directions: Assess clinical endpoints (hospitalization, symptom resolution) in high-risk populations and evaluate combination or sequential antiviral strategies guided by pharmacometric endpoints.
2. UBXN7 facilitates SARS-CoV-2 replication via inhibiting the K48-linked ubiquitination of viral N protein.
UBXN7 interacts with the SARS-CoV-2 nucleocapsid (N) protein via its UBX domain to block K48-linked ubiquitination and proteasomal degradation, resulting in N accumulation and enhanced replication. The effect extends to other human coronaviruses, but not VSV or RSV, highlighting UBXN7 as a potential pan-coronavirus host target.
Impact: Identifies a druggable host pathway linking ubiquitin-mediated proteostasis to coronavirus genome assembly and pinpoints a specific N protein residue (K257) as critical for replication.
Clinical Implications: Targeting UBXN7–N interactions or restoring K48-linked ubiquitination of N may yield pan-coronavirus therapeutics less susceptible to viral resistance than direct-acting antivirals.
Key Findings
- UBXN7 increases dsRNA production and replication of SARS-CoV-2 and other human coronaviruses.
- UBXN7 interacts with viral N via UBX domain, inhibiting K48-linked ubiquitination and proteasomal degradation.
- N protein residue K257 is the critical site mediating UBXN7’s stabilization effect.
- No effect on replication of VSV or RSV, indicating specificity for coronaviruses.
Methodological Strengths
- Use of complementary reverse genetics and interaction mapping to define mechanism.
- Cross-virus testing establishes specificity and pan-coronavirus relevance.
Limitations
- Predominantly in vitro data without in vivo efficacy or safety assessment.
- No small-molecule or peptide inhibitor prototypes were tested in disease models.
Future Directions: Develop and test inhibitors disrupting UBXN7–N binding or promoting N ubiquitination in animal models; evaluate host toxicity and broad coronavirus coverage.
3. Radiotherapy-free pembrolizumab combined with chemotherapy for locally advanced non-small-cell lung cancer with PD-L1 tumour proportion score of 50% or higher (Evolution trial): a multicentre, single-arm, phase 2 study.
In 21 PD-L1-high, unresectable, locally advanced NSCLC patients, radiotherapy-free pembrolizumab plus platinum-based chemotherapy achieved a 2-year PFS of 67% after a median follow-up of 32.5 months, with manageable grade ≥3 toxicities (notably neutropenia 38%). No treatment-related deaths occurred.
Impact: Challenges the chemoradiotherapy paradigm by demonstrating feasibility of a radiation-sparing regimen in a biomarker-defined subset, warranting randomized confirmation.
Clinical Implications: For PD-L1 TPS ≥50% unresectable stage III NSCLC, a radiotherapy-free IO-chemo induction/maintenance approach may be considered in trials or select settings; however, practice change requires randomized data versus standard chemoradiation.
Key Findings
- Two-year progression-free survival rate was 67% (90% CI 46–83) with radiotherapy-free pembrolizumab plus chemotherapy.
- Median follow-up was 32.5 months; no treatment-related deaths occurred.
- Most common grade ≥3 AEs: neutropenia (38%), leukopenia (19%), pneumonia (14%).
Methodological Strengths
- Prospective multicenter design with long median follow-up.
- Biomarker-enriched cohort (PD-L1 TPS ≥50%) targeting likely IO responders.
Limitations
- Single-arm, small sample size (n=21) without a contemporaneous control.
- Generalizability limited to PD-L1-high population; radiotherapy omission risks untested in randomized setting.
Future Directions: Randomized trials versus chemoradiation plus durvalumab, translational biomarker analyses to identify optimal candidates, and evaluation of local control without radiotherapy.