The Choice of Biologics in Patients with Severe Chronic Rhinosinusitis with Nasal Polyps

doi:10.1016/j.jaip.2021.07.023

The Journal of Allergy and Clinical Immunology: In Practice

Volume 9, Issue 12, December 2021, Pages 4235-4238

https://doi.org/10.1016/j.jaip.2021.07.023 Get rights and content

Patients with severe chronic rhinosinusitis with nasal polyps represent an unmet clinical need in terms of recurrent disease despite current medical and surgical therapy. Targeting type 2 inflammatory cytokines (IL4/5/13) appears to be a promising therapeutic approach for such patients akin to what has already been seen in severe asthma. An indirect comparison from phase 3 placebo-controlled trials has shown relative improvements in the coprimary end point of nasal polyp score (NPS) ranging from a 15% reduction (−0.8 units) with mepolizumab, 18% with omalizumab (−1.14 units), and 35% (−2.06 units) with dupilumab. This trend was mirrored by relative improvements in health status with the 22-item Sinonasal Outcome Test score showing a 21% reduction (−13.7 units) with mepolizumab, 27% (−16.1 units) with omalizumab, and 43% (−21.1 units) with dupilumab, all exceeding the minimal clinically important difference of 8.9 units. All biologics improved the coprimary end point of nasal airway blockage and also reduced the need for rescue medical and/or surgical polypectomy. We advocate performing real-life studies looking at the response to biologics in patients who are at increased risk for disease recurrence, including initial optimal medical and surgical polyp clearance before commencing biologics.

Section snippets

Phase 3 Biologic Trials in CRSwNP

It therefore seems timely to appraise the data from recent phase 3 placebo-controlled trials that have evaluated type 2 biologics including anti-interleukin receptor 4 alpha (IL4rα) with dupilumab (SINUS 24 and SINUS 52 over 24 and 52 weeks), anti-IgE with omalizumab (POLYP 1 and POLYP 2 both over 24 weeks), and anti-IL5 with mepolizumab (SYNAPSE over 52 weeks), dupilumab, and omalizumab having already been approved for CRSwNP.3, 4, 5

All of these trials followed a similar pattern in employing

Type 2 Endotype and Response

Real-world head-to-head comparisons are required in severe CRSwNP to establish which particular type 2 endotypes predict the best response to biologics. In SYNAPSE, there was no significant interaction between baseline blood eosinophil counts and either the subsequent NPS or nasal obstruction score in response to mepolizumab, despite the latter markedly reducing blood eosinophils.⁴ Chan et al¹² observed a disconnect with mepolizumab in terms of improvements in asthma control but not NPS or

Conclusions and the Way Forward

In summary, currently available type 2 biologics already approved for asthma appear to be also effective in CRSwNP. An overall indirect comparison of phase 3 trials suggests a better objective response to dupilumab in CRSwNP, although such putative differences in efficacy would require more formal confirmation by meta-analysis. The phase 3 WAYPOINT trial (NCT04851964) is currently investigating the effects of tezepelumab in severe CRSwNP, a monoclonal antibody targeting the alarmin thymic

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The definition of asthma phenotypes has not been fully established, neither there are cluster studies showing homogeneous results to solidly establish clear phenotypes. The purpose of this study was to develop a classification algorithm based on unsupervised cluster analysis, identifying clusters that represent clinically relevant asthma phenotypes that may share asthma-related outcomes.
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Four clusters were identified. Cluster 1 (31.5% of subjects) includes adult-onset atopic patients with better lung function, lower BMI, good asthma control, low ICS dose, and few exacerbations. Cluster 2 (23.6%) is made of adolescent-onset atopic asthma patients with normal lung function, but low adherence to treatment (59% well-controlled) and smokers (48%). Cluster 3 (17.1%) includes adult-onset patients, mostly severe non-atopic, with overweight, the worse lung function and asthma control, and receiving combination of treatments. Cluster 4 (26.7%) consists of the elderly-onset patients, mostly female, atopic (64%), with high BMI and normal lung function, prevalence of smokers and comorbidities.
We defined four phenotypes of asthma using unsupervised cluster analysis. These clusters are clinically relevant and differ from each other as regards FEV1, age of onset, age, BMI, atopy, asthma severity, exacerbations, control, social class, smoking and nasal polyps.
Comparison of Different Biologics for Treating Chronic Rhinosinusitis With Nasal Polyps: A Network Analysis
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Citation Excerpt :
Apart from Oykhman 2021, similar ITCs were published by Peter16 and Wu17; however, they compared no more than 3 biologics. Lipworth18 performed a simple indirect comparison of dupilumab, omalizumab, and mepolizumab without meta-analyses, whereas Chong19 conducted meta-analyses on each biologic without performing an indirect comparison. Overall, our conclusion is consistent with these reviews, showing that dupilumab might be more effective than other evaluated mAbs.
Several promising clinical trials have demonstrated the effects of type 2 biologics compared with placebos in chronic rhinosinusitis with nasal polyps (CRSwNP). However, there are no head-to-head randomized controlled trials (RCTs) between the biologics.
To compare the efficacy and safety of different biologics used for the treatment of CRSwNP.
We systematically identified RCTs investigating the effects of biologics for CRSwNP. Primary outcomes were nasal polyp score (NPS), nasal congestion severity, and serious adverse events. Secondary outcomes included the 22-item Sino-Nasal Outcome Test (SNOT-22) score, loss of smell severity, the University of Pennsylvania Smell Identification Test score, and the Lund-Mackay computed tomography score. Bucher indirect treatment comparison (ITC) was used to compare the outcome parameters.
Seven RCTs (Bachert 2017, OSTRO, POLYP 1, POLYP 2, SINUS-24, SINUS-52, and SYNAPSE) involving 1913 patients and 4 biologics (benralizumab, dupilumab, mepolizumab, and omalizumab) were included for ITC. Dupilumab presented better effects in decreasing NPS and nasal congestion severity compared with the other 3 biologics at 24 weeks of the treatment and at the end of follow-up (more than 48 weeks). Benralizumab was the least effective in reducing nasal congestion severity and SNOT-22 score at 24 weeks. No significant differences were observed between the effects of the other biologics.
Our current findings suggest that dupilumab exhibits the best efficacy and safety for the treatment of CRSwNP.
Targeting Downstream Type 2 Cytokines or Upstream Epithelial Alarmins for Severe Asthma
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Citation Excerpt :
Benralizumab is more effective in patients with asthma and CRSwNP than patients with asthma alone although this might be due to the presence of higher PBE in such patients.52 All biologics currently used for the treatment of asthma are efficacious in CRSwNP although at present when using indirect treatment comparisons dupilumab seems to be the most effective.64,65 Studies demonstrating similar associations with other combinations of T2 conditions would be of interest as further characterization of the disease endotype could help clinicians choose optimal biologic therapy.
Biologics, including omalizumab, mepolizumab, benralizumab, and dupilumab, targeting downstream IgE, cytokines IL-5, and IL-4/13, respectively, have shown promising effects in terms of reduction in annualized asthma exacerbation rates (AER), oral corticosteroid-sparing effects, improvements in forced expiratory volume in 1 second, and improved Asthma Control Questionnaire scores. However, despite these welcome advances, approximately 30% of patients with severe asthma receiving biologics tailored to their specific downstream type 2 biomarkers, including total IgE, peripheral blood eosinophils, and fractional exhaled nitric oxide, do not experience meaningful improvements in their AER. Instead of blocking downstream cytokines, targeting upstream epithelial alarmins, including IL-33, thymic stromal lymphopoietin, and IL-25, has been proposed to tackle the immunologic heterogeneity of asthma. This review article aims to pragmatically summarize the latest key clinical data on antialarmin therapies in severe asthma and put these findings into context with regard to currently available downstream cytokine blockers.
Mepolizumab response in severe chronic rhinosinusitis with nasal polyps is dissociated from blood eosinophil levels
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Fevipiprant in CRSwNP and comorbid asthma: Wrong target population or wrong PGD<inf>2</inf> receptor?
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: No funding was received for this work.

: Conflicts of interest: B. J. Lipworth reports nonfinancial support (equipment) from GlaxoSmithKline; grants, personal fees (consulting, talks, and advisory board), and other support (attending American Thoracic Society and European Respiratory Society meetings) from AstraZeneca; grants, personal fees (consulting, talks, and advisory board), and other support (attending ERS meetings) from Teva; grants and personal fees (consulting, talks) from Sanofi, in relation to the submitted work; personal fees (consulting) from Lupin, Glenmark, Vectura, Dr Reddys, Novartis, and Sandoz; grants and personal fees (consulting, talks, and advisory board) from Circassia and other support (attending BTS meetings) from Boehringer Ingelheim; grants and personal fees (advisory board and talks) from Mylan, outside of the submitted work; and that his son is presently an employee of AstraZeneca. R. Chan has no relevant conflicts of interest.

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Review and Feature ArticleThe Choice of Biologics in Patients with Severe Chronic Rhinosinusitis with Nasal Polyps

Section snippets

Phase 3 Biologic Trials in CRSwNP

Type 2 Endotype and Response

Conclusions and the Way Forward

J Allergy Clin Immunol Pract

J Allergy Clin Immunol

Lancet Respir Med

Lancet

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol Pract

J Allergy Clin Immunol Pract

Review and Feature Article
The Choice of Biologics in Patients with Severe Chronic Rhinosinusitis with Nasal Polyps