Daily Respiratory Research Analysis
A twice-yearly anti–IL-5 biologic (depemokimab) significantly improved polyp burden and nasal obstruction in chronic rhinosinusitis with nasal polyps in two parallel phase 3 RCTs. Bispecific antibodies targeting SARS-CoV-2 NTD and RBD maintained potent neutralization across Omicron variants with in vivo efficacy. A large prospective cohort showed persistent long COVID burden up to 3 years, with vaccination associated with better physical and mental health outcomes.
Summary
A twice-yearly anti–IL-5 biologic (depemokimab) significantly improved polyp burden and nasal obstruction in chronic rhinosinusitis with nasal polyps in two parallel phase 3 RCTs. Bispecific antibodies targeting SARS-CoV-2 NTD and RBD maintained potent neutralization across Omicron variants with in vivo efficacy. A large prospective cohort showed persistent long COVID burden up to 3 years, with vaccination associated with better physical and mental health outcomes.
Research Themes
- Biologics for airway inflammatory disease
- Variant-resilient SARS-CoV-2 antibody therapeutics
- Long COVID trajectories and vaccination benefits
Selected Articles
1. Efficacy and safety of twice per year depemokimab in chronic rhinosinusitis with nasal polyps (ANCHOR-1 and ANCHOR-2): phase 3, randomised, double-blind, parallel trials.
Two replicate phase 3 randomized, double-blind trials showed depemokimab significantly reduced total nasal polyp score and nasal obstruction at 52 weeks versus placebo with comparable safety. The ultra–long-acting anti–IL-5 enables twice-yearly dosing, potentially reducing treatment burden for CRSwNP.
Impact: First replicated phase 3 evidence that a twice-yearly anti–IL-5 biologic improves CRSwNP outcomes with acceptable safety, offering a new dosing paradigm.
Clinical Implications: Depemokimab could become a convenient biologic option for severe, type 2–driven CRSwNP uncontrolled on standard therapy, with less frequent dosing than current agents.
Key Findings
- Met both co-primary endpoints: greater reductions in total endoscopic nasal polyp score and mean nasal obstruction score vs placebo at week 52.
- Consistent efficacy across two parallel, replicate phase 3 trials with integrated analyses showing similar effect sizes.
- Safety profile comparable to placebo with similar rates of adverse events across trials.
Methodological Strengths
- Two concurrent, replicate, randomized double-blind, placebo-controlled phase 3 trials across 190 centers in 16 countries
- Pre-specified co-primary endpoints with masked assessment and integrated analyses
Limitations
- Effect sizes were modest in absolute terms on ordinal symptom scales
- Follow-up limited to 52 weeks; long-term durability and surgical avoidance not yet established
Future Directions: Head-to-head comparisons with existing biologics, long-term durability, health-economic analyses, and biomarker-driven patient selection.
2. Bispecific antibodies targeting the N-terminal and receptor binding domains potently neutralize SARS-CoV-2 variants of concern.
Engineering NTD–RBD bispecific antibodies (CoV2-biRNs) yielded potent and breadth-resilient neutralization across Omicron variants (XBB.1.5, BA.2.86, JN.1), outperforming monotherapy/cocktail parents. Prophylactic bsAb delivery reduced XBB.1.5 lung viral load in K18-hACE2 mice.
Impact: Demonstrates a generalizable antibody architecture that maintains potency against highly evasive Omicron lineages, with structural rationale and in vivo validation.
Clinical Implications: Supports development of bispecific antibody therapeutics resilient to VOC escape; may inform next-generation COVID-19 prophylaxis or treatment strategies.
Key Findings
- C1596 NTD mAb recognizes a distinct epitope outside the NTD site i supersite, enabling broad binding.
- NTD–RBD bispecifics (CoV2-biRN5/7) retained potent neutralization against Omicron variants XBB.1.5, BA.2.86, and JN.1, outperforming parental mAbs/cocktails.
- Prophylactic CoV2-biRN5 reduced lung viral load in K18-hACE2 mice challenged with XBB.1.5.
Methodological Strengths
- Integrated structural (cryo-EM), in vitro neutralization across multiple VOCs, and in vivo mouse efficacy
- Rational antibody engineering based on epitope mapping enabling mechanistic insight
Limitations
- Lack of human clinical efficacy or safety data for bsAbs
- Manufacturing complexity and potential immunogenicity of bispecific constructs not addressed
Future Directions: Advance bsAbs to phase 1 human trials, assess durability against emerging variants, and compare prophylactic vs. therapeutic use.
3. Differences in Long COVID severity by duration of illness, symptom evolution, and vaccination: a longitudinal cohort study from the INSPIRE group.
In 3,663 participants followed up to 3 years, current long COVID was associated with worse PROMIS physical and mental health, higher stress, fatigue, and dyspnea. Only 1.8% reported resolution; vaccination dose count correlated with better outcomes across measures.
Impact: Provides long-horizon, multi-domain evidence of persistent long COVID burden and quantifies vaccination’s association with improved outcomes, informing public health and clinical follow-up.
Clinical Implications: Supports sustained monitoring and multidisciplinary management of long COVID; reinforces vaccination as a strategy linked to better long-term outcomes.
Key Findings
- Current long COVID associated with significantly worse PROMIS Physical and Mental Health scores vs never-long COVID.
- Higher odds of stress, loneliness, moderate-to-severe fatigue, insufficient activity, and dyspnea in current long COVID.
- Only 1.8% reported resolved long COVID; more vaccine doses correlated with better outcomes across domains.
Methodological Strengths
- Prospective, multisite cohort with up to 3-year follow-up and validated patient-reported outcome tools
- Stratification by long COVID status and vaccination with multivariable analyses
Limitations
- Operational definition relied on reported long COVID status; potential misclassification
- Not all participants had documented prior infection in claims/EHR; residual confounding possible
Future Directions: Mechanistic studies linking symptom domains to biomarkers, and interventional trials testing vaccination timing/boosting and targeted therapies.