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.
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) symptoms are frequently driven by type 2 inflammation. Depemokimab is the first ultra-long-acting biological drug engineered with enhanced interleukin-5 binding affinity, high potency, and an extended half-life, enabling twice per year dosing and sustained type 2 inflammation inhibition. The ANCHOR-1 and ANCHOR-2 trials investigated the efficacy and safety of depemokimab in people with CRSwNP. METHODS: ANCHOR-1 and ANCHOR-2 were randomised, double-blind, placebo-controlled, parallel-group, replicate phase 3 trials conducted concurrently at 190 centres (hospitals, specialised clinics, and clinical trial sites) in 16 countries (Argentina, Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Romania, Spain, Sweden, Türkiye, the UK, and the USA). Individuals aged 18 years or older at the time of consent, with inadequately controlled CRSwNP, an endoscopic bilateral nasal polyps score of 5 or more, previous surgery for CRSwNP or previous treatment with or intolerance to systemic corticosteroids, and severe symptoms were stratified by previous CRSwNP surgery and randomly assigned 1:1 to receive either depemokimab (100 mg subcutaneously) or placebo every 26 weeks (with standard of care). Allocation was computer generated. The trial sponsor, site staff, and participants were masked. The coprimary endpoints were change from baseline in total endoscopic nasal polyps score (0-8) at week 52 and mean nasal obstruction score (verbal response scale [0-3]) over weeks 49-52, assessed in the full analysis set. Integrated analyses were conducted. Adverse events on treatment and after treatment were monitored. The trials are complete and are registered with ClinicalTrials.gov (NCT05274750 and NCT05281523). FINDINGS: Between April 18, 2022, and Aug 7, 2023, 540 individuals were randomly assigned across ANCHOR-1 and ANCHOR-2; 528 participants comprised the full analysis set (depemokimab, n=272; placebo, n=256). Depemokimab had statistically significant improvements from baseline versus placebo in the coprimary endpoints of total nasal polyps score (treatment difference: ANCHOR-1, -0·7, 95% CI -1·1 to -0·3; p<0·001; ANCHOR-2, -0·6, -1·0 to -0·2; p=0·004; integrated, -0·7, -0·9 to -0·4) and mean nasal obstruction verbal response scale score (ANCHOR-1, -0·23, -0·46 to 0·00; p=0·047; ANCHOR-2, -0·25, -0·46 to -0·03; p=0·025; integrated, -0·24, -0·39 to -0·08). Adverse events were similar between depemokimab and placebo in ANCHOR-1 (74% [n=106] vs 79% [n=101]) and ANCHOR-2 (76% [n=98] vs 80% [n=102]). INTERPRETATION: Depemokimab significantly improved clinically relevant coprimary endpoints versus placebo and was well tolerated, supporting its use as a twice per year treatment option, with the potential to reduce treatment burden for people with CRSwNP. FUNDING: GSK.
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.
The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)- and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596's favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.
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.
BACKGROUND: Although short-term outcomes of Long COVID have been described, longer-term physical and mental health outcomes of Long COVID are less well-established. This study sought to assess differences in long-term physical and mental health outcomes extending up to three years among those with current, resolved, and no Long COVID, as well as duration of Long COVID and vaccination status. METHODS: This was a prospective, multisite, study of participants with SARS-CoV-2 infection from 12/7/2020-8/29/2022, with data collected through 4/2/2024. Surveys included validated tools for physical and mental health. Data were analyzed by Long COVID status (never-had, resolved, current), Long COVID duration and vaccination status. FINDINGS: Of 3663 participants, 2604 (71.1%) never had Long COVID, 994 (27.1%) reported current Long COVID, and 65 (1.8%) reported resolved Long COVID. Compared to never having Long COVID, current Long COVID had lower/worse scores for Patient-Reported Outcomes Measurement Information System (PROMIS) version 29 Physical (7.8; 95% confidence interval [CI] 7.3-8.3) and Mental Health (9.4; 95% CI 8.8-10.1) and higher likelihood of moderate-to-high stress (adjusted odds ratio [aOR]: 2.0; 95% CI 1.6-2.4), moderate-to-high loneliness (aOR: 1.6; 95% CI 1.4-2.0), moderate-to-severe fatigue (aOR: 3.0; 95% CI 2.5-3.7), insufficient activity (aOR for Speedy Nutrition and Physical Activity Assessment ≤4: 0.6; 95% CI 0.5-0.7; aOR for Exercise Vital Sign ≤150 min/week: 0.7, 95% CI 0.6-1.0), and worse dyspnea (aOR: 5.0; 95% CI 4.3-5.8). Resolved Long COVID had lower scores for PROMIS Physical by 2.0 (95% CI 0.2-3.8) and Mental Health by 2.3 (95% CI 0.2-4.4) than the never-had-Long COVID cohort. Number of COVID-19 vaccinations was associated with better outcomes across all measures. INTERPRETATION: Among participants followed up to 3 years after initial infection, those with current Long COVID had worse physical and mental health outcomes. The majority of those with Long COVID did not resolve, with less than 2% having resolved Long COVID. The resolved Long COVID cohort had moderately worse physical and mental health compared with those never-having-Long COVID. COVID-19 vaccination was associated with better outcomes. FUNDING: Centers for Disease Control and Prevention.