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While industry and regulators' interest in decentralized clinical trials (DCTs) is long-standing, the Covid-19 pandemic accelerated and broadened the adoption and experience with these trials. The key idea in decentralization is bringing the clinical trial design, typically on-site, closer to the patient's experience (on-site or off-site). Thus, potential benefits of DCTs include reducing the burden of participation in trials, broadening access to a more diverse population, or using innovative endpoints collected off-site. This paper helps researchers to carefully evaluate the added value and the implications of DCTs beyond the operational aspects of their implementation. The proposed approach is to use the ICH E9(R1) estimand framework to guide the strategic decisions around each decentralization component. Furthermore, the framework can guide the process for clinical trialists to systematically consider the implications of decentralization, in turn, for each attribute of the estimand. We illustrate the use of this approach with a fully DCT case study and show that the proposed systematic process can uncover the scientific opportunities, assumptions, and potential risks associated with a possible use of decentralization components in the design of a trial. This process can also highlight the benefits of specifying estimand attributes in a granular way. Thus, we demonstrate that bringing a decentralization component into the design will not only impact estimators and estimation but can also correspond to addressing more granular questions, thereby uncovering new target estimands., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Introduction: Elevated neutrophil counts in blood, sputum, or lung have been associated with poor clinical outcomes and more severe disease in patients with type 2 asthma. In the phase 3 LIBERTY ASTHMA QUEST (NCT02414854), add-on dupilumab 200 and 300 mg every 2 weeks compared with matched placebo significantly reduced severe asthma exacerbations and improved forced expiratory volume in 1 s (FEV 1 ) in patients with uncontrolled, moderate-to-severe asthma. This post hoc analysis explored the efficacy of dupilumab in patients with type 2 asthma enrolled in QUEST with or without elevated blood neutrophil counts., Methods: Annualized severe exacerbation rates during the 52-week treatment period and least-squares mean change from baseline in FEV 1 over time were evaluated for patients with elevated type 2 biomarkers at baseline (blood eosinophils ≥ 150 cells/ µ L or fractional exhaled nitric oxide (FeNO) ≥ 20 ppb; and eosinophils ≥ 300 cells/ µ L or FeNO ≥ 50 ppb) and low (<4,000 cells/ µ L) or high (≥4,000 cells/ µ L) neutrophil counts., Results: Dupilumab significantly reduced annualized severe exacerbation rates compared with placebo during the 52-week treatment period in patients with elevated type 2 biomarkers, irrespective of baseline neutrophil count ( P < 0.0001 for all comparisons). Significant improvements in FEV 1 versus placebo were observed as early as Week 2 and over the 52-week treatment period, irrespective of baseline neutrophil count ( P < 0.001 for all comparisons). Safety findings were similar across all subgroups, regardless of neutrophil counts at baseline., Conclusions: Dupilumab treatment significantly reduced annualized severe exacerbation rates and improved lung function in patients with uncontrolled, moderate-to-severe, type 2 asthma, irrespective of baseline blood neutrophil count. This trial is registered with NCT02414854., Competing Interests: E. R. Bleecker reports clinical trials from AstraZeneca, Boehringer Ingelheim, Genentech, MedImmune, Novartis, Regeneron Pharmaceuticals Inc., and Sanofi Genzyme through his employer, Wake Forest School of Medicine and University of Arizona; and personal fees (paid consultant) from ALK-Abelló, AstraZeneca, GlaxoSmithKline, MedImmune, Novartis, Regeneron Pharmaceuticals Inc., Sanofi Genzyme, and Teva. R. A. Panettieri has no conflicts of interest to disclose. N. L. Lugogo has received clinical trial funding from AstraZeneca, Genentech, GlaxoSmithKline, and Sanofi; and is an advisory board member and consultant for AstraZeneca, Genentech, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals Inc., Sanofi, and Teva. J. Corren reports research grants (consultant) from AstraZeneca, Genentech, Novartis, Regeneron Pharmaceuticals Inc., and Sanofi; and speaker fees from AstraZeneca, Genentech, and Novartis. N. Daizadeh is a former employee of Sanofi and may hold stock and/or stock options in the company. J. A. Jacob-Nara, P. J. Rowe, T. J. Ferro, and C. N. Hansen are employees of Sanofi, and may hold stock and/or stock options in the company. Y. Deniz, A, Khodzhayev, and X. Soler are employees and shareholders of Regeneron Pharmaceuticals Inc., (Copyright © 2023 Eugene R. Bleecker et al.)

Objective: The open-label extension TRAVERSE study (NCT02134028) assessed dupilumab long-term safety and efficacy in patients who completed Phase 2/3 dupilumab asthma studies. This post hoc analysis evaluated long-term efficacy in type 2 patients with and without evidence of allergic asthma who enrolled in TRAVERSE from Phase 3 QUEST (NCT02414854) and Phase 2b (NCT01854047) studies. Non-type 2 patients with evidence of allergic asthma were also assessed., Methods: Unadjusted annualized exacerbation rates during parent study and TRAVERSE treatment period, and changes from parent study baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) and in 5-item Asthma Control Questionnaire (ACQ-5) scores were assessed in patients from QUEST and Phase 2b; change from parent study baseline in total IgE level was assessed in patients enrolled from Phase 2b., Results: 2062 patients from Phase 2b and QUEST enrolled in TRAVERSE. Of these, 969 were type 2 with evidence of allergic asthma; 710 were type 2 without evidence of allergic asthma; and 194 were non-type 2 with evidence of allergic asthma at parent study baseline. In these populations, reductions in exacerbation rates observed during parent studies were sustained during TRAVERSE. Type 2 patients who switched from placebo arm to dupilumab in TRAVERSE experienced similar reductions in severe exacerbation rates, and improvements in lung function and asthma control to those patients who already received dupilumab during the parent study., Conclusion: Dupilumab efficacy was sustained for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 inflammatory asthma, with or without evidence of allergic asthma.ClinicalTrials.gov identifier: NCT02134028.

Background: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of VOYAGE (NCT02948959), dupilumab efficacy was evaluated in patients aged 6-11 years with type 2 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L)., Methods: Annualized severe exacerbation rates (AER) and changes in pre-bronchodilator (Pre-BD) forced expiratory volume in one second (FEV 1 ), percent-predicted pre-BD FEV 1 (ppFEV 1 ), and Asthma Control Score (ACQ)-7 were assessed during the treatment period., Results: 350 children (261 with and 89 without evidence of allergic asthma) were included. Dupilumab versus placebo significantly reduced AER in patients with (0.24 vs. 0.62, relative risk reduction [RRR]: 62% [95% CI, 39-76], P < .0001) and without (0.39 vs. 0.80, RRR: 51% [95% CI, 0-76], P < .05) evidence of allergic asthma. Significant improvements in ppFEV 1 , pre-bronchodilator FEV 1 , and ACQ-7 scores were observed in dupilumab versus placebo throughout the treatment period in patients with evidence of allergic asthma. In patients without evidence of allergic asthma, numerical improvements in pre-bronchodilator FEV 1 and asthma control were observed by Week 52., Conclusion: Dupilumab versus placebo reduced asthma exacerbations in children with type 2 asthma irrespective of evidence of allergic asthma; similar trends were observed in changes in lung function. Significant improvement in asthma control was observed in patients with evidence of allergic asthma, but not in those without., (© 2023 Sanofi and The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: FeNO may have a role as both a prognostic and predictive biomarker in combination with eosinophils for assessing responsiveness to some biological therapies., Objective: We evaluated the value of baseline FeNO, adjusted for baseline blood eosinophil levels and other clinical characteristics, as an independent predictor of treatment response to dupilumab in patients with uncontrolled moderate-to-severe asthma., Methods: We performed a post hoc analysis of LIBERTY ASTHMA QUEST (NCT02414854), a phase 3, double-blind study in patients aged 12 years and older with uncontrolled moderate-to-severe asthma, who received dupilumab 200 or 300 mg, or placebo every 2 weeks up to 52 weeks. We assessed the annualized event rate of severe exacerbations and least-squares mean change from baseline in prebronchodilator FEV 1 at weeks 12 and 52 in relationship to baseline FeNO, adjusted for eosinophils and other clinical characteristics., Results: The annualized event rate increased with increasing baseline FeNO in placebo and decreased in dupilumab groups. The relative risk of severe exacerbations was 22·7%, 58·3%, and 69·3% lower for dupilumab versus placebo for the FeNO less than 25, 25 to less than 50, and 50 and greater parts per billion subgroups. The magnitude of FEV 1 improvement increased with higher baseline FeNO for dupilumab and was consistent across the continuum of FeNO levels in placebo. Both findings were independent of blood eosinophil levels. Significant differences were observed between FeNO subgroups., Conclusions: Increased baseline FeNO was associated with greater clinical effects in dupilumab versus placebo independently of eosinophil levels and other clinical characteristics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4/-13, key and central drivers of type 2 (T2) inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), dupilumab vs placebo significantly reduced asthma exacerbation rates (AER) and improved pre-bronchodilator forced expiratory volume in 1 second (FEV 1 ) in patients with uncontrolled, moderate-to-severe asthma, with greater effects in patients with elevated T2 biomarkers (≥150 eosinophils/µL or fractional exhaled nitric oxide [FeNO] ≥25 parts per billion). Overall safety was consistent with the known dupilumab safety profile. This post hoc analysis assessed dupilumab efficacy in QUEST patients with T2 asthma with evidence of an allergic phenotype (baseline serum IgE ≥30 IU/mL and aeroallergen-specific IgE ≥0.35 IU/mL) by number of aeroallergen sensitizations: 1, 2, 3, or ≥4. Non-sensitized patients (serum total IgE <30 IU/mL without evidence of allergic phenotype) were also assessed., Patients and Methods: Endpoints were annualized AER, change from baseline in pre-bronchodilator FEV 1 and asthma control (5-item Asthma Control Questionnaire [ACQ-5]), and FeNO and serum total IgE levels over the 52-week treatment period., Results: In all subgroups by number of allergens sensitized, dupilumab vs placebo reduced AER by 35-67% and improved both pre-bronchodilator FEV 1 at Week 12 (least squares mean differences: 0.10-0.26 L across subgroups) and ACQ-5 score at Week 52 (-0.26 to -0.43). Dupilumab significantly reduced FeNO and total IgE levels at Week 52 compared with placebo. Similar results were observed in non-sensitized patients., Conclusion: Dupilumab improved clinical outcomes and reduced biomarker levels in patients with uncontrolled, moderate-to-severe T2 asthma irrespective of allergen sensitization status or number., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02414854., Competing Interests: Dr Corren reports research grants and serving as a consultant for AstraZeneca, Genentech, Novartis, Regeneron Pharmaceuticals, Inc., and Sanofi; and speaker fees from AstraZeneca, Genentech, and Novartis. Dr Jackson reports advisory board fees from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Sanofi, and Teva. Dr Casale reports research support from American Lung Association, Genentech, NIH, Novartis, PCORI, and Sanofi; serving as a consultant for AstraZeneca, Boehringer Ingelheim, Genentech, Novartis, and Regeneron Pharmaceuticals, Inc.; and serving on the speakers’ bureau for Genentech. Dr Borish is an advisory board member of Genentech, Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme; and reports research funding from Astra Zeneca, GSK, NIH, and Regeneron Pharmaceuticals, Inc. Dr Rabe reports speaker fees and is a consultant for AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Chiesi Pharmaceutical, GSK, Novartis, Roche Pharma, Sanofi & Regeneron, and Teva. Dr Busse is a consultant and reports speaker fees from AstraZeneca, Genentech, GSK, Novartis, Sanofi & Regeneron, and Teva. Dr Maspero is a consultant for AstraZeneca and Sanofi; reports speaker fees from GSK, Menarini, Novartis, Teva, and Uriach; and reports research grants from Novartis. Dr Jackson is a consultant for AstraZeneca, Genentech, GSK, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, and Vifor Pharma; and is a member of the data and safety monitoring board of Pfizer. He also reports grants from NIH/NIAID and NIH/NHLBI. Dr Daizadeh is a former employee of Sanofi and may hold stock and/or stock options in the company. Mr Altincatal, Dr Djandji, Dr Jacob-Nara, and Dr Rowe are employees of Sanofi and may hold stock and/or stock options in the company. Dr Radwan, Dr Khodzhayev, and Dr Deniz are employees and shareholders of Regeneron Pharmaceuticals, Inc. The authors report no other conflicts of interest in this work., (© 2023 Corren et al.)

Background: Severe asthma impacts quality of life (QoL), including dyspnea, sleep, and activity limitation. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4 and -13, which are key and central drivers of type 2 inflammation. Phase 3 LIBERTY ASTHMA VENTURE (NCT02528214) and LIBERTY ASTHMA TRAVERSE open-label extension (NCT02134028) evaluated dupilumab 300 mg vs placebo every 2 weeks for 24 weeks (VENTURE) and dupilumab only for an additional 48 to 96 weeks (TRAVERSE) in patients with oral corticosteroid (OCS)-dependent severe asthma., Objective: To assess dupilumab's impact on Asthma QoL Questionnaire (AQLQ) items related to breathing symptoms, sleep, and activity limitation, and on OCS reduction., Methods: The proportion of patients with AQLQ scores of 6 or 7 for breathing symptoms-, sleeping-, and activity-related items in VENTURE and TRAVERSE, together with OCS dose reductions in VENTURE., Results: In VENTURE, significantly greater proportions of dupilumab- vs placebo-treated patients achieved scores of 6 or 7 by week 24 in breathing symptoms-related (42.7%-60.2% vs 22.4%-39.3%), sleeping-related (45.6%-65.0% vs 27.1%-47.7%), and activity-related (44.7%-51.5% vs 22.4%-34.6%) AQLQ items. Improvements were maintained through TRAVERSE in the dupilumab/dupilumab group and increased to dupilumab treatment levels in the placebo/dupilumab group. Significant OCS dose reductions were observed in VENTURE; up to 90% and 60% of dupilumab-treated vs 65% and 41% of placebo-treated patients with AQLQ scores of 6 or 7 in breathing symptoms-, sleeping-, and activity-related items achieved greater than or equal to 50% dose reduction and eliminated OCS at week 24, respectively., Conclusion: In patients with severe OCS-dependent asthma, dupilumab improved QoL related to breathing symptoms, sleep, and activity limitation, and reduced OCS use., Trial Registration: ClinicalTrials.gov Identifiers: NCT02528214 and NCT02134028., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The 52-week, phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) in patients aged above or equal to 12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks vs matched placebo., Objective: To assess whether dupilumab improves clinical outcomes in QUEST patients with persistent airflow obstruction (PAO) defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity ratio less than 0.7 at baseline., Methods: End points were annualized rate of severe exacerbations, pre and post-bronchodilator forced expiratory volume in 1 second over time, proportion achieving reversal of PAO, and quality of life. Efficacy was evaluated in patients with or without PAO at baseline in subpopulations with eosinophils ≥ 150 cells/µL or fractional exhaled nitric oxide (FeNO) ≥ 25 ppb or eosinophils ≥ 300 cells/µL and FeNO ≥ 25 ppb., Results: Of 1902 patients enrolled in QUEST, 1039 (55%) had PAO at baseline. Dupilumab vs placebo rapidly and significantly improved lung function in patients with PAO and elevated type 2 inflammatory biomarkers at baseline. Dupilumab improved probability of reversing airflow obstruction (hazard ratio vs placebo 1.616 [95% confidence interval, 1.272-2.052] and 1.813 [1.291-2.546]; both P < .001) and significantly reduced severe exacerbations by 69% (relative risk, 0.411; 95% confidence interval [0.327-0.516]; P < .0001) and by 75% (0.252 [0.178-0.356]; P < .0001) in patients with PAO with eosinophils ≥ 150 cells/µL or FeNO ≥ 25 ppb and eosinophils ≥ 300 cells/µL and FeNO ≥ 25 ppb, respectively. Similar results were observed in patient subgroups without PAO., Conclusion: In patients with uncontrolled moderate-to-severe asthma, treatment with dupilumab facilitates reversal of PAO status and improves clinical outcomes., Trial Registration: ClinicalTrials.gov identifier: NCT02414854., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe asthma exacerbations increase the risk of accelerated lung function decline. This analysis examined the effect of dupilumab on forced expiratory volume in 1 s (FEV 1 ) in patients with moderate-to-severe asthma and elevated type 2 biomarkers from phase 3 LIBERTY ASTHMA QUEST (NCT02414854)., Methods: Changes from baseline in pre- and post-bronchodilator (BD) FEV 1 and 5-item Asthma Control Questionnaire (ACQ-5) scores were assessed in patients with elevated type 2 biomarkers at baseline (type 2-150/25: eosinophils ≥150 cells/μl and/or fractional exhaled nitric oxide [FeNO] ≥25 ppb; type 2-300/25: eosinophils ≥300 cells/μl and/or FeNO ≥25 ppb), stratified as exacerbators (≥1 severe exacerbation during the study) or non-exacerbators., Results: In exacerbators and non-exacerbators, dupilumab increased pre-BD FEV 1 by Week 2 vs placebo; differences were maintained to Week 52 (type 2-150/25: LS mean difference (LSMD) vs placebo: 0.17 L (95% CI: 0.10-0.24) and 0.17 L (0.12-0.23); type 2-300/25: 0.22 L (0.13-0.30) and 0.21 L (0.15-0.28)), in exacerbators and non-exacerbators, respectively (p < .0001). Similar trends were seen for post-BD FEV 1 . Dupilumab vs placebo also showed significantly greater improvements in post-BD FEV 1 0-42 days after first severe exacerbation in type 2-150/25 (LSMD vs placebo: 0.13 L [0.06-0.20]; p = .006) and type 2-300/25 (0.14 L [0.06-0.22]; p = .001) patients. ACQ-5 improvements were greater with dupilumab vs placebo in both groups., Conclusion: Dupilumab treatment led to improvements in lung function independent of exacerbations and appeared to reduce the impact of exacerbations on lung function in patients who experienced a severe exacerbation during the study., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: The Global Initiative for Asthma report recommends consideration of add-on biologics for patients with type 2 inflammation (blood eosinophils ≥150 cells/μL, fractional exhaled nitric oxide [Feno] ≥20 parts per billion or allergic asthma) whose asthma cannot be controlled by high-dose inhaled corticosteroids. In QUEST (NCT02414854), add-on dupilumab versus placebo was efficacious in patients with uncontrolled, moderate to severe asthma, including those with eosinophils greater than or equal to 150 cells/μL and/or Feno greater than or equal to 25 parts per billion., Objective: To assess dupilumab efficacy in patients with a type 2 phenotype in the presence or absence of allergic asthma phenotype., Methods: Patients aged 12 years or older received add-on dupilumab 200/300 mg versus matched placebo every 2 weeks for 52 weeks. Allergic asthma phenotype was defined as baseline serum total IgE greater than or equal to 30 IU/mL and 1 or more perennial aeroallergen-specific IgE level greater than or equal to 0.35 kU/L. Annualized rate of severe asthma exacerbations and changes from study baseline in prebronchodilator and postbronchodilator FEV 1 were evaluated in patients with allergic and nonallergic phenotype with baseline blood eosinophils greater than or equal to 150 cells/μL and/or Feno greater than or equal to 20 parts per billion., Results: Of 1902 patients in QUEST, 83.3% had eosinophils and/or Feno above Global Initiative for Asthma thresholds; 56.9% had evidence for allergic asthma. Dupilumab significantly reduced the rate of severe asthma exacerbations in patients with (48.8%) and without (64.0%) evidence of allergic asthma and improved prebronchodilator and postbronchodilator FEV 1 in patients with elevated type 2 biomarkers, irrespective of whether they showed evidence of an allergic asthma phenotype., Conclusions: In patients with type 2 biomarkers over Global Initiative for Asthma thresholds, dupilumab significantly reduced exacerbations and improved lung function. Efficacy was not impacted by allergic status., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), add-on dupilumab 200 and 300 mg every 2 weeks reduced severe exacerbations, improved pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ), and was generally well tolerated in patients with uncontrolled moderate-to-severe asthma. This post hoc analysis assessed dupilumab efficacy in subpopulations of patients with type 2 asthma and high-dose inhaled corticosteroids (ICS)., Methods: Adjusted annualized severe exacerbation rates over the treatment period, least squares (LS) mean change from baseline at Week 12 in pre-bronchodilator FEV 1 , and LS mean change from baseline at Week 24 in 5-item Asthma Control Questionnaire (ACQ-5) scores were analyzed in subgroups of patients receiving high-dose (>500 μg) ICS with baseline blood eosinophils ≥150 cells/μL and/or fractional exhaled nitric oxide ≥25 ppb. Subgroups included allergic phenotype (with/without), comorbid chronic rhinosinusitis and/or nasal polyposis (with/without), pre-bronchodilator FEV 1 /forced vital capacity (<70%/≥70%), blood eosinophil level, exacerbation history, median baseline pre-bronchodilator FEV 1 , age at asthma onset (≤40/>40 years), median FEV 1 reversibility, body mass index (<30/≥30 kg/m 2 ), and sex., Results: Dupilumab vs placebo reduced exacerbations and improved pre-bronchodilator FEV 1 at Week 12 and ACQ-5 at Week 24 across subgroups of patients with type 2 asthma and high-dose ICS at baseline. Dupilumab was also effective in patients receiving medium-dose ICS., Conclusion: Dupilumab reduced severe exacerbations and improved lung function and asthma control in subgroups of patients with type 2 asthma and high-dose ICS at baseline., Clinical Trial Registration Number: NCT02414854., Competing Interests: Declaration of competing interest Bourdin A: GSK – non-financial support during the conduct of the study; Acceleron Pharma, Actelion, Galapagos, Merck Sharp & Dohme, Nuvaira, Pulmonx, United Therapeutics, Vertex Pharmaceuticals – other; Boehringer Ingelheim – grants, personal fees; AstraZeneca, Chiesi, GSK, Regeneron Pharmaceuticals, Inc., Sanofi – personal fees. Virchow JC: Altana, AstraZeneca, Avontec, Bayer, Bencard Allergie, Bionorica, Boehringer Ingelheim, Chiesi, Essex Pharma Development, GSK, Hexal, Janssen-Cilag, Leti, Meda Pharmaceuticals, Merck, MSD, Mundipharma, Novartis, Nycomed, Pfizer, Revotar Biopharmaceuticals, Sandoz, Stallergenes Greer, Schwarz Pharma, Teva, UCB, Zydus Cadila – honoraria. Avontec, Boehringer Ingelheim, Chiesi, Essex Pharma Development, GSK, Hexal, Janssen-Cilag, Meda Pharmaceuticals, MSD, Mundipharma, Novartis, Regeneron Pharmaceuticals, Inc., Revotar Biopharmaceuticals, Roche, sanofi-aventis, Sandoz, Schwarz Pharma, Teva, UCB – advisory board participant. Deutsche Forschungsgesellschaft, GSK, Land Mecklenburg-Vorpommern, MSD – research grants. Papi A: AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma, Teva – report grants, personal fees, nonfinancial support, other; Menarini, Novartis, Zambon – personal fees, nonfinancial support; Sanofi – grants (all outside the submitted work). Lugogo NL: Amgen, AstraZeneca, Avillion, Genentech, Gossamer Bio, GSK, Regeneron Pharmaceuticals, Inc., Sanofi, Teva − research support paid to institution; Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi, Teva − advisory board member, consultant; AstraZeneca – travel support; AstraZeneca, GSK – honoraria for non-speaker's bureau presentations. Bardin P: AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Sanofi – consultant, speaker fees. Antila M: AbbVie, Angion Biomedica Corp, AstraZeneca, BeiGene, EMS, Eurofarma, GSK, Humanigen, Janssen, Novartis, Sanofi – clinical trial funding; Aché, AstraZeneca, Chiesi, Eurofarma, IPI ASAC Brasil, Sanofi – honoraria; AstraZeneca, GSK, Novartis, Sanofi – meeting or travel support; Abbott, AstraZeneca, Chiesi, Sanofi, Zambon – data safety monitoring board and/or advisory board member. Halpin DMG: AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Novartis, Pfizer, Sandoz, Sanofi – advisory board member, speaker fees. Daizadeh N: Sanofi – former employee, may hold stock and/or stock options in the company. Djandji M, Jacob-Nara JA, Rowe PJ: Sanofi − employees, may hold stock and/or stock options in the company. Ortiz B: Regeneron – former employee, may hold stock and/or stock options in the company. Gall R, Deniz Y: Regeneron Pharmaceuticals, Inc. – employees and shareholders., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Transient increases in blood eosinophil counts have been observed in dupilumab clinical trials., Objective: To assess eosinophil counts and eosinophilia-related treatment-emergent adverse events (TEAEs) across 11 dupilumab clinical trials, comparing adult and adolescent patients with asthma and adult patients with chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis, and eosinophilic esophagitis., Methods: Eosinophil counts, rates of eosinophilia-related TEAEs or treatment-emergent eosinophilia (>1,500 cells/μL), discontinuations, clinical symptoms, and efficacy in patients with asthma or CRSwNP with treatment-emergent eosinophilia are presented., Results: Transient increases in mean eosinophil counts were observed in dupilumab-treated patients with asthma (mean range across studies at baseline: 349-370 cells/μL; week 4: 515-578 cells/μL), CRSwNP (baseline: 440-448 cells/μL; week 16: 595 cells/μL), and atopic dermatitis (baseline: 434-600 cells/μL; week 4: 410-710 cells/μL), followed by a decline starting by week 24 to baseline or lower. No increases were seen in patients with eosinophilic esophagitis (baseline: 310 cells/μL; week 4: 230 cells/μL). In dupilumab-treated patients across all studies, rates of eosinophilia TEAEs were 0% to 13.6%. Clinical symptoms associated with increased eosinophils were rare (seven of 4,666 dupilumab-treated patients, including six cases of eosinophilic granulomatosis with polyangiitis) and occurred only in patients with asthma or CRSwNP. Eosinophilia was not associated with reduced dupilumab efficacy., Conclusions: Transient increases in eosinophil counts with dupilumab treatment did not affect efficacy and were rarely of clinical consequence. It remains important for physicians to base judgment on individual patient history and baseline eosinophil counts and to be alert to hypereosinophilic symptoms., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many patients with severe asthma require chronic corticosteroid treatment to maintain asthma control., Research Question: Are the reduction in oral corticosteroid (OCS) use and the clinical efficacy observed with dupilumab treatment maintained long-term in patients with severe OCS-dependent asthma?, Study Design and Methods: The LIBERTY ASTHMA TRAVERSE study (ClinicalTrials.gov identifier: NCT02134028) was a multinational, multicenter, single-arm, open-label extension study in patients ≥ 12 years of age with asthma who participated in previous dupilumab studies. Treatment consisted of dupilumab 300 mg every 2 weeks for up to 96 weeks. In this analysis, we present the data from patients who initially enrolled in the LIBERTY ASTHMA VENTURE study (ClinicalTrials.gov identifier: NCT02528214), a 24-week placebo-controlled study of dupilumab in patients with OCS-dependent severe asthma, and continued in the TRAVERSE study. The subgroups analyzed were: those who received dupilumab in both (dupilumab/dupilumab group) and those who received placebo in the VENTURE study and dupilumab in the TRAVERSE study (placebo/dupilumab group). Outcomes included OCS use, exacerbation rates, and measures of lung function and asthma control., Results: Ninety patients treated with dupilumab/dupilumab and 97 patients treated with placebo/dupilumab in the VENTURE study were enrolled and treated in the TRAVERSE study, with a mean OCS dosage of 11.0 mg/d (dupilumab) and 11.6 mg/d (placebo) at VENTURE study baseline. At TRAVERSE week 0, the mean daily OCS dosage was 3.1 mg/d and 6.4 mg/d (percentage decrease from the VENTURE study baseline, 68.8% and 41.3%) for the dupilumab/dupilumab group and placebo/dupilumab group, respectively, and decreased to 2.2 mg/d and 4.9 mg/d (78.3% and 53.4%) at week 48 and to 1.2 mg/d and 3.0 mg/d (89.3% and 74.4%) at week 96, respectively. Exacerbation rates were low during the TRAVERSE study. Further improvements from the VENTURE to TRAVERSE studies also were seen in FEV 1 and 5-item Asthma Control Questionnaire scores. Safety findings were consistent with the known dupilumab safety profile., Interpretation: In the open-label TRAVERSE study, dupilumab demonstrated the ability to sustain the OCS dosage reduction from the parent OCS-sparing study, while maintaining a low exacerbation rate and improved lung function., Trial Registry: ClinicalTrials.gov; Nos.: NCT02134028 (TRAVERSE) and NCT02528214 (VENTURE); URL: www., Clinicaltrials: gov., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4/-13, key and central drivers of type 2 inflammation in multiple diseases. In the phase 3 LIBERTY ASTHMA VENTURE (VENTURE) study (NCT02528214), dupilumab versus placebo reduced oral corticosteroid (OCS) dose and improved clinical outcomes in patients with OCS-dependent severe asthma. Dupilumab efficacy in patients with varying disease burden (defined by baseline OCS dose) has not been assessed., Objective: This post hoc analysis of VENTURE evaluated dupilumab efficacy across subgroups defined by baseline OCS dose., Methods: The OCS dose, proportion no longer needing OCS at week 24, annualized severe exacerbation rate, and least squares mean change from baseline in pre- and post-bronchodilator forced expiratory volume in 1 second at week 24 were evaluated in VENTURE patients with OCS-dependent severe asthma receiving dupilumab 300 mg every 2 weeks versus placebo, categorized by a baseline OCS dose of less than 10 mg/d or 10 or more mg/d., Results: Dupilumab reduced daily OCS dose from baseline at week 24 in both dose groups. In dupilumab-/placebo-treated patients with a baseline OCS dose of less than 10 mg/d and 10 or more mg/d, 72%/42% and 37%/23% stopped OCS by week 24 (P < .01/P < .05), respectively. Dupilumab significantly reduced the annualized severe exacerbation rate by 71% and 48% (P < .01/P < .05). At week 24, dupilumab improved pre- and post-bronchodilator forced expiratory volume in 1 second in patients in both dose groups., Conclusions: In patients with OCS-dependent severe asthma receiving lower or higher baseline OCS doses, dupilumab significantly reduced the OCS dose and improved the likelihood of no longer requiring OCS while also reducing exacerbations and improving lung function., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Nicole A Hanania has received research support from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline; and reports consultancy for Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi, Teva. Jorge F Maspero is a consultant for AstraZeneca, Sanofi, Teva; has received speaker fees from GlaxoSmithKline, Inmunotek, Menarini, Novartis, Uriach; and research grants from Novartis. David MG Halpin reports advisory board and speaker fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline, Novartis, Pfizer, Sandoz, Sanofi. David Jackson has received advisory board fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, Teva. Reynold A Panettieri is a consultant for AstraZeneca, Avillion, MedImmune, Bayer, Teva, RIFM, Equillium, Theravance Biopharma; and a speaker for AstraZeneca, Genentech, Regeneron Pharmaceuticals, Inc., Sanofi; has received research grants from ACTIV-1, Origo, NIH, Janssen, Vault Health, AstraZeneca, Equillium, Genentech, MedImmune, OncoArendi Therapeutics, RIFM. Mario Castro reports research support from American Lung Association, AstraZeneca, GlaxoSmithKline, NIH, Novartis, PCORI, Pulmatrix, Sanofi-Aventis, Shionogi; is a consultant for Genentech, Novartis, Sanofi-Aventis, Teva; has received speaker fees from AstraZeneca, Genentech, GlaxoSmithKline, Regeneron Pharmaceuticals, Inc., Sanofi, Teva, Merck and Amgen; and royalties from Elsevier. Christian Domingo has received travel and speaker fees from ALK, Allergy Therapeutics, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, Ferrer, GlaxoSmithKline, HAL Allergy, Inmunotek, Menarini, Novartis, Pfizer, Sanofi-Aventis, Stallergenes Greer, Takeda, Teva. Nadia Daizadeh is a former Sanofi employee and may hold stock and/or stock options in the company. Juby A Jacob-Nara, Michel Djandji, Paul J Rowe are Sanofi employees and may hold stock and/or stock options in the company. Rebecca Gall, Benjamin Ortiz, Yamo Deniz are employees and shareholders of Regeneron Pharmaceuticals, Inc. Rebecca Gall also reports non-financial support from Excerpta Medica. The authors report no other conflicts of interest in this work.

Background: Type 2 inflammatory diseases often coexist in patients. Dupilumab targets type 2 inflammation and has demonstrated treatment benefits in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP) with an acceptable safety profile., Objective: This post hoc analysis across five phase 3 studies in patients with moderate to severe AD or asthma, or severe CRSwNP, evaluated time of onset and duration of the treatment response., Methods: Patients received subcutaneous dupilumab 200/300 mg or placebo. Assessments included the Eczema Area and Severity Index, Peak Pruritus Numerical Rating Scale, and Dermatology Life Quality Index in AD; pre-bronchodilator FEV 1 , daily morning peak expiratory flow, and symptom scores in asthma; and University of Pennsylvania Smell Identification Test, daily nasal congestion, and loss of smell scores in CRSwNP., Results: At week 2 after the initiation of dupilumab versus placebo, 67.8% versus 36.5% of AD patients achieved a clinically meaningful benefit (Eczema Area and Severity Index: 50% or greater improvement; Peak Pruritus Numerical Rating Scale: 3 point or greater improvement; or Dermatology Life Quality Index: 4 point or greater improvement) (P < .001). Moreover, 61.6% versus 39.9% of asthma patients achieved improvements in pre-bronchodilator FEV 1 of 100 mL or greater and 48.8% versus 26.3% achieved 200 mL or greater improvement (both P < .001); 33.2% versus 5.6% of CRSwNP patients regained a sense of smell (P < .001). Treatment effects further improved or were sustained to the end of treatment., Conclusions: Clinically meaningful responses were achieved rapidly after the first dupilumab dose in AD, asthma, or CRSwNP and were sustained throughout treatment (see Video in this article's Online Repository at www.jaci-inpractice.org)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: About one-tenth of patients with difficult-to-treat chronic rhinosinusitis with nasal polyps (CRSwNP) have comorbid non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Dupilumab, a fully human monoclonal antibody that blocks the shared interleukin (IL)-4/IL-13 receptor component, is an approved add-on treatment in severe CRSwNP. This post hoc analysis evaluated dupilumab efficacy and safety in patients with CRSwNP with/without NSAID-ERD., Methods: Data were pooled from the phase 3 SINUS-24 and SINUS-52 studies in adults with uncontrolled severe CRSwNP who received dupilumab 300 mg or placebo every 2 weeks. CRSwNP, nasal airflow, lung function, and asthma control outcomes at Week 24 were evaluated, and treatment-subgroup interactions were assessed for patients with and without NSAID-ERD., Results: Of 724 patients, 204 (28.2%) had a diagnosis of NSAID-ERD. At Week 24, least squares mean treatment differences demonstrated significant improvements in nasal polyp score, nasal congestion (NC), Lund-Mackay computed tomography, 22-item Sinonasal Outcome Test (SNOT-22), Total Symptom Score (TSS), rhinosinusitis severity visual analog scale, peak nasal inspiratory flow (PNIF), six-item Asthma Control Questionnaire score, and improvement in smell with dupilumab versus placebo (all p < .0001) in patients with NSAID-ERD. Treatment comparisons demonstrated significantly greater improvements with dupilumab in patients with versus without NSAID-ERD for NC (p = .0044), SNOT-22 (p = .0313), TSS (p = .0425), and PNIF (p = .0123)., Conclusions: In patients with uncontrolled severe CRSwNP, dupilumab significantly improved objective measures and patient-reported symptoms to a greater extent in the presence of comorbid NSAID-ERD than without. Dupilumab was well tolerated in patients with/without NSAID-ERD., (© 2021 Sanofi Genzyme. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Loss of smell (LoS) is one of the most troublesome and difficult-to-treat symptoms of severe chronic rhinosinusitis with nasal polyps (CRSwNP)., Objective: To assess the impact of dupilumab on sense of smell in severe CRSwNP., Methods: In the randomized SINUS-24 and SINUS-52 studies, adults with severe CRSwNP received dupilumab 300 mg subcutaneously or matching placebo every 2 weeks for 24 or 52 weeks, respectively. Smell was assessed using daily patient-reported LoS score (0-3) and University of Pennsylvania Smell Identification Test (UPSIT; 0-40). Data from the 2 studies were pooled through week 24. Relationships between patient phenotypes and smell outcomes were also assessed., Results: We randomized 724 patients (286 placebo, 438 dupilumab); mean CRSwNP duration was 11 years; 63% had prior sinonasal surgery. Mean baseline LoS was 2.74. Dupilumab produced rapid improvement in LoS, evident by day 3, which improved progressively throughout the study periods (least squares mean difference vs placebo -0.07 [95% CI -0.12 to -0.02]; nominal P < .05 at day 3, and -1.04 [-1.17 to -0.91]; P < .0001 at week 24). Dupilumab improved mean UPSIT by 10.54 (least squares mean difference vs placebo 10.57 [9.40-11.74]; P < .0001) at week 24 from baseline (score 13.90). Improvements were unaffected by CRSwNP duration, prior sinonasal surgery, or comorbid asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease. Baseline olfaction scores correlated with all measured local and systemic type 2 inflammatory markers except serum total immunoglobulin E., Conclusions: Dupilumab produced rapid and sustained improvement in sense of smell, alleviating a cardinal symptom of severe CRSwNP., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Alemtuzumab efficacy and safety was demonstrated in CARE-MS I and extension studies (CAMMS03409; TOPAZ)., Objective: Evaluate serum neurofilament light chain (sNfL) in CARE-MS I patients and highly active disease (HAD) subgroup, over 7 and 2 years for alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), respectively., Methods: Patients received SC IFNB-1a 44 µg 3×/week or alemtuzumab 12 mg/day at baseline and month 12, with further as-needed 3-day courses. sNfL was measured using single-molecule array (Simoa™). HAD definition was ⩾2 relapses in year before randomization and ⩾1 baseline gadolinium-enhancing lesion., Results: Baseline median sNfL levels were similar in alemtuzumab ( n = 354) and SC IFNB-1a-treated ( n = 159) patients (31.7 vs 31.4 pg/mL), but decreased with alemtuzumab versus SC IFNB-1a until year 2 (Y2; 13.2 vs 18.7 pg/mL; p < 0.0001); 12.7 pg/mL for alemtuzumab at Y7. Alemtuzumab-treated patients had sNfL at/below healthy control median at Y2 (72% vs 47%; p < 0.0001); 73% for alemtuzumab at Y7. HAD patients ( n = 102) had higher baseline sNfL (49.4 pg/mL) versus overall population; alemtuzumab HAD patients attained similar levels (Y2, 12.8 pg/mL; Y7, 12.7 pg/mL; 75% were at/below control median at Y7)., Conclusion: Alemtuzumab was superior to SC IFNB-1a in reducing sNfL, with levels in alemtuzumab patients remaining stable through Y7., Clinicaltrials.gov Identifier: NCT00530348, NCT00930553, NCT02255656.

Objectives/hypothesis: Dupilumab, a fully human monoclonal antibody that blocks the shared interleukin (IL)-4/IL-13 receptor component, significantly improved outcomes for patients with chronic rhinosinusitis with nasal polyps (CRSwNP) in the SINUS-24 and SINUS-52 studies. This post hoc analysis evaluated dupilumab's effect on patient-reported symptoms and objective outcome measures using thresholds of clinically meaningful within-patient change from baseline., Methods: Patients with CRSwNP receiving subcutaneous dupilumab or placebo every 2 weeks in SINUS-24/SINUS-52 were analyzed. Patients recorded severity of nasal congestion (NC), loss of smell (LoS), and anterior/posterior rhinorrhea (each within range 0-3) daily. Total Symptom Score (TSS) was calculated as a composite severity score (0-9) for these symptoms. Objective measures included University of Pennsylvania Smell Identification Test (UPSIT; 0-40), nasal polyps score (NPS; 0-8), and Lund-Mackay computed tomography score (LMK-CT; 0-24). Thresholds of within-patient change in scores from baseline at weeks 24 and 52 considered clinically meaningful were ≥1.0 (NC, LoS), ≥3.0 (TSS), ≥8.0 (UPSIT), ≥1.0 (NPS), and ≥5.0 (LMK-CT)., Results: A total of 724 and 303 patients were included in the week 24 and 52 analyses, respectively. Responder rates were significantly higher with dupilumab versus placebo at week 24 for NC (64% vs. 24%), LoS (63% vs. 14%), TSS (62% vs. 15%), UPSIT (54% vs. 6%), NPS (63% vs. 14%), and LMK-CT (59% vs. 3%); all P < .0001. Results were consistent at week 52., Conclusion: Significantly greater proportions of dupilumab-treated patients with CRSwNP compared with placebo demonstrated clinically meaningful improvements in patient-reported sinonasal symptoms and objective outcomes., Level of Evidence: 2 Laryngoscope, 132:259-264, 2022., (© 2021 Sanofi Genzyme. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing-remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW., Methods: CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed., Results: Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a -0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a -0.10-point mean EDSS score change; 98% had stable or improved EDSS scores., Conclusion: CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9., (© 2021. The Author(s).)

Background: Fractional exhaled nitric oxide (FeNO) has potential as a prognostic biomarker in asthma, but its prognostic value among other recognised indicators is unclear. We assessed the added prognostic value of baseline FeNO to blood eosinophil count and prior severe asthma exacerbations for subsequent exacerbations., Methods: In this post-hoc analysis of the 52-week, double-blind, phase 3 LIBERTY ASTHMA QUEST study, we identified 620 patients with moderate-to-severe asthma who were randomly assigned to placebo; had uncontrolled asthma with inhaled glucocorticoids plus up to two controllers; one or more exacerbations in the previous year; FEV 1 percent predicted 40-80%; FEV 1 reversibility of 12% or higher and 200 mL; Asthma Control Questionnaire (ACQ-5) score of 1·5 or higher; and complete data on baseline type 2 biomarkers (FeNO, eosinophils, and total IgE) with no baseline minimum requirement. Annualised severe exacerbation rate was assessed by baseline FeNO (<25 ppb, ≥25 to <50 ppb, ≥50 ppb; negative binomial model) and cross-classified by baseline blood eosinophils (<150 cells per μL, ≥150 to <300 cells per μL, ≥300 cells per μL) and prior exacerbations (one, two or more), all adjusted for baseline ACQ-5, postbronchodilator FEV 1 , and other clinical characteristics. Post-hoc analyses were done in the intention-to-treat population. The LIBERTY ASTHMA QUEST STUDY is registered on ClinicalTrials.gov, NCT02414854, and is complete., Findings: Patients with baseline FeNO of 50 ppb or higher (n=144) had a 1·54-times higher exacerbation rate than patients with FeNO of less than 25 ppb (n=291; relative risk 1·54 [95% CI 1·11-2·14]; p=0·0097). Patients with baseline FeNO of 25 to <50 ppb (n=185) had a 1·33-times higher exacerbation rate than patients with FeNO of less than 25 ppb (1·33 [0·99-1·78]; p=0·0572). Patients with baseline FeNO of 25 ppb or higher, a blood eosinophil count of 150 cells per μL or higher, and two or more prior exacerbations (n=157) had an exacerbation rate 3·62-times higher than patients with FeNO of less than 25 ppb, a blood eosinophil count of less than 150 cells per μL, and one prior exacerbation (n=116; 3·62 [1·67-7·81]; p=0·0011)., Interpretation: In uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations., Funding: Sanofi and Regeneron Pharmaceuticals., Competing Interests: Declaration of interests WWB declares consultant fees from AstraZeneca, Genentech, GlaxoSmithKline (GSK), Novartis, Regeneron Pharmaceuticals, and Sanofi, and is on the data safety monitoring board (DSMB) for Boston Scientific. SEW reports involvement in industry trials for AstraZeneca, Boehringer Ingelheim, GSK, Novartis, and Sanofi. TBC declares research support provided by American Lung Association, Genentech, Novartis, Patient-Centered Outcomes Research Institute, and Sanofi; was a consultant for AstraZeneca, Boehringer Ingelheim, Genentech, Novartis, and Regeneron Pharmaceuticals; was part of the speaker bureau for Genentech; and is on the DSMB for Novartis. JMF reports being an advisory board member for and receiving personal fees from American Lung Association, Boehringer Ingelheim, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi, and Teva; received peer-review funding from AllerGen NCE, BC Lung Association, and Canadian Institutes of Health Research; had research funding paid directly to the University of British Columbia from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, and Sanofi; and received speaker fees or honoraria from AstraZeneca, Boehringer Ingelheim, GSK, and Novartis. MSR, ND, NP, and PJR are employees of Sanofi. NMHG is a former employee and shareholder of Regeneron Pharmaceuticals. YD and SH are employees and shareholders of Regeneron Pharmaceuticals. TOR was a prior employee of Sanofi. IDP reports receiving speaker fees from Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi, and Teva; received payments for organisation of educational events from AstraZeneca, GSK, Sanofi, Regeneron Pharmaceuticals, and Teva; received consultant fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, Merck Sharp & Dohme, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough, and Teva; received international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, and Teva; and reports a research grant from Chiesi., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline., Methods: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab., Results: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups., Conclusion: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups., Clinicaltrialsgov Identifiers: NCT00530348; NCT00548405; NCT00930553., Competing Interests: Conflict of interest statement: AJC reports receiving consulting fees, lecture fees, and institutional grant support from Sanofi prior to 2017. DLA reports receiving consulting fees and/or grants from Acorda, Adelphi, Alkermes, Biogen, Celgene, Frequency Therapeutics, Genentech, Genzyme, Hoffmann-La Roche, Immune Tolerance Network, Immunotec, MedDay, Merck Serono, Novartis, Pfizer, Receptos, Roche, Sanofi-Aventis, Canadian Institutes of Health Research, MS Society of Canada, International Progressive MS Alliance, and an equity interest in NeuroRx Research. ADB reports receiving research funding, compensation for medical advisory boards, and compensation for speakers bureaus from Actelion, Biogen, EMD Serono, Genentech-Roche, Mallinckrodt, Novartis, Sanofi, and TG Therapeutics. ALB reports receiving consulting fees and/or speaking fees for non-CME services from Biogen, Mallinckrodt, Medtronic, Novartis, Sanofi, and Teva. DASC reports receiving consulting fees, grant, and research support from Sanofi, and lecture fees from Bayer-Schering Pharma and Sanofi, prior to 2017. ÓF reports receiving speaking and/or consulting fees for Allergan, Almirall, Bayer-Schering Pharma, Biogen, Merck Serono, Novartis, Sanofi, and Teva, and research support from the Hospital Foundation FIMABIS; he also serves as editor of the Revista Española de Esclerosis Múltiple. EKH reports receiving honoraria and grant support from Actelion, Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi, and Teva, and is supported by the Ministry of Education of the Czech Republic, project PROGRES Q27/LF1. KN reports speaking fees and research support from Biogen and Sanofi, along with royalty fees for licenses with Biogen. AT reports receiving consulting and/or speaking fees, along with grant and research support, from Biogen, Chugai, Roche, Sanofi, and Teva. TZ reports receiving consulting and/or speaking fees from Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva, along with grant and research support from Biogen, Novartis, Sanofi, and Teva. AJ, DHM, XH, and MCC report being employees of Sanofi during the time of the analysis. ND reports receiving personal compensation as an employee of Sanofi. KWS reports receiving consulting and/or speaking fees from Biogen, Merck, Novartis, Roche, Sanofi, and Synthon., (© The Author(s), 2021.)

Background: Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ])., Methods: Post hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years)., Results: Compared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22-0.24 vs. 0.38-0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%-92% vs. 62%-88%; achievement of 6-month confirmed disability improvement [CDI]: 20%-31% vs. 13%-25%), increased proportions free of MRI disease activity (70%-86% vs. 42%-63% per year), and slowed brain volume loss (BVL; -0.45% to -0.87% vs. -0.50% to -1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%-2.2% vs. >45 years: 8.1%) and deaths (0%-1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts., Conclusions: Alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed., (Copyright © 2020. Published by Elsevier B.V.)

Background: Conjunctivitis is a known comorbidity of atopic dermatitis. Dupilumab clinical trials for moderate-to-severe atopic dermatitis in adults showed a higher conjunctivitis incidence for dupilumab-treated patients than placebo-treated patients, whereas trials for uncontrolled asthma reported lower rates for both dupilumab and placebo., Objective: The objective of this study was to evaluate the incidence and severity of conjunctivitis in dupilumab clinical trials in adolescents with moderate-to-severe atopic dermatitis or uncontrolled asthma., Methods: We evaluated the incidence of conjunctivitis in adolescents (aged 12 to < 18 years) in three phase III trials. Ocular events were diagnosed and treated based on patient-reported symptoms and an external eye examination by study investigators, in most cases without an ophthalmologic referral. In LIBERTY AD ADOL (16-week, randomized, placebo-controlled, double-blinded trial), adolescents with moderate-to-severe atopic dermatitis were randomized to subcutaneous placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks (200 mg, patients < 60 kg at baseline; 300 mg, ≥ 60 kg at baseline). In LIBERTY AD PED-OLE (open-label extension), pediatric patients from previous dupilumab atopic dermatitis trials received dupilumab 2 mg/kg or 4 mg/kg weekly (up to 300 mg) or 300 mg every 4 weeks. In LIBERTY ASTHMA QUEST (randomized, double-blinded, placebo-controlled trial), patients with uncontrolled moderate-to-severe asthma were randomized to 52 weeks of add-on therapy with dupilumab 200 or 300 mg every 2 weeks or matched-volume placebo., Results: In ADOL, more dupilumab-treated (17/165; 10.3%) than placebo-treated patients (4/85; 4.7%) reported one or more conjunctivitis event. All events were mild to moderate in severity; 12 (7.3%) dupilumab-treated and 4 (4.7%) placebo-treated patients received treatment. Most patients with conjunctivitis (dupilumab, 12/17; placebo, 4/4) recovered/resolved during the treatment period. The risk of conjunctivitis showed no relationship with dupilumab serum concentration. In PED-OLE, 12/275 adolescents (4.4%) reported one or more conjunctivitis event. Most conjunctivitis events were mild to moderate. Ten patients received treatment for conjunctivitis. Ten patients recovered/resolved during the study. In QUEST, similar low proportions of dupilumab-treated (2/68, 2.9%) and placebo-treated (1/39, 2.6%) adolescents reported one or more conjunctivitis event. All events were mild to moderate. One dupilumab-treated patient received treatment for conjunctivitis. All cases recovered/resolved during the study. No patients in these trials discontinued study treatment temporarily or permanently because of conjunctivitis. In ADOL, one case of unspecified viral keratitis (specific viral etiology not known) in the dupilumab 300-mg every 4 weeks group and one case of allergic blepharitis in the placebo group were reported; both events resolved during the treatment period, and neither led to treatment discontinuation., Conclusions: Dupilumab-treated adolescents in atopic dermatitis trials had a higher incidence of conjunctivitis than placebo-treated patients, whereas overall rates of conjunctivitis among adolescents in the asthma trial were lower than in atopic dermatitis trials and were similar for dupilumab- and placebo-treated patients. Most events were mild to moderate, most recovered/resolved, and none prompted study withdrawal. These results are similar to those reported in adult trials and support a drug-disease interaction. CLINICALTRIALS., Gov Identifiers: NCT03054428, NCT02612454, NCT02414854. Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma (MP4 18453 kb).

Background: Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies., Objective: Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies., Methods: Patients ( N  = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse., Results: Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%-4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and analysis of core study subcutaneous interferon beta-1a-treated patients who received alemtuzumab in the extension. Patients converting to secondary progressive MS were older, and had higher EDSS scores and greater brain lesion volumes at baseline, but did not need additional alemtuzumab or other therapies., Conclusions: The 6-year conversion rate to secondary progressive MS was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression. ClinicalTrials.gov identifiers: NCT00530348, NCT00548405, NCT00930553., (© The Author(s) 2020.)

Background: Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses., Objective: To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif ® Efficacy in Multiple Sclerosis) studies and their extensions., Methods: Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course., Results: In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (12 months before: 43% and 53%, respectively; 12 months after: 73% and 74%). Safety was similar across groups; serious events occurred irrespective of the number of courses., Conclusion: Additional alemtuzumab courses significantly improved outcomes, without increased safety risks, in CARE-MS patients with continued disease activity after Course 2. How this compares to outcomes if treatment is switched to another DMT instead remains unknown.