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.
BACKGROUND: Ensitrelvir is an oral antiviral treatment for COVID-19 with the same molecular target (the main protease) as ritonavir-boosted nirmatrelvir-the current oral first-line treatment. We aimed to compare the clinical antiviral effects of the two drugs. METHODS: In an open-label, phase 2, randomised, controlled, adaptive pharmacometric platform trial, low-risk adult outpatients aged 18-60 years with early symptomatic COVID-19 (<4 days of symptoms) were recruited from hospital acute respiratory infection clinics in Thailand and Laos. Patients were randomly assigned in blocks (block sizes depended on the number of interventions available) to one of eight treatment groups, including oral ensitrelvir and oral ritonavir-boosted nirmatrelvir at standard doses, both given for 5 days, and no study drug. The primary endpoint was the oropharyngeal SARS-CoV-2 viral clearance rate assessed between day 0 and day 5 in the modified intention-to-treat population (defined as patients with at least 2 days of follow-up). Patients had four oropharyngeal swabs taken on day 0 and two swabs taken daily from days 1 to 7, then on days 10 and 14. Viral clearance rates were derived under a Bayesian hierarchical linear model fitted to log
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.
Host factor-mediated post-translational modification of coronavirus proteins has been demonstrated as an important strategy for regulating viral proliferation. Identification of key host genes involved in this process may provide potential therapeutic targets. In this study, we used the complementary reverse genetic system to determine that UBXN7 promotes SARS-CoV-2 viral double-stranded RNA (dsRNA) production and also promotes the replication of other human coronaviruses. However, UBXN7 does not affect the replication of VSV and RSV, suggesting that it may be a potential pan human coronaviral anti-infection target. Our results revealed that UBXN7 did not affect the viral invasion of cells, but instead hijacked viral genome assembly by interacting with SARS-CoV-2 N protein via its UBX domain. Further data indicated that UBXN7 inhibits K48-linked ubiquitination and proteasomal degradation of SARS-CoV-2 N protein, leading to N protein accumulation. Moreover, K257 of N protein was identified as specific target site of UBXN7 which are critical for viral replication. These findings reveal a novel relationship between host gene-mediated protein ubiquitylation and viral genome assembly, providing new strategies for potential pan-coronavirus drug design.
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.
BACKGROUND: The standard of care for unresectable, locally advanced non-small-cell lung cancer (NSCLC) is chemoradiotherapy followed by durvalumab. This study (Evolution trial WJOG11819L) aimed to evaluate the efficacy and safety of radiotherapy-free pembrolizumab and chemotherapy in patients with unresectable, locally advanced NSCLC with a PD-L1 tumour proportion score (TPS) of 50% or higher. METHODS: This prospective, multicentre, single-arm, phase 2 study was conducted in nine institutes in Japan. Inclusion criteria were age 20 years or older, histologically confirmed unresectable, locally advanced NSCLC with a PD-L1 TPS of 50% or higher, an Eastern Cooperative Oncology Group performance status of 0 or 1, at least one measurable lesion, no previous systemic therapy, and adequate organ function. Patients received intravenous induction therapy comprising pembrolizumab 200 mg every 3 weeks plus platinum-based chemotherapy for four cycles: either cisplatin 75 mg/m FINDINGS: Between May 18, 2020, and Feb 22, 2022, 21 patients were assessed for eligibility and all were enrolled. Median age was 73 years (IQR 68-80); 16 (76%) patients were male; race and ethnicity data were not collected. Three (14%) patients discontinued and 18 (86%) patients completed the induction therapy; eight (38%) patients discontinued during maintenance therapy and ten (48%) patients completed the maintenance therapy. Median follow-up was 32·5 months (IQR 26·2-39·5). The 2-year progression-free survival rate was 67% (90% CI 46-83). The most common grade 3 or worse adverse events were neutropenia (eight [38%] of 21 patients), leukopenia (four [19%]), and pneumonia (three [14%]). Serious adverse events occurred in seven (33%) patients. No treatment-related deaths were reported. INTERPRETATION: These findings suggest that pembrolizumab combined with platinum-based chemotherapy, without radiotherapy, might provide a feasible and promising alternative treatment strategy for patients with unresectable, locally advanced NSCLC with a PD-L1 TPS of 50% or higher. FUNDING: Merck Sharp & Dohme.