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Background: Dupilumab has shown long-term treatment benefits in children with uncontrolled asthma. We assessed in more detail the impact of dupilumab on asthma control and health-related quality of life (HRQoL) in children and their caregivers., Methods: Children aged 6-11 years with uncontrolled moderate-to-severe type 2 asthma (baseline blood eosinophils ≥150 cells·µL -1 or fractional exhaled nitric oxide ≥20 ppb; n=350) were treated with dupilumab or placebo for 52 weeks in the VOYAGE study. Primary outcomes of these analyses were asthma control (change from baseline in Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) and achieving a clinically meaningful response of ≥0.5 points); proportion of patients achieving well-controlled asthma or better (ACQ-7-IA ≤0.75 points); effect on patients' (Standardised Paediatric Asthma Quality of Life Questionnaire Interviewer-Administered (PAQLQ(S)-IA)) and caregivers' (Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ)) HRQoL; and allergic rhinitis-related QoL., Results: Dupilumab versus placebo significantly improved children's ACQ-7-IA scores by week 4 with sustained improvements through week 52 (least squares mean difference at week 52: -0.44, 95% CI -0.59- -0.30; p<0.0001); a higher proportion achieved a clinically meaningful response (week 52: 86% versus 75%; p=0.0051). At weeks 24 and 52, more children who received dupilumab achieved well-controlled asthma (ACQ-7-IA ≤0.75 points: 61% versus 43%; p=0.0001 and 70% versus 46%; p<0.0001, respectively). Significant improvements in PAQLQ(S)-IA and PACQLQ scores were observed by week 52., Conclusions: In children aged 6-11 years with moderate-to-severe type 2 asthma, dupilumab treatment was associated with rapid, sustained improvements in asthma control. HRQoL was significantly improved for children and their caregivers., Competing Interests: Conflict of interest: A.G. Fiocchi has served as an advisory board member for Abbott, Danone, DBV Technologies, HiPP Organic, Novartis and Stallergenes Greer, and reports research sponsorship from Danone, Ferrero, HiPP Organic and Sanofi. W. Phipatanakul has served as a consultant and has received clinical trial support/medication support from Genentech, GSK for Asthma Therapeutics, Merck, Regeneron Pharmaceuticals Inc. and Sanofi. R.S. Zeiger has served as a deputy editor for the AAAAI and a consultant for the ACAAI, received research support from ALK and the NIH, received research support from and served as an advisory board member for AstraZeneca, Genentech/Novartis, GSK and Teva, served as an advisory board member for Sanofi-Regeneron Pharmaceuticals Inc., and reports royalties from UpToDate. J. Cole has no conflicts of interest to disclose. J. Msihid, J.A. Jacob-Nara, P.J. Rowe, M. Hardin and A.H. Khan are Sanofi employees and may hold stock and/or stock options in the company. S.R. Durrani, R. Gall, Y. Deniz and D.J. Lederer are employees and shareholders of Regeneron Pharmaceuticals Inc. Y. Zhang is a former employee of Regeneron Pharmaceuticals Inc. and may hold shares and/or share options in the company., (Copyright ©The authors 2023.)

Background: Patients with asthma often experience sleep disturbances. We assessed the 5-item Asthma Control Questionnaire (ACQ-5) score ≥2.5 as a useful threshold to identify patients with moderate-to-severe type 2 asthma and high sleep disturbance (HSD) and investigated dupilumab efficacy on clinical and sleep-related outcomes among patients with HSD., Methods: QUEST (NCT02414854) data were used in this post hoc analysis. A composite endpoint from validated patient-reported outcomes was developed to identify patients with HSD using sleep-related items from the ACQ-5, Asthma-Related Quality-of-Life Questionnaire, Rhino-Conjunctivitis Quality-of-Life Questionnaire, and Sino-Nasal Outcome Test-22. Impairment in at least 1 item was considered an indication of HSD. Change from baseline to Week 52 in nighttime symptoms, ACQ-5 score, lung function, annualized severe exacerbation rates (AER), and short-acting β-agonists use during treatment was used to assess dupilumab efficacy., Results: In type 2 asthma patients, 64% had HSD at baseline; of those with ACQ-5 ≥2.5 at baseline, 82% had HSD. In this population, dupilumab reduced nighttime symptoms and ACQ-5 score by 0.31 and 0.56 points, respectively, by Week 52 versus placebo, and led to a 66% reduction in AER during QUEST and 0.34 L improvement in pre-bronchodilator (pre-BD) forced expiratory volume in 1 s (FEV 1 ) at Week 52., Conclusion: A majority of patients with moderate-to-severe type 2 asthma with ACQ-5 ≥2.5 at baseline had HSD. Dupilumab reduced nighttime symptoms and exacerbations, and improved lung function, overall asthma control, and quality of life. Further studies are needed to confirm the association between ACQ-5 score ≥2.5 and higher sleep disturbance rates., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: While advances in asthma care have been made in Latin America, there is still a large unmet need in patients with uncontrolled asthma. This post hoc analysis of the QUEST study assessed safety and efficacy of dupilumab in the subgroup of patients enrolled in Latin American countries with a type 2 inflammatory asthma phenotype (blood eosinophils ≥ 150cells/µL or FeNO ≥25ppb)., Methods: LIBERTY ASTHMA QUEST (NCT02414854) was a phase 3, multinational, randomized, double-blind, placebo-controlled study in patients with uncontrolled, moderate-to-severe asthma. Eligible patients ≥ 12 years of age were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on subcutaneous dupilumab 200 or 300 mg every 2 weeks or matched-volume placebos. Pre-specified co-primary efficacy endpoints were the annualized rate of severe exacerbations during the treatment period and the change from baseline in pre-bronchodilator FEV 1 at treatment week 12. Asthma control, changes in asthma biomarker levels, and dupilumab safety were also evaluated., Results: 530 (27.9% of the overall QUEST population; dupilumab: 353, placebo: 177) Latin-American patients were recruited; 420 (79.2%) had a type 2 inflammatory asthma phenotype. Dupilumab vs placebo reduced the annualized rate of severe exacerbations by 52.7% ( P  < 0.001) and increased pre-bronchodilator FEV 1 at week 12 by 0.15 L ( P  < 0.001), in the type 2 population. Safety was consistent with the known dupilumab safety profile., Conclusions: Consistent with the results in the overall population, dupilumab reduced the risk of severe asthma exacerbations and improved lung function in Latin American patients with uncontrolled, moderate-to-severe asthma and a type 2 phenotype.

Background: Type 2 cytokines IL-4/IL-5/IL-13 play an important role in pathogenesis of type 2 conditions, including asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In phase 2b (P2B) (NCT01854047) and phase 3 VENTURE (NCT02528214), dupilumab reduced annualized severe exacerbation rates (AER), improved forced expiratory volume in 1 second (FEV 1 ), and was generally well tolerated in patients with uncontrolled, moderate-to-severe, or oral corticosteroid (OCS)-dependent severe asthma., Objective: The post hoc assessment of dupilumab efficacy versus placebo in P2B and VENTURE in patients stratified by allergic status., Methods: Allergic asthma was defined as total serum IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35 kU/L at baseline. AER, prebronchodilator (BD) FEV 1 , FEV 1 /forced vital capacity (FVC) ratio, asthma control (5-item Asthma Control Questionnaire), health-related quality of life (HRQoL; Asthma Quality of Life Questionnaire), type 2 biomarkers, specific IgE, and OCS reduction (VENTURE only) were assessed., Results: In patients with allergic asthma, dupilumab (P2B: pooled 200/300 mg; VENTURE: 300 mg) every 2 weeks versus placebo reduced AER (P2B: -60%, P < .01; VENTURE: -72%, P < .001), and, in P2B, increased pre-BD FEV 1 (P < .01) and FEV 1 /FVC (P < .05). In both studies, dupilumab significantly improved asthma control and HRQoL and reduced most type 2 biomarkers. Dupilumab significantly reduced OCS use in VENTURE. Similar benefits were observed in patients without evidence of allergic asthma., Conclusions: Dupilumab significantly reduced AER and improved lung function, asthma control, and HRQoL in patients with or without evidence of allergic asthma., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate within-patient symptom improvement in the dupilumab SINUS-24/-52 studies in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (NCT02912468/NCT02898454)., Methods: Patients received dupilumab 300 mg or placebo every 2 weeks for 24 (SINUS-24) or 52 weeks (SINUS-52) on background intranasal corticosteroids. Patients daily reported symptoms of nasal congestion (NC), loss of smell (LoS) and rhinorrhoea on a scale of 0-3 (0 - no symptoms, 1 - mild, 2 - moderate, 3 - severe symptoms). The proportions of patients with moderate-to-severe symptoms (score ≥ 2) at baseline who improved to no-to-mild symptoms (score ≤ 1) were determined at Weeks 2, 24 (pooled studies) and 52 (SINUS-52). Subgroups with prior sinonasal surgery and coexisting asthma were analysed., Results: At baseline in the pooled intention-to-treat population ( n  = 724), the proportions of patients with scores ≥ 2 for NC, LoS and rhinorrhoea were 87, 94 and 64%, respectively. Significantly, more patients achieved scores ≤ 1 (no/mild symptoms) with dupilumab vs placebo for each symptom at each time point {Week 2 NC 12% vs 2% [odds ratio 8.9 (95% CI 3.0-26.3)], LoS 5% vs 1% [4.6 (1.3-16.8)], rhinorrhoea 9% vs 2% [4.8 (1.5-15.4)], all P  < 0.05; Week 24 NC 54% vs 14% [8.7 (5.6-13.5)], LoS 43% vs 6% [14.4 (7.9-26.0)], rhinorrhoea 53% vs 16% [6.6 (4.1-10.9)], all P  < 0.0001}. Results were similar in subgroups with prior surgery and coexisting asthma., Conclusion: Significantly, more patients achieved improvement from moderate-to-severe symptoms to no-to-mild symptoms with dupilumab than placebo, regardless of prior surgery or coexisting asthma. Improvement was observed as early as Week 2 and continued through to Week 52., Competing Interests: PG receives clinical trial funding and is an advisory board member for 3NT, Argenx, Genentech, Novartis, Regeneron Pharmaceuticals Inc., Roche, Sanofi and Stallergenes Greer. SEL receives clinical trial funding and is an advisory board member for GlaxoSmithKline and Sanofi, receives clinical trial funding from AstraZeneca and Genentech, and is an advisory board member for Novartis and Regeneron Pharmaceuticals Inc. RAS receives research grants, fees for lectures and is an advisory board member for AstraZeneca, GlaxoSmithKline and Regeneron Pharmaceuticals Inc., receives fees for lectures and is an advisory board member for Grifols, Pharming and Sanofi, receives research grants and fees for lectures from Genentech, receives fees for lectures from Boehringer Ingelheim, OptiNose and Takeda, is an advisory board member for Aimmune Therapeutics, ALK, BioCryst, DBV Technologies and Pfizer, and receives research grants from Chiesi, Merck, Novartis and Stallergenes Greer. MW is a member of national and international scientific advisory boards (consulting), receives fees for lectures and research grants from ALK‐Abelló, Allakos, AstraZeneca, GlaxoSmithKline, HAL, Meda Pharmaceuticals, Novartis, Otonomy, Roche, Sanofi‐Aventis, Stallergenes Greer, Strekin and Teva. C‐CC, JAJ‐N, AHK and JM are employees and may hold stock and/or stock options in Sanofi. SK and SN are employees and shareholders of Regeneron Pharmaceuticals Inc. SS is a former employee and may hold stock and/or stock options in Regeneron Pharmaceuticals Inc., (© 2023 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: Safety and efficacy data for dupilumab beyond 1 year are lacking for patients from Japan with moderate-to-severe asthma., Methods: The TRAVERSE open-label extension (OLE) study (NCT02134028) assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in 2282 patients who completed a previous dupilumab asthma study. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included annualized severe exacerbation rate and change from parent study baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV 1 ), asthma control, quality of life, and blood eosinophil levels. Anti-drug antibodies (ADA) were evaluated. We report results in 160 (7.8% of exposed population) patients recruited from Japanese centers with non-oral corticosteroid (OCS)-dependent asthma rolled over from two parent studies, and in subgroups with a type 2 inflammatory phenotype., Results: TEAEs were consistent with the parent studies and the known safety profile of dupilumab. One patient permanently discontinued treatment due to TEAEs. Exacerbation rates remained low and were sustained to Week 96, as were improvements in pre-bronchodilator FEV 1 . Rapid, sustained improvements were observed in dupilumab-treated patients who previously received placebo in a parent study, while further improvements in exacerbation rates, asthma control, and asthma-related quality of life were observed in those continuing dupilumab. Blood eosinophil levels decreased progressively while on treatment. Treatment-emergent ADA responses were highest in patients who had previously received placebo. Efficacy results were consistent in patients with a type 2 phenotype., Conclusions: Long-term dupilumab treatment was well tolerated and efficacious in patients with non-OCS-dependent, moderate-to-severe asthma recruited from Japan. (Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov identifier, NCT02134028)., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2-mediated inflammatory disease with high symptom burden and reduced health-related quality of life (HRQoL). This report aimed to comprehensively understand the effects of dupilumab on domains of HRQoL, their individual elements, and health status in patients with severe CRSwNP from phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) trials., Methods: Patients were randomized to dupilumab (n = 438) or placebo (n = 286) for 24 weeks (SINUS-24), or 52 weeks (SINUS-52). Disease-specific HRQoL using 22-item sino-nasal outcome test (SNOT-22), and health status using EuroQoL-visual analog scale (EQ-VAS) was evaluated in the pooled intention-to-treat (ITT) population (Week 24), SINUS-52 ITT (Week 52) and in the subgroups with/without asthma; non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD); and prior sinus surgery., Results: At baseline, patients had poor disease-specific HRQoL and general health status and identified "Decreased sense of smell/taste" and "Nasal blockage" as the most important symptoms. Dupilumab significantly improved SNOT-22 total, domain (Nasal, Sleep, Function, Emotion, and Ear/facial), and 22-item scores, and EQ-VAS, at Week 24 vs placebo (all p < .0001), with continued improvements to Week 52 in SINUS-52. Improvements occurred irrespective of comorbid asthma, NSAID-ERD, or prior surgery. A significantly greater proportion of dupilumab-treated patients exceeded clinically meaningful thresholds for SNOT-22 total score and EQ-VAS vs placebo (all subgroups p < .05 except patients without surgery at Week 24)., Conclusions: Dupilumab treatment led to significant clinically meaningful improvements across all aspects of disease-specific HRQoL, and general health status in patients with severe CRSwNP., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Currently, five biologic treatment options are available for use in patients with uncontrolled persistent asthma: three interleukin (IL)-5 antagonists, which either bind to the anti-IL-5 ligand (mepolizumab, reslizumab) or to the IL-5 receptor (benralizumab); one anti-immunoglobulin E (anti-IgE) therapy (omalizumab); and one anti-IL-4/IL-13 therapy (dupilumab). To date, no comparative data from head-to-head clinical trials are available for these biologics., Objective: An indirect treatment comparison (ITC) of dupilumab versus each of the anti-IL-5 and anti-IgE therapies using the endpoints of annualized severe asthma exacerbation rates and change in pre-bronchodilator forced expiratory volume in 1 s (FEV 1 )., Methods: Embase®, MEDLINE®, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for studies published between January 1, 1980 and March 25, 2019. Eligible articles included randomized controlled trials (RCTs) in patients aged ≥ 12 years with persistent/uncontrolled asthma using at least medium-to-high dose inhaled corticosteroid plus long-acting β 2 -agonist with add-on biologic therapy. Bucher ITCs were performed to compare subgroups of dupilumab patients with the anti-IL-5s and anti-IgE trial populations., Results: Fourteen RCTs were included in the analyses. The matched dupilumab subgroups were associated with greater reductions in annualized severe exacerbation rates compared with benralizumab, mepolizumab, reslizumab, and omalizumab (54%, 28%, 38%, and 26% greater reduction, respectively). A greater improvement in FEV 1 was also observed for dupilumab at week 12 and/or week 24/52 than for the other biologics (0.06-0.14 L)., Conclusion: In this ITC, dupilumab was associated with lower severe asthma exacerbation rates and greater improvements in lung function than anti-IL-5s and omalizumab., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: Dupilumab is approved as first-line systemic treatment for adults/adolescents with moderate-to-severe atopic dermatitis (AD) in Europe and elsewhere owing to its favourable benefit-risk profile. However, systemic non-steroidal immunosuppressants (NSISS) are often used as first-line therapy in clinical practice. Impact of prior therapy with NSISS on dupilumab's treatment effect vs. control has not been described previously. This study assessed dupilumab's efficacy vs. control in patients with moderate-to-severe AD, comparing treatment effect in patients with/without prior systemic NSISS therapy, in four phase 3 trials., Methods: This post hoc analysis included 1553 patients randomized to placebo or dupilumab (300 mg q2w) as monotherapy for 16 weeks, or with concomitant topical corticosteroids (TCS) for 16/52 weeks, from four randomized, double-blind, placebo-controlled, phase 3 trials. Patients were stratified by prior use of systemic NSISS and dupilumab-treated patients were analysed against control groups (treated with placebo or placebo + TCS)., Results: Dupilumab-treated patients, regardless of prior treatment with NSISS, achieved a significantly higher percentage reduction from baseline in Eczema Area and Severity Index (EASI), SCORing Atopic Dermatitis (SCORAD), Dermatology life Quality Index (DLQI), and Patient-Oriented Eczema Measure (POEM) vs. control; significantly more achieved EASI score ≤ 7, Peak Pruritus Numerical Rating Scale ≤ 4, POEM ≤ 7, and DLQI ≤ 5 by week 4. These rapid, significant improvements were seen with or without concomitant TCS and sustained through end-of-treatment., Conclusions: Dupilumab treatment (monotherapy or + TCS) provides rapid, significant, sustained improvements in signs, symptoms, and quality of life in patients with moderate-to-severe AD compared with control, regardless of prior systemic NSISS use., Clinical Trial Registration: LIBERTY AD SOLO 1: ClinicalTrials.gov identifier NCT02277743, EudraCT 2014-001198-15. LIBERTY AD SOLO 2: ClinicalTrials.gov identifier NCT02277769, EudraCT 2014-002619-40., Liberty Ad Chronos: ClinicalTrials.gov identifier NCT02260986, EudraCT 2013-003254-24. LIBERTY AD CAFÉ: ClinicalTrials.gov identifier NCT02755649, EudraCT 2015-002653-35., (© 2021. The Author(s).)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease treated with sinus surgery when refractory to medical intervention. However, recurrence postsurgery is common. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor for interleukin 4 (IL-4) and IL-13, key and central drivers of type 2 inflammation. We report the efficacy of dupilumab in patients with CRSwNP from the SINUS-24/SINUS-52 trials (NCT02912468/NCT02898454), by number of prior surgeries and time since last surgery., Methods: Patients were randomized to placebo or dupilumab 300 mg every 2 weeks. Post hoc subgroup analyses were performed for patients with 0, ≥1, 1/2, or ≥3 prior surgeries, and for patients who had surgery within <3, 3 to <5, 5 to <10, or ≥10 years. Efficacy outcomes at 24 weeks included co-primary endpoints nasal polyp score (NPS) and nasal congestion (NC), and Lund-Mackay (LMK), 22-item Sino-Nasal Outcome Test (SNOT-22), and smell scores., Results: Of 724 patients randomized, 459 (63.4%) had ≥1 prior surgery. Baseline sinus disease (NPS, NC, LMK) and olfactory dysfunction (University of Pennsylvania Smell Identification Test [UPSIT] and loss of smell) scores were worse for patients with ≥3 prior surgeries vs no surgery. Baseline NPS and LMK were worse in patients with <3 years since last surgery than in patients with ≥5 years since last surgery. Dupilumab significantly improved all outcome measures vs placebo in all subgroups by number of surgeries and by time since last surgery. Improvements in NPS and LMK were greater in patients with <3 years since last surgery than patients with ≥5 years. Safety results were consistent with the known dupilumab safety profile., Conclusion: Dupilumab improved CRSwNP outcomes irrespective of surgery history, with greater improvements in endoscopic outcomes in patients with shorter duration since last surgery., (© 2021 Sanofi. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Among patients with chronic rhinosinusitis with nasal polyps (CRSwNP), randomized clinical trials (RCTs) of biologics, such as anti-interleukin-4/interleukin-13 (dupilumab) and anti-immunoglobulin E (omalizumab), have demonstrated efficacy compared with intranasal corticosteroids (INCS). However, no head-to-head RCTs exist between biologics., Objective: To perform an indirect treatment comparison (ITC) of the efficacy of biologics plus INCS versus placebo (INCS) as a common comparator., Methods: Embase, MEDLINE, and Cochrane were searched for RCTs of biologics in CRSwNP. Bucher ITCs were performed for outcomes at week 24: nasal polyp score (NPS) (range, 0-8), nasal congestion (NC) (range, 0-3), loss of smell (range, 0-3), University of Pennsylvania Smell Identification Test (range, 0-40), total symptom score (range, 0-12), 22-item sinonasal outcome test (range, 0-110), and responder analyses based on NPS or NC improvement of 1 point or greater., Results: Assessment of trial design, baseline characteristics, and outcome measures suggested that ITC was feasible with four phase 3 RCTs: dupilumab SINUS-24 and SINUS-52 (NCT02912468/NCT02898454) and omalizumab POLYP 1 and POLYP 2 (NCT03280550/NCT03280537). In the intent-to-treat population, dupilumab had significantly greater improvements from baseline to week 24 versus omalizumab across key outcomes: NPS (least squares mean difference [95% confidence interval], -1.04 [-1.63 to -0.44]), NC (-0.35 [-0.60 to -0.11]), loss of smell (-0.66 [-0.90 to -0.42]), University of Pennsylvania Smell Identification Test (6.70 [4.67-8.73]), and total symptom score (-1.18 [-1.95 to -0.41]). Improvement in the 22-item sinonasal outcome test was greater in dupilumab versus omalizumab but was not statistically significant. Dupilumab patients were significantly more likely to achieve ≥1-point improvement in NPS (odds ratio [95% CI] = 3.58 [1.82-7.04]) and NC (2.13 [1.12-4.04]) versus omalizumab., Conclusions: Although ITCs have limitations, these results demonstrated that dupilumab had consistently greater improvements in key CRSwNP outcomes versus omalizumab at week 24., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Increased levels of cytokines, including interleukin-6 (IL-6), reflect inflammation and have been shown to be predictive of therapeutic responses, fatigue, pain, and depression in patients with rheumatoid arthritis (RA), but limited data exist on associations between IL-6 levels and health-related quality of life (HRQoL). This post hoc analysis of MONARCH phase III randomized controlled trial data evaluated the potential of baseline IL-6 levels to differentially predict HRQoL improvements with sarilumab, a fully human monoclonal antibody directed against both soluble and membrane-bound IL-6 receptor α (anti-IL-6Rα) versus adalimumab, a tumor necrosis factor α inhibitor, both approved for treatment of active RA., Methods: Baseline serum IL-6 levels in 300/369 randomized patients were categorized into low (1.6-7.1 pg/mL), medium (7.2-39.5 pg/mL), and high (39.6-692.3 pg/mL) tertiles. HRQoL was measured at baseline and week (W)24 and W52 by Short Form 36 (SF-36) physical/mental component summary (PCS/MCS) and domain scores, Functional Assessment of Chronic Illness Therapy -fatigue, and duration of morning stiffness visual analog scale (AM-stiffness VAS). Linear regression of changes from baseline in HRQoL (IL-6 tertile, treatment, region as a stratification factor, and IL-6 tertile-by-treatment interaction as fixed effects) assessed predictivity of baseline IL-6 levels, with low tertile as reference. Pairwise comparisons of improvements between treatment groups were performed by tertile; least squares mean differences and 95% CIs were calculated. Similar analyses evaluated W24 patient-level response on minimum clinically important differences (MCID)., Results: At baseline, patients with high versus medium or low IL-6 levels (n = 100, respectively) reported worse (nominal p < 0.05) SF-36 MCS and role-physical, bodily pain, social functioning, role-emotional domain, and AM-stiffness VAS scores. There was a greater treatment effect with sarilumab versus adalimumab in high tertile versus low tertile groups in SF-36 PCS, physical functioning domain, and AM-stiffness VAS (nominal interaction p < 0.05). PCS improvements ≥MCID were higher in high (odds ratio [OR] 6.31 [2.37, 16.81]) versus low (OR 0.97 [0.43, 2.16]) tertiles with sarilumab versus adalimumab (nominal interaction p < 0.05). Adverse events between IL-6 tertiles were similar., Conclusions: Patients with high baseline IL-6 levels reported better improvements in PCS, physical functioning domain, and AM-stiffness scores with sarilumab versus adalimumab and safety consistent with IL-6R blockade., Trial Registration: NCT02332590 . Registered on 5 January 2015.

Objective: The development of biomarkers to guide treatment decisions is a major research focus in rheumatoid arthritis (RA). Patients with RA have elevated interleukin-6 (IL-6) levels; however, the utility of IL-6 as a predictor of treatment response is unclear. This study was undertaken to investigate, by post hoc analysis, whether baseline IL-6 levels are predictive of sarilumab treatment responses in 2 phase III studies., Methods: Serum IL-6 concentrations were measured in patients with RA prior to receiving sarilumab 200 mg (n = 148) or adalimumab 40 mg (n = 152) every 2 weeks (in the MONARCH trial; ClinicalTrials.gov identifier: NCT02332590) or sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks plus methotrexate (MTX) (n = 401, n = 396, and n = 397, respectively) (in the MOBILITY trial; ClinicalTrials.gov identifier: NCT01061736). Efficacy and patient-reported outcomes were compared between and within groups according to IL-6 tertile using linear and logistic regression., Results: In MONARCH, patients with high baseline IL-6 levels (all ≥3 times the upper limit of normal; n = 100) had higher disease activity at baseline than those with low IL-6 levels (n = 100). The magnitude of clinical improvement over 24 weeks with sarilumab versus adalimumab was greater in patients with high compared to those with low baseline IL-6 levels. In MOBILITY, compared to patients with low IL-6 levels (n = 397), patients with high IL-6 levels (n = 398) had higher disease activity and joint damage at baseline, were more likely to have joint progression, and had less clinical improvement over 52 weeks' treatment with placebo plus MTX compared to sarilumab 150 mg or 200 mg plus MTX. Baseline IL-6 and C-reactive protein levels were both predictive of outcomes. Safety profiles were similar between defined IL-6 tertiles., Conclusion: IL-6 may be a prognostic marker of disease progression and severity, and patients with high IL-6 levels may be likely to benefit from sarilumab compared to adalimumab or MTX. Prospective validation is warranted to confirm the results of these post hoc analyses., (© 2020 Regeneron Pharmaceuticals Inc. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Eliglustat is a first-line oral treatment for adults with Gaucher disease type 1 who have cytochrome P450 (CYP) 2D6 extensive, intermediate, or poor metabolizer phenotypes. Per International Conference on Harmonisation (ICH) E14 guidance, a Phase 1 thorough electrocardiographic (ECG) study was done during drug development to assess eliglustat's effects on cardiac repolarization by measuring ECG intervals in healthy adult subjects. Using data from the thorough ECG study, we performed pharmacokinetic/pharmacodynamic-ECG modeling to establish the relationship between eliglustat concentrations and their effects on ECG intervals. We then used that concentration-response relationship to predict the effects of eliglustat on each ECG interval for each CYP2D6 metabolizer phenotype (the main determinant of eliglustat exposure) and in different drug-drug interaction scenarios. These predictions, together with other exposure-related factors, contributed to the CYP2D6 phenotype-based dosing recommendations for eliglustat, including dose adjustments and contraindications when co-administered with drugs metabolized by the CYP2D6 and CYP3A pathways., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in the pathogenesis of rheumatoid arthritis. Sarilumab is a human monoclonal antibody that binds membrane-bound and soluble IL-6 receptor-α to inhibit IL-6 signalling. The aim of this study was to compare the effects of sarilumab and adalimumab (a tumour necrosis factor alpha inhibitor) monotherapy on levels of circulating biomarkers associated with the acute-phase response, bone remodelling, atherothrombosis, anaemia of chronic disease and markers purported to reflect synovial lymphoid and myeloid cell infiltrates, as well as the potential of these biomarkers to differentially predict clinical and patient-reported outcomes with sarilumab vs. adalimumab., Methods: In this post hoc analysis, serum samples were analysed at baseline and prespecified post-treatment timepoints up to week 24 in adults with moderate-to-severe active rheumatoid arthritis intolerant of or inadequate responders to methotrexate from the MONARCH trial (NCT02332590)., Results: Greater reductions in C-reactive protein (CRP; - 94.0% vs. -24.0%), serum amyloid A (SAA; - 83.2% vs. -17.4%), total receptor activator of nuclear factor-κB ligand (RANKL; - 18.3% vs. 10.5%) and lipoprotein (a) (- 41.0% vs. -2.8%) were observed at week 24 with sarilumab vs. adalimumab, respectively (adjusted p < 0.0001). Greater increases in procollagen type 1 N-terminal propeptide (P1NP) were observed with sarilumab vs. adalimumab at week 24 (22.8% vs. 6.2%, p = 0.027). Patients with high baseline SAA, CRP and matrix metalloproteinase-3 (MMP-3) were more likely to achieve clinical efficacy, including American College of Rheumatology 20% improvement criteria and Disease Activity Score (28 joints)-CRP < 3.2, and report improvements in patient-reported outcomes, including Health Assessment Questionnaire-Disability Index and pain visual analogue scale, with sarilumab than adalimumab., Conclusion: Sarilumab was associated with greater positive effects on bone remodelling and decreases in biomarkers of the acute-phase response, synovial inflammation and cardiovascular risk vs. adalimumab. High baseline concentrations of SAA, CRP and MMP-3 are predictive of clinical and patient-reported outcome responses to sarilumab treatment and prospective validation is warranted to confirm these results., Trial Registration: ClinicalTrials.gov, NCT02332590. Registered on 5 January 2015.

Background: The ongoing "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies (SPRINTT)" randomized controlled trial (RCT) is testing the efficacy of a multicomponent intervention in the prevention of mobility disability in older adults with physical frailty & sarcopenia (PF&S). Here, we describe the procedures followed for PF&S case finding and screening of candidate participants for the SPRINTT RCT. We also illustrate the main demographic and clinical characteristics of eligible screenees., Methods: The identification of PF&S was based on the co-occurrence of three defining elements: (1) reduced physical performance (defined as a score on the Short Physical Performance Battery between 3 and 9); (2) low muscle mass according to the criteria released by the Foundation for the National Institutes of Health; and (3) absence of mobility disability (defined as ability to complete the 400-m walk test in 15 min). SPRINTT was advertised through a variety of means. Site-specific case finding strategies were developed to accommodate the variability across centers in catchment area characteristics and access to the target population. A quick "participant profiling" questionnaire was devised to facilitate PF&S case finding., Results: During approximately 22 months, 12,358 prescreening interviews were completed in 17 SPRINTT sites resulting in 6710 clinic screening visits. Eventually, 1566 candidates were found to be eligible for participating in the SPRINTT RCT. Eligible screenees showed substantial physical function impairment and comorbidity burden. In most centers, project advertisement through mass media was the most rewarding case finding strategy., Conclusion: PF&S case finding in the community is a challenging, but feasible task. Although largely autonomous in daily life activities, older adults with PF&S suffer from significant functional impairment and comorbidity. This subset of the older population is therefore at high risk for disability and other negative health-related events. Key strategies to consider for successfully intercepting at-risk older adults should focus on mass communication methods., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Interleukin-6 (IL-6) orchestrates formation of an inflammatory pannus, leading to joint damage in rheumatoid arthritis (RA). Sarilumab is a human monoclonal antibody blocking the IL-6Rα. In TARGET (NCT01709578), a phase 3 study in adults with moderate-to-severe RA and inadequate response or intolerance to tumour necrosis factor inhibitors, subcutaneous sarilumab 200 mg or 150 mg every 2 weeks (q2w) plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) significantly reduced disease activity versus placebo plus csDMARDs., Methods: Circulating levels of biomarkers associated with synovial inflammation (matrix metalloproteinase 3 (MMP-3), collagen type I MMP-cleaved fragment (C1M), collagen type III MMP-cleaved fragment (C3M)), myeloid (soluble intercellular adhesion molecule 1 (sICAM-1), IL-8 and calprotectin) and lymphoid activation (chemokine, CXC motif, ligand 13 (CXCL13), CXCL10, B cell-activating factor) and bone remodelling (receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin and osteocalcin) were evaluated in patients from a TARGET substudy., Results: Sarilumab significantly decreased C1M, C3M, CXCL13, MMP-3 and total RANKL levels at week 24 versus placebo; some markers were significantly suppressed at week 2 and normalised to levels in healthy controls. Levels of sICAM-1 were predictive of disease activity score by C-reactive protein and clinical disease activity index low disease activity (LDA) response in the sarilumab 200 mg q2w group at week 12. A trend was observed in which patients with lower sICAM-1 levels at baseline had better response compared with patients with higher sICAM-1., Conclusions: Sarilumab plus csDMARDs decreased circulating biomarkers of synovial inflammation and bone resorption; sICAM-1 was predictive of achieving LDA with sarilumab., Trial Registration Number: NCT01709578; Post-results., Competing Interests: Competing interests: CG has received consulting fees from Roche, Merck, AbbVie, Pfizer, Bristol-Myers Squibb, Sanofi and AB2 Bio. JM, MZ and CP are employees of Sanofi R&D and may hold stock and/or stock options in the company. YL is an employee of Sanofi Genzyme and may hold stock and/or stock options in the company. NMHG and AB are employees of Regeneron Pharmaceuticals, Inc, and may hold stock and/or stock options in the company.

This article describes how a frequentist model averaging approach can be used for concentration-QT analyses in the context of thorough QTc studies. Based on simulations, we have concluded that starting from three candidate model families (linear, exponential, and Emax) the model averaging approach leads to treatment effect estimates that are quite robust with respect to the control of the type I error in nearly all simulated scenarios; in particular, with the model averaging approach, the type I error appears less sensitive to model misspecification than the widely used linear model. We noticed also few differences in terms of performance between the model averaging approach and the more classical model selection approach, but we believe that, despite both can be recommended in practice, the model averaging approach can be more appealing because of some deficiencies of model selection approach pointed out in the literature. We think that a model averaging or model selection approach should be systematically considered for conducting concentration-QT analyses. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Interleukin 6 (IL-6) signaling plays a key role in the pathophysiology of rheumatoid arthritis (RA) and is inhibited by sarilumab, a human monoclonal antibody blocking the IL-6 receptor alpha (IL-6Rα). The effects of sarilumab plus methotrexate (MTX) on serum biomarkers of joint damage and bone resorption were assessed in two independent studies (phase II (part A) and phase III (part B)) of patients with RA with a history of inadequate response to MTX from the MOBILITY study (NCT01061736)., Methods: Serum samples were analyzed at baseline and prespecified posttreatment time points. Biomarkers of tissue destruction, cartilage degradation, and synovial inflammation were measured in part A; assessment of these markers was repeated in part B and included additional analysis of biomarkers of bone formation and resorption (including soluble receptor activator of nuclear factor-kB ligand (sRANKL)). A mixed model for repeated measures was used to compare treatment effects on change in biomarkers. Additionally, changes from baseline in biomarkers were compared between American College of Rheumatology 50 % responders and nonresponders and between patients who achieved or did not achieve low disease activity (LDA), separately by treatment group, at week 24., Results: In part A, sarilumab 150 and 200 mg every 2 weeks (q2w) significantly reduced biomarkers of tissue destruction, cartilage degradation, and synovial inflammation at both 2 and 12 weeks posttreatment (p < 0.05 vs placebo). These results were replicated in part B, with markers of these damaging processes reduced at weeks 2 and 24 (p < 0.05 vs placebo). Additionally, sarilumab 200 mg q2w significantly reduced both sRANKL and sRANKL/osteoprotegerin ratio at week 24 (p < 0.01 vs placebo). Trends for reduction were noted for several biomarkers in patients who achieved LDA compared with those who did not., Conclusions: Sarilumab plus MTX significantly suppressed biomarkers of bone resorption and joint damage, as compared with placebo plus MTX, in patients with RA. Additional work is needed to determine whether differences in biomarker profiles at baseline or posttreatment can identify patients who achieve improvement in disease activity., Trial Registration: ClinicalTrials.gov, NCT01061736 , February 2, 2010.

Our aim in this study was to examine the relationship between regular exercise and major cardiovascular events in hypertensive elderly with established coronary heart disease (CHD) in the primary care setting. The PREHACOR study recruited 3193 hypertensive patients, aged 74 +/- 6 years, 67% male, with CHD. Regular exercise assessed by questionnaire was defined as recreational activity >20 min/day, >3 times/week. Endpoints at 6 months were new cardiovascular events (NCEs: myocardial infarction and hospitalization for stroke, unstable angina, congestive heart failure, or coronary revascularization). New cardiovascular events occurred in 376 patients (11.8%), with 17 deaths (0.5%). New cardiovascular events patients were older, with higher body mass index, and were more likely to have diabetes, arrhythmia, history of congestive heart failure, and noncardiac organ damage than non-NCE patients. Blood pressure was significantly and similarly reduced in both groups. Multivariate logistic regression associated NCEs positively and independently with a history of congestive heart failure (odds ratio [OR] 2.50; confidence interval [CI] = 1.9-3.23), noncardiac target organ damage (OR 1.51; CI = 1.20-1.90), and beta-blocker use (OR 1.28; CI = 1.02-1.59), and inversely and independently with combination low-dose angiotensin converting enzyme inhibitor + diuretic therapy (OR 0.66; CI = 0.45-0.95) and regular exercise (OR 0.70; CI = 0.54-0.90). Regular exercise is significantly associated with fewer major cardiovascular events in hypertensive elderly subjects with established CHD.