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Jorge F Maspero,1 Asif H Khan,2 Carl Philpott,3 Peter W Hellings,4 Claire Hopkins,5 Martin Wagenmann,6 Shahid Siddiqui,7 Jérôme Msihid,8 Scott Nash,7 Chien-Chia Chuang,9 Siddhesh Kamat,7 Paul J Rowe,10 Yamo Deniz,7 Juby A Jacob-Nara10 1Allergy & Respiratory Research Unit, Fundación CIDEA, Buenos Aires, Argentina; 2Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 3Rhinology and ENT Research Group, Norwich Medical School, University of East Anglia, Norwich, UK; 4Department of Otorhinolaryngology – Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; 5Department of Otorhinolaryngology, King’s College London, London, UK; 6Department of Otorhinolaryngology, Düsseldorf University Hospital (UKD), Düsseldorf, Germany; 7Medical Affairs, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 8Health Economics and Value Assessment, Sanofi, Chilly-Mazarin, France; 9Health Economics and Value Assessment, Sanofi, Cambridge, MA, USA; 10Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Jorge F Maspero, Allergy & Respiratory Research Unit, Fundación CIDEA, Paraguay 2035, 2SS, Buenos Aires, Argentina, Tel +54 9 11 4183-7294, Email jorge.maspero@fundacioncidea.org.arPurpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease with a high symptom burden. Data are lacking on the comparative health status of patients with CRSwNP. This analysis compared baseline physical and mental health-related quality of life (HRQoL) and overall health status of patients with severe CRSwNP enrolled in a Phase 3 clinical trial with general population norms and with other chronic diseases.Methods: In this post hoc cross-sectional analysis of baseline data from the SINUS-24 study (NCT02912468), HRQoL was measured using the 36-item Short Form (SF-36) questionnaire and general health status was measured using the EuroQol-5 Dimension visual analog scale (EQ-VAS). Analyses included the intention-to-treat (ITT) population and subgroups defined by prior sinonasal surgery, systemic corticosteroid use, and coexisting asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Scores were compared with published values for population norms (50 for SF-36 physical component summary (PCS) and mental component summary (MCS), 70.4− 83.3 for EQ-VAS) and for rheumatoid arthritis, type 2 diabetes, and asthma.Results: In the ITT population (n=276), mean SF-36 physical component summary (PCS), SF-36 mental component summary (MCS), and EQ-VAS scores were below general population norms (46.4, 48.6, and 66.0, respectively). Mean SF-36 PCS and EQ-VAS scores were below population norms across all subgroups; mean SF-36 MCS scores were below the population norm in all subgroups except no prior surgery. SF-36 PCS and MCS scores from SINUS-24 were generally similar to other chronic diseases, except SF-36 PCS which was lower in rheumatoid arthritis. EQ-VAS scores in SINUS-24 were lower than in other chronic diseases. HRQoL scores weakly correlated with objective measures of disease severity.Conclusion: In patients with severe CRSwNP, including those with coexisting asthma/NSAID-ERD, HRQoL was worse than population norms and as burdensome as diseases such as type 2 diabetes, asthma, and rheumatoid arthritis.Graphical Abstract: Keywords: chronic rhinosinusitis with nasal polyps, health-related quality of life, symptom burden

Claire Hopkins,1 Kathleen M Buchheit,2 Enrico Heffler,3,4 Noam A Cohen,5 Heidi Olze,6 Asif H Khan,7 Jérôme Msihid,8 Shahid Siddiqui,9 Scott Nash,9 Juby A Jacob-Nara,10 Paul J Rowe,10 Yamo Deniz9 1Department of Otorhinolaryngology – Head and Neck Surgery, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, Boston, MA, USA; 3Personalized Medicine, Asthma & Allergy – Humanitas Clinical and Research Center IRCCS, Milan, Italy; 4Department of Biomedical Sciences, Humanitas University, Milan, Italy; 5Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 6Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany; 7Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 8Health Economics and Value Assessment, Sanofi, Chilly-Mazarin, France; 9Medical Affairs, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 10Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Claire Hopkins, Department of Otorhinolaryngology – Head and Neck Surgery, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UK, Tel +44 2071882215, Email clairehopkins@yahoo.comAbstract: Patients with asthma frequently have comorbid chronic rhinosinusitis (CRS) with or without nasal polyps, increasing disease burden and complicating treatment. These post hoc analyses investigated disease-specific health-related quality of life (HRQoL) and general health status in the randomized, placebo-controlled QUEST study (NCT02414854) in patients treated with dupilumab for moderate-to-severe asthma with comorbid CRS. Patients received 300 mg of dupilumab or placebo every 2 weeks for 52 weeks. CRS HRQoL was assessed by the 22-item Sino-Nasal Outcome Test (SNOT-22; items scored 0– 5). The 22 items are categorized into 5 domains (nasal, ear/facial, sleep, function, and emotion), and patients report the top 5 most important items affecting their health. General health status was assessed by Euro-QoL visual analog scale (EQ-VAS). Of 1902 patients, 382 (20.1%) self-reported comorbid CRS; 193 patients receiving dupilumab 300 mg q2w or matched placebo were included in this analysis. At baseline, the most impacted SNOT-22 domain was nasal, and general health status was below population norms. Patients rated “decreased sense of taste/smell,” “nasal blockage,” “cough,” “reduced productivity,” and “wake up tired” as the 5 most important SNOT-22 items affecting their health. Percentage change from baseline in SNOT-22 total score was significantly greater for dupilumab vs placebo at Weeks 24, 36, and 52 (all p < 0.05). Improvements from baseline were significantly greater for dupilumab vs placebo at Week 52 for all SNOT-22 domains (p < 0.05), except emotion. At Week 52, significant changes from baseline with dupilumab vs placebo were observed for all 5 most important SNOT-22 items affecting their health (all p < 0.05). EQ-VAS was significantly improved with dupilumab vs placebo by Week 12, with improvements sustained to Week 52 (all p < 0.01). In patients with moderate-to-severe asthma who self-reported comorbid CRS, dupilumab treatment vs placebo improved CRS-specific HRQoL and general health status.Keywords: asthma, chronic rhinosinusitis, nasal polyps, dupilumab, health-related quality of life, SNOT-22

Background: Prurigo nodularis (PN) is characterized by intensely itchy nodules/lesions and skin pain, which can have a substantial impact on health‐related quality of life (HRQoL). Treatment benefits on such symptoms and impacts are best assessed in trials using patient‐reported outcome (PROs) instruments such as Skin Pain Numerical Rating Scale (NRS), Sleep‐NRS and Dermatology Life Quality Index (DLQI). However, no guidance exists for interpreting meaningful changes in scores using these PROs in patients with PN. Objectives: The main objective was to derive within‐patient (responder definition) and between‐group improvement thresholds for interpreting Skin Pain‐NRS, Sleep‐NRS and DLQI total scores in patients with PN. The measurement properties of the three PROs were also evaluated. Methods: Intention‐to‐treat (ITT), blinded and pooled data were used from the Phase 3 PRIME (NCT04183335) and PRIME2 (NCT04202679) studies evaluating the efficacy of dupilumab in adult patients with PN. Anchor‐ and distribution‐based methods were applied to derive responder definition and between‐group thresholds for Skin Pain‐NRS, Sleep‐NRS and DLQI. Data were additionally used to examine the instrument measurement properties, including reliability, validity and responsiveness. Results: A total of 311 patients (mean age 49.5 years, 65.3% female) were included in the pooled ITT population. The within‐patient improvement threshold for Skin Pain‐NRS was estimated as 4.0 points, 2.0 points for Sleep‐NRS and 9.0 points for DLQI total score. A 1.5‐point improvement in Skin Pain‐NRS scores, 1.0‐point in Sleep‐NRS and 4.0‐point in DLQI indicated a between‐group meaningful change. Adequate to good psychometric properties were demonstrated for all three instruments. Conclusions: The results of this study can aid interpretation of Skin Pain‐NRS, Sleep‐NRS and DLQI scores in patients with PN in both clinical trials and clinical practice to better understand and treat PN‐related skin pain and the impact of PN on sleep quality and HRQoL. [ABSTRACT FROM AUTHOR]

Background: Prurigo nodularis (PN) also known as chronic prurigo, is a chronic inflammatory skin disease characterized by intensely itchy nodules/lesions which occur due to intensive scratching. PN management is, in part, based on clinician evaluations of PN lesions, which can be supported by clinician-reported outcomes (ClinRO) such as the Prurigo Activity and Severity (PAS) instrument. A 5-item version of PAS was included in recent phase-3 dupilumab PN trials (PRIME [NCT04183335]/PRIME2 [NCT04202679]). The PAS score was derived using the unweighted sum of 3-items of the 5-item PAS (range, 0-11; higher score indicates worse activity and severity): Item 2 (number of lesions), Item 5a (percentage of lesions with excoriations/crusts) and Item 5b (percentage of healed lesions) for use in clinical practice and for communication of treatment benefit to physicians., Objectives: To evaluate the measurement properties of PAS score and derive within-patient (responder definition) and between-group improvement thresholds for interpreting changes in PAS score in patients with PN., Methods: The data source was the pooled treatment group, intention-to-treat (ITT) data from the phase-3 PRIME (NCT04183335) and PRIME2 (NCT04202679) studies evaluating the efficacy of dupilumab in adult patients with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. PAS score reliability, validity and sensitivity to change were evaluated, and anchor- and distribution-based methods were applied to derive meaningful change thresholds., Results: The pooled ITT population included 311 patients (mean age 49.5 years, 65.3% female). Adequate to good psychometric properties were demonstrated for PAS score. The within-patient meaningful improvement threshold was estimated as 3.0 points (absolute change) and 37% (per cent change). A 1.7-point (absolute change) and 20% (per cent change) improvement were estimated to reflect a between-group meaningful change in PAS score., Conclusions: PAS score is a simple, clinically relevant indicator of PN lesion activity and severity supported by suitable psychometric performance., (© 2024 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Prurigo nodularis (PN) is an intensely pruritic disease characterized by itchy nodules on the trunk/extremities; it is often accompanied by skin pain and sleep disruption with negative impacts on the quality of life (QoL). The patient-reported outcome (PRO) instruments, Worst Itch-Numeric Rating Scale (WI-NRS), Skin Pain-NRS, Sleep-NRS and Dermatology Life Quality Index (DLQI) have been psychometrically validated and the clinically meaningful within-patient improvement thresholds (responder definition) have been established through data pooled from the two Phase-3 trials (PRIME, NCT04183335 and PRIME2, NCT04202679) of dupilumab in adults with PN uncontrolled on topical therapies., Objectives: To estimate the proportion of dupilumab-treated patients (vs. placebo) achieving clinically meaningful improvement in itch, skin pain, sleep and QoL, either alone or in combination, from the data pooled from PRIME and PRIME2 trials., Methods: The patient-level data pooled from the two Phase-3 trials (N = 311) were used for this post hoc analysis. Thresholds of clinically meaningful within-patient improvement in PRO instrument scores from baseline at Week 24 used for defining responders were 4 (WI-NRS and Skin Pain-NRS), 2 (Sleep-NRS) and 9 points (DLQI). The proportion of dupilumab-treated patients, versus placebo, achieving the thresholds, and the time taken to achieve the thresholds were evaluated for the individual and combination of PROs., Results: Responder rates were significantly higher with dupilumab, versus placebo at Week 24 for WI-NRS (58.8% vs. 19.0%, p < 0.0001), Skin Pain-NRS (49.7% vs. 20.9%, p < 0.0001), Sleep-NRS (42.5% vs. 23.4%, p < 0.0001) and DLQI (64.7% vs. 22.8%, p < 0.0001). Proportion of patients achieving simultaneous improvement in symptoms and QoL (24.8% vs. 6.3%, p < 0.0001) were significantly higher in dupilumab-treated patients versus placebo. The time needed for achieving clinically meaningful improvement in symptoms were significantly lower in dupilumab-treated patients, versus placebo., Conclusions: Significantly greater proportion of dupilumab-treated patients with PN, versus placebo, demonstrated clinically meaningful improvements in PRO measures of symptoms and QoL., (© 2024 Sanofi. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Frequently reported outcomes of clinical trials in chronic rhinosinusitis with nasal polyps (CRSwNP) may have limited relatability for patients., Objective: To enhance the patient relatability of outcomes in dupilumab clinical trials for CRSwNP, daily symptom scores were used to determine new patient‑centered end points: mild-to-no-symptom months (MSM) and symptom-free months (SFM)., Methods: This work is a post hoc analysis of patients receiving dupilumab 300 mg or placebo every 2 weeks for 24 weeks (SINUS-24 study; NCT02912468) or 52 weeks (SINUS‑52; NCT02898454). Patients recorded symptom severity scores daily for each of nasal congestion, loss of smell, and anterior and posterior rhinorrhea on a scale of 0 to 3 (0 = no symptoms; 1 = mild; 2 = moderate; 3 = severe). We assessed the proportions of patients reporting only MSM or SFM throughout the 28‑day period before randomization, week 24 (pooled studies), and week 52 (SINUS‑52)., Results: Significantly more dupilumab‑treated than placebo-treated patients achieved MSM for all 4 symptoms (week 24: 31.0% vs 4.4%; odds ratio [OR] 12.9 [95% CI 6.4-25.8]; week 52: 38.3% vs 2.6%; OR 15.6 [5.9-41.0]; both P < .0001). In addition, significantly more dupilumab-treated than placebo‑treated patients achieved SFM for at least 1 of the 4 symptoms (week 24: 35.4% vs 10.8%; OR 4.9 [95% CI 3.1-7.8]; week 52: 50.0% vs 9.2%; OR 9.1 [95% CI 4.6-17.9]; both P < .0001)., Conclusion: One-third of patients with severe CRSwNP treated with dupilumab achieved MSM for all 4 cardinal symptoms (nasal congestion, loss of smell, and anterior and posterior rhinorrhea). Moreover, half of the patients achieved SFM for at least 1 of the 4 symptoms. These results support the benefit of dupilumab in improving patient‑centered outcomes., Trial Registration: ClinicalTrials.gov Identifiers: NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52)., Competing Interests: Disclosures Professor Bachert is an advisory board member for AstraZeneca, Novartis, and Sanofi. Professor Hopkins is an advisory board member for AstraZeneca, BioInspire Technologies, GlaxoSmithKline, and Sanofi. Professor Han is an advisory board member for AstraZeneca, Genentech, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals Inc, and Sanofi. Professor Fokkens has received research grants from BioInspire Technologies, GlaxoSmithKline, Mylan, Novartis, and Sanofi. Dr Khan, Dr Mannent, Mr Msihid, and Dr Rowe are employees of Sanofi and may hold stock and/or stock options in the company. Dr Borsos and Dr Jacob-Nara are former employees of Sanofi and may hold stock and/or stock options in the company. Mr Kamat, Dr Nash, and Dr Deniz are employees and shareholders of Regeneron Pharmaceuticals Inc. Dr Sacks is an employee of Regeneron Pharmaceuticals Inc and a shareholder in OptiNose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Dupilumab and mepolizumab have shown efficacy and safety in treating chronic rhinosinusitis with nasal polyps (CRSwNP)., Objective: Without available results from head-to-head randomized control trials (RCTs) comparing dupilumab with other biologics, we conducted an indirect treatment comparison (ITC) with mepolizumab., Methods: A systematic literature review identified RCTs of biologics in CRSwNP. A Bucher ITC was performed, including nasal polyp score (NPS; range 0-8), nasal congestion (NC; 0-3), loss of smell (LOS; 0-3), University of Pennsylvania Smell Identification Test (UPSIT; 0-40), visual analog score (VAS; 0-10), Sino-Nasal Outcome Test (SNOT-22; 0-110), systemic corticosteroids (SCS) use or surgery for nasal polyps (NPs), and binary responder analyses for NPS and SNOT-22 improvement by ≥1/≥2 and ≥8.9, respectively. Matching-adjusted indirect comparisons (MAIC) were conducted as supporting analyses., Results: SINUS-24/-52 (SYNAPSE-like subpopulation only) and SYNAPSE were identified for ITC. At 24 weeks, change from baseline in NPS and proportion of patients with a binary responder outcome of NPS improvement ≥1 were significantly (P<0.05) greater in patients receiving dupilumab versus mepolizumab. At 52 weeks, improvements in NPS, NC, LOS, UPSIT, and VAS were significantly (P<0.05) greater for dupilumab versus mepolizumab. Proportion of patients achieving binary responder outcomes of NPS and SNOT-22 improvement by ≥1/≥2 and ≥8.9, respectively, was significantly (P<0.05) higher, while SCS use was significantly (P<0.05) reduced, for dupilumab versus mepolizumab. Surgery rate was numerically reduced with dupilumab versus mepolizumab. The MAIC analyses confirmed these results., Conclusions: Dupilumab was associated with greater improvements in CRSwNP-related outcomes versus mepolizumab., (Copyright © 2024. Published by Elsevier Inc.)

Background: Responder analyses of SINUS phase 3 study data have shown clinically meaningful improvements across multiple outcomes of treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) with dupilumab., Objective: Our aim was to gain a better understanding of dynamics of the response to dupilumab over 52 weeks., Methods: We used data from the SINUS-52 (ClinicalTrials.gov identifier NCT02898454) intention-to-treat population to perform a post hoc analysis of patients with severe CRSwNP who had received dupilumab, 300 mg once every 2 weeks, or placebo. Response, which was defined as an improvement from baseline of a least 1 point in Nasal Polyp Score (NPS), nasal congestion (NC) score, and loss of smell (LoS) score, as well as an improvement of at least 8.9 points on the 22-Item Sino-Nasal Outcome Test (SNOT-22), was assessed for rapidity, maintenance, and durability., Results: The study included 303 patients (150 of whom received dupilumab and 153 of whom received placebo). For each outcome measure, a greater proportion of patients achieved a first response by week 16 (rapidity) with dupilumab versus with placebo; specifically, the respective differences in indicators between the 2 groups by week 16 were as follows: NPS, 75.3% versus 39.2%; NC score, 60.0% versus 24.2%; LoS score, 60.7% versus 15.7%; and SNOT-22 score, 83.3% versus 66.0%. Of those patients given dupilumab who had a response by week 16, more than 80% maintained their response at week 52 (maintenance). Over 52 weeks, greater proportions of those patients given dupilumab were responders on at least 80% of time points; specifically, the respective differences in indicators between the 2 groups by week 16 were as follows: NPS, 46.7% versus 2.6%; NC score, 46.7% versus 9.2%; LoS score, 47.3% versus 3.9%; and SNOT-22 score, 62.0% versus 21.6% (durability)., Conclusion: Most patients with CRSwNP achieve clinically meaningful responses to dupilumab by week 16, and most such patients in our study had maintenance and durability of response with continued treatment over time., Competing Interests: Disclosure statement Supported by Sanofi, France, and Regeneron Pharmaceuticals, Inc, United States. Disclosure of potential conflict of interest: C. Bachert is an advisory board member of AstraZeneca, Novartis, and Sanofi. W. J. Fokkens reports research grants from BioInspire Technologies, GlaxoSmithKline, Mylan, Novartis, and Sanofi. C. Hopkins is an advisory board member of AstraZeneca, BioInspire Technologies, GlaxoSmithKline, and Sanofi. P. Gevaert reports clinical trial funding from and is an advisory board member of 3NT, Argenx, Genentech, Novartis, Regeneron Pharmaceuticals, Roche, Sanofi, and Stallergenes Greer. J. K. Han is an advisory board member of AstraZeneca, Genentech, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals, and Sanofi. P. W. Hellings is an advisory board member of Regeneron Pharmaceuticals and Sanofi. S. E. Lee reports receiving clinical trial funding from and being an advisory board member of AstraZeneca, Genentech, GlaxoSmithKline, and Sanofi and being an advisory board member of Novartis and Regeneron Pharmaceuticals. A. H. Khan, J. Msihid, J. A. Jacob-Nara, and P. J. Rowe are employees of Sanofi and may hold stock and/or stock options in the company. S. Nash and Y. Deniz are employees and shareholders of Regeneron Pharmaceuticals. H. Sacks is an employee of Regeneron Pharmaceuticals and a shareholder of Optinose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Prurigo nodularis (PN) is a debilitating skin disease characterized by the hallmark symptom of chronic itch; the intensity of itch in PN was assessed using the Worst Itch Numeric Rating Scale (WI-NRS) to evaluate the primary efficacy end point of 2 recent phase 3 studies of dupilumab treatment for PN., Objective: To validate the psychometric properties and to determine the clinically meaningful improvement threshold for WI-NRS in patients with moderate to severe PN., Design, Setting, and Participants: In this secondary analysis of the PRIME and PRIME2 trials, content validity of WI-NRS was assessed through in-depth patient interviews. Psychometric assessments used pooled data from masked, intention-to-treat (ITT) patients with PN from randomized, double-masked, and placebo-controlled studies. Psychometric assessments included test-retest reliability, construct validity, known-groups validity, and sensitivity to change in adult patients with moderate-to-severe PN. Thresholds for meaningful within-patient improvement in the WI-NRS score were determined using anchor and distribution-based approaches. Data were analyzed after completion of each study, December 2019 to November 2021 for PRIME and January 2020 to August 2021 for PRIME2., Exposures: Dupilumab (300 mg) or placebo subcutaneously every 2 weeks for 24 weeks., Main Outcomes and Measures: WI-NRS score at specified time points up to 24 weeks after randomization., Results: A total of 20 patients were included across the 2 studies (mean [SD] age, 49.3 [17.2] years; 11 female [55%]); 311 patients were included in the pooled intention-to-treat analysis (mean [SD] age, 49.5 [16.1] years; 203 female [65.3%]). The WI-NRS questions (20 of 20 patients), recall period (19 of 20 patients), and response scale (20 of 20 patients) were easy to understand and relevant for patients with PN. Adequate test-retest reliability was observed between screening and baseline (intraclass correlation coefficient = 0.72, using Patient Global Impression of Severity [PGIS] to define stable patients). Convergent and discriminant validity was supported by moderate to strong correlations (absolute r range = 0.34-0.73) with other conceptually related measures and weaker correlations (absolute r range = 0.06-0.32) with less-related measures, respectively. WI-NRS was sensitive to change, as demonstrated by differences in change from baseline among groups (per PGIS change and PGI of Change [PGIC]). Using anchor-based approach with PGIS and PGIC, the clinically meaningful improvement threshold was 4 points (range, 3.0-4.5), which was also supported by distribution-based methods., Conclusion and Relevance: This study found that WI-NRS may be a fit-for-purpose instrument to support efficacy end points measuring the intensity of itching in adults with PN., Trial Registration: NCT04183335 (PRIME) and NCT04202679 (PRIME2).

Acid sphingomyelinase deficiency (ASMD) is a rare, lysosomal storage disease with limited evidence on its natural history. This retrospective, medical record abstraction study aimed to characterize the natural history of ASMD (types B and A/B) during childhood and adolescence. Recruiting sites were European centers (i.e., France, Germany, Italy, and the United Kingdom) from the ASCEND-Peds trial (NCT02292654); these sites were targeted because of the rarity of ASMD and specialized care provided at these centers. The study population comprised ASMD trial patients (before exposure to treatment) and ASMD non-trial participants who were managed at the same trial sites. Overall, 18 patients were included (11 trials; 7 non-trials; median [Q1; Q3] age at ASMD diagnosis: 2.5 [1.0; 4.0] years). Median follow-up duration was 10.0 years. Frequently reported medical conditions were hepatobiliary (17 [94.4%]) and blood and lymphatic system disorders (16 [88.9%]). Adenoidectomy (3 [16.7%]) was the most commonly reported surgical procedure; gastroenteritis (5 [27.8%]) was the most frequently reported infection, and epistaxis (6 [33.3%]) was the most commonly reported bleeding event. Abnormal spleen (16 [88.9%]) and liver (15 [83.3%]) size and respiratory function (8 [44.4%]) were commonly reported during physical examination. Overall, 11 (61.1%) patients were hospitalized; 6 (33.3%) patients had emergency room visits. Findings were consistent with published literature and support the current understanding of natural history of ASMD., Competing Interests: Declaration of competing interest Eugen Mengel received research grants, speakers' fees, and consulting honoraria from Sanofi, Orphazyme, Takeda, Cyclo Therapeutics, Idorsia, JCR, Denali, Amicus, and Avrobio. Maurizio Scarpa received funds for research and honoraria from Sanofi, Takeda, Chiesi, Ultragenyx, Amicus, Azafaros, BioMarin, and Orchard. Nathalie Guffon received some fees from Sanofi, Chiesi, and Ultragenyx as an expert in Advisory Board and is an employee of Reference Center for Inherited Metabolic Disorders that received a grant for clinical trials (Sanofi, Chiesi, BioMarin, Takeda, and JCR). Simon A Jones received speaker's and consultancy fees from Sanofi and BioMarin. Vishal Goriya and Carly Rodriguez reported being employed by IQVIA, which received funding from Sanofi for this research. Valerie Dyevre, Jérôme Msihid, Maja Gasparic, and Ruth Pulikottil-Jacob are employees of Sanofi and may hold stocks and/or stock options in the company. Lubomyra Nalysnyk holds stocks in Sanofi. Fernando Laredo was an employee of Sanofi at the time of this research., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Cold agglutinin disease (CAD) is a rare subtype of autoimmune haemolytic anaemia characterised by classical complement pathway-mediated haemolysis, fatigue, and poor quality of life (QoL). Sutimlimab, a C1s inhibitor, rapidly halted haemolysis, and improved patient-reported outcomes (PROs) in patients with CAD in two phase 3 trials (CARDINAL and CADENZA). Here we report PROs from the CADENZA open-label extension (Part B)., Methods: The first patient was enrolled in CADENZA (NCT03347422) in March 2018 (Part A) and the last patient completed the study in December 2021 (Part B). All patients who completed the 26-week Part A were eligible to receive biweekly doses of sutimlimab in Part B for up to 1 year after the last patient completed Part A. PROs were assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout., Findings: In total, 32/39 patients completed Part B; median Part B treatment duration: 99 weeks. Patients switching from placebo to sutimlimab in Part B experienced rapid improvement in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and other PROs. Sustained, clinically important improvements in FACIT-Fatigue were observed throughout Part B in patients who switched to sutimlimab and those continuing sutimlimab treatment (combined-group mean [SE] change from baseline at LV: 8.8 [2.1]). Similarly, the combined-group mean [SE] change for 12-Item Short Form Health Survey physical (4.9 [1.7]) and mental (4.0 [1.8]) component scores exceeded clinically important changes from baseline at LV. EuroQol visual analogue scale showed consistent and sustained increases from baseline with sutimlimab treatment. Following a 9-week washout, all PROs approached baseline values., Interpretation: Continued inhibition of the classical complement pathway with sutimlimab results in meaningful long-term improvements in PROs (fatigue and QoL) in patients with CAD., Funding: Sanofi., Competing Interests: AR has received consultancy fees from Alexion Pharmaceuticals, Inc, Apellis Pharmaceuticals, Bioverativ, a Sanofi company, Novartis, Roche, and Sanofi; honoraria from Alexion, Amgen, Apellis, Novartis, Roche, Sanofi and Sobi, and advisory board fees from Alexion, Amgen, Apellis, Bioverativ, Novartis, Roche, Sanofi, and Sobi. CMB has received research support from Alexion, Argenx, Electra, Novartis, and Sanofi; honoraria from Alexion, Argenx, and Sanofi; and advisory board fees from Argenx, Novartis, and Sanofi. WB has received research support from Alexion; honoraria from Agios, Alexion, Apellis, Biocryst, Incyte, Janssen, Momenta, Novartis, Sanofi, and Sobi; and advisory board fees from Alexion, Novartis, Roche, Sanofi, and Sobi. BJ has received reimbursement for travel costs related to scientific advice and scientific presentations from Sanofi. QAH has received research support from Alexion; consultancy fees from Amgen, Argenx, Gliknik, Grifols, Incyte, Immunovant, Janssen, Novartis, ReAlta, Sanofi, and Sobi; and honoraria from Amgen, Argenx, Bioverativ, Gliknik, Grifols, Incyte, Immunovant, Janssen, Novartis, ReAlta, Sanofi, Shire, and Sobi. DC has received research support to his institution from Astellas and consulting fees from Sanofi. THAT has received honoraria from Ablynx, Alexion, and Novartis. MY has no disclosures. IM has received consultancy fees and honoraria from Alexion, Apellis, Momenta/Janssen, Novartis, Rigel, Sanofi. ICW has received consultancy fees from Alexion, Apellis, Novartis, and Biocryst; and honoraria from Alexion. ML, FS, MW, DJ, RY and JM are Sanofi employees and may hold stock and/or stock options in the company., (© 2024 The Author(s).)

Purpose: Long-term data are limited on the safety and efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma from Korea. The current subgroup analysis was designed to evaluate the long-term safety and efficacy of dupilumab in patients enrolled from Korean centers in the parent studies (phase 2b and QUEST) and who participated in the TRAVERSE open-label extension (OLE) study., Methods: TRAVERSE was a global, multicenter, OLE study that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks for up to 96 weeks in patients (n = 2,282) with uncontrolled, moderate-to-severe asthma who completed prior dupilumab asthma clinical trials. The primary outcome was the incidence of any treatment-emergent adverse events (TEAEs); the secondary outcomes included annualized severe exacerbation rate, pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1), and 5-item Asthma Control Questionnaire (ACQ-5) score., Results: Safety outcomes were consistent with the parent studies and the overall TRAVERSE population; out of 74 patients, 70 experienced ≥ 1 TEAE, and 6 (8.1%) discontinued because of adverse events. During the treatment period, the unadjusted annualized severe exacerbation rate was low (0.470). Improvement in pre-BD FEV1 was seen as early as Week 2 with a mean change from the parent study baseline (PSBL), standard deviation (SD) of 0.42 L (0.47), which was sustained until Week 96. Mean change from PSBL (SD) in ACQ-5 score was -1.32 (0.76) at Week 48., Conclusions: This subgroup analysis of TRAVERSE showed the long-term safety and efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma enrolled from Korean centers., Trial Registration: ClinicalTrials.gov Identifier: NCT02134028., Competing Interests: Chin Kook Rhee, Heung-Woo Park, and You Sook Cho are on the advisory panel on Sanofi, Korea; Hayeon Noh and Jerome Msihid are employees of Sanofi and may hold stocks or stock options in the company. Heung-Woo Park serves as a deputy editor for the Allergy, Asthma & Immunology Research journal and recuses himself from the editorial decisions on this manuscript. Jung-Won Park and You Sook Cho serve as editorial board members for the Allergy, Asthma & Immunology Research journal and recuse themselves from the editorial decisions on this manuscript., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Background: The efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on forced vital capacity percent predicted (FVCpp) in patients with late-onset Pompe disease (LOPD) has been assessed in the Phase 3 COMET trial (NCT02782741). Due to the rarity of LOPD and thus small sample size in COMET, additional data were analyzed to gain further insights into the efficacy of AVA versus ALG., Methods: Data from treatment-naive patients with LOPD were pooled from COMET and Phase 1/2 NEO1/NEO-EXT (NCT01898364/NCT02032524) trials for patients treated with AVA, and Phase 3 LOTS trial (NCT00158600) for patients treated with ALG. Regression analyses using mixed models with repeated measures consistent with those pre-specified in COMET were performed post-hoc. Analyses were adjusted for trials and differences in baseline characteristics. Four models were developed: Model 1 considered all trials; Model 2 included Phase 3 trials; Model 3 included Phase 3 trials and was adjusted for baseline ventilation use; Model 4 included COMET and NEO1/NEO-EXT (i.e., AVA trials only)., Results: Overall, 100 randomized patients from COMET (AVA, n  = 51, ALG, n  = 49), 60 from LOTS (ALG arm only), and three patients from NEO1/NEO-EXT (who received open-label AVA only) were considered for analysis. Mean age at enrollment was similar across trials (45.3-50.3 years); however, patients from LOTS had a longer mean duration of disease versus COMET and NEO1/NEO-EXT trials (9.0 years and 0.5-2.2 years, respectively) and younger mean age at diagnosis (36.2 years and 44.7-48.6 years, respectively). Least squares mean (95% confidence interval) improvement from baseline in FVCpp at Week 49-52 for AVA versus ALG was 2.43 (-0.13; 4.99) for COMET ( n  = 98); 2.31 (0.06; 4.57) for Model 1 ( n  = 160); 2.43 (0.21; 4.65) for Model 2 ( n  = 157); 2.80 (0.54; 5.05) for Model 3 ( n  = 154); and 2.27 (-0.30; 4.45) for Model 4 ( n  = 101)., Conclusions: Models 1 to 3, which had an increased sample size versus COMET, demonstrated a nominally significant effect on FVCpp favoring AVA versus ALG after 1 year of treatment, consistent with results from COMET., Competing Interests: TM has participated in advisory boards for AbbVie, Alexion, Amicus, Argenx, Audentes, Maze Therapeutics, Momenta, Ra-Pharmaceuticals, Sanofi, Sarepta Therapeutics, Spark Therapeutics, UCB, Ultragenyx, and Zogenix, and Speaker's bureau for Sanofi; and has received research funding from Alexion, Amicus, Argenx, Audentes, Bristol Myers-Squibb, Cartesian, Grifols, Momenta, Ra-Pharmaceuticals, Sanofi, Spark Therapeutics, UCB, and Valerion. JM, KAH, TZ, and LP are employees and may hold stock and/or stock options in Sanofi. MP: was an employee of Sanofi at the time of study participation and may still hold stock and/or stock options, and is currently employed as the Global Medical Lead for Early Indications and New Programs – Rare Diseases at UCB. LRF was an employee of Sanofi at the time the research took place and is now an employee of Aixial, a contract research organization working with Sanofi. He holds stock in Sanofi. PS and IP are employees of Evidera, part of ThermoFisher Scientific. VS has received consulting fees from Novartis Gene Therapies, Roche, Sanofi, Sarepta Therapeutics, and Vertex Pharmaceuticals, and honoraria from Sanofi; and has conducted contracted research for Sanofi and Sarepta Therapeutics., (© 2024 The Authors. Published by Elsevier Inc.)

Objectives: To assess the severity of the top 5 22-item Sino-Nasal Outcome Test (SNOT-22) items ranked most important by patients with chronic rhinosinusitis with nasal polyps (CRSwNP), the effect of dupilumab on these items, and their association with objective disease measures., Study Design: Post hoc analysis of the SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) clinical trials., Setting: Multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies., Methods: Patients ranked the SNOT-22 items most affecting their health at baseline. Item symptom severity (0-5 scale) was assessed at baseline, Week 24 (W24), and Week 52 (W52). Changes in nasal polyps score (NPS) and Lund-Mackay (LMK) scores were assessed in patients with/without SNOT-22 items improvements of at least 1 severity group point at W24 and W52., Results: The SNOT-22 items ranked most important at baseline were "decreased sense of smell/taste" (87% of patients), followed by "nasal blockage" (82%), "postnasal discharge" (40%), "thick nasal discharge" (37%), and "wake up at night" (26%); 82%, 61%, 32%, 40%, and 26% of patients reported severe symptoms (score 4 or 5) for these items, respectively. Dupilumab improved score severity for all top 5 items versus placebo at W24 and W52. Improvements in NPS and LMK scores were numerically greater in patients with improvements in the SNOT-22 top 5 items., Conclusion: Loss of smell/taste was ranked as the most important symptom by patients with CRSwNP. Dupilumab reduced the severity of the top 5 most important SNOT-22 items versus placebo, in parallel with improvements in objective disease measures., Clinical Trial Registration: SINUS-24 and SINUS-52 clinical trials were registered with ClinicalTrials.gov, identifiers NCT02912468 and NCT02898454, respectively., (© 2023 The Authors. Otolaryngology‐Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology‐Head and Neck Surgery Foundation.)

Background: The Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures., Methods: Adults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0-1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0-1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement)., Results: The analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p < 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p > 0.05)., Conclusions: These analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD., Competing Interests: Declaration of Competing Interest KAH: is an employee and may hold stock and/or stock options in Sanofi. KIB: has served as a consultant to Sanofi, Amicus Therapeutics, Takeda, Valerion, and has participated in advisory boards for Sanofi, AskBio, Spark Therapeutics and Takeda; he is currently an employee of Sanofi. PD: is an employee and may hold stock and/or stock options in Sanofi. MMD: serves or recently served as a consultant for Abcuro, Amazentis/Vandria, ArgenX, Astellas, Catalyst, Cello, CNSA, Covance/Labcorp, CSL-Behring, Dianthus, EcoR1, EMD Serono/Merck, Janssen, Kezar, MDA, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences Inc., Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, TACT, Abata/Third Rock, UCB Biopharma, and UpToDate. MMD received research grants, contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, UCB Biopharma/RaPharma, Viromed/Healixmith & TMA. AH: is an employee and may hold stock and/or stock options in Sanofi. PSK: has received research/grant support from Sanofi Genzyme and Amicus Therapeutics; has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer and Asklepios Biopharmaceutical, Inc. (AskBio); is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Baebies; and has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals, and may receive milestone payments related to that equity in the future. JM: is an employee and may hold stock and/or stock options in Sanofi. LP: is an employee and may hold stock and/or stock options in Sanofi. BS: Unrestricted research grants from Amicus, Astellas, Marigold Foundation, AMDA Foundation. Speaker honoraria from Kedrion, Alexion. Scientific advisor for Amicus, Argenx, Astellas, Maze, Pepgen, Sanofi, Spark, and Taysha. No stocks or shares. NT: is an employee and may hold stock and/or stock options in Sanofi. AT: has received honorarium as a scientific board component (Sanofi, Amicus, and Aro) and as a speaker for Sanofi, Spark, and Amicus. NvdB: received speaker honoraria from Sanofi and Amicus Therapeutics, and has served as scientific advisor for Sanofi under agreements with Erasmus MC University Medical Center and the relevant industry. TZ: is an employee and may hold stock and/or stock options in Sanofi., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)