Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomised, double-blind, multicentre phase 3 trial.

BACKGROUND: Phase 3 trials have assessed efficacy of abrocitinib versus placebo in moderate-to-severe atopic dermatitis, a common immunoinflammatory skin disease. This study assessed the efficacy and safety of abrocitinib versus dupilumab. METHODS: This randomised, double-blind, double-dummy, active-controlled, parallel-treatment, phase 3 trial enrolled adults with moderate-to-severe atopic dermatitis who requir=ed systemic therapy or had inadequate response to topical medications. Participants were enrolled from 151 sites, located in Australia, Bulgaria, Canada, Chile, Finland, Germany, Hungary, Italy, Latvia, Poland, Slovakia, South Korea, Spain, Taiwan, and the USA. These participants were then randomly assigned (1:1) with block randomisation to receive oral abrocitinib (200 mg per day) or subcutaneous dupilumab (300 mg every 2 weeks) for 26 weeks. Participants were required to apply topical corticosteroids (medium or low potency), topical calcineurin inhibitors, or a topical phosphodiesterase 4 inhibitor to active lesion areas. Primary endpoints were response based on achieving a 4 point or higher improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) at week 2 and a 90% or better improvement in Eczema Area and Severity Index (EASI-90) at week 4. Family-wise type 1 error was controlled via a sequential multiple-testing procedure (two sided, α=0·05). Randomly assigned participants who received at least one dose of study intervention were included in the efficacy and safety analysis sets. This trial was completed on July 13, 2021 (NCT04345367). FINDINGS: Between June 11, 2020, and Dec 16, 2020, 940 patients were screened and 727 were enrolled (362 in the abrocitinib group and 365 in the dupilumab group). Compared with dupilumab, a larger proportion of patients treated with abrocitinib reached the primary outcomes, PP-NRS4 at week 2 (172 [48%] of 357, 95% CI 43·0-53·4 vs 93 [26%] of 364, 21·1-30·0; difference 22·6%, 15·8-29·5; p<0·0001), and EASI-90 at week 4 (101 [29%] of 354, 23·8-33·2 vs 53 [15%] of 364, 10·9-18·2; difference 14·1%, 8·2-20·0; p<0·0001). Treatment-emergent adverse events were reported by 268 (74%) of 362 patients treated with abrocitinib and by 239 (65%) of 365 patients treated with dupilumab. Two non-treatment-related deaths occurred in the abrocitinib group. INTERPRETATION: Abrocitinib 200 mg per day was more efficacious than dupilumab in adults with moderate-to-severe atopic dermatitis on background topical therapy in inducing early reductions of itch and atopic dermatitis disease signs. Both treatments were well tolerated over 26 weeks. FUNDING: Pfizer.

Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis. METHODS: This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment [IGA] score 3-4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to <15 kg: 200 mg; bodyweight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0-1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434. FINDINGS: Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0-1 (23 [28%] vs three [4%], difference 24% [95% CI 13-34]; p<0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29-55]; p<0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation. INTERPRETATION: Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults. FUNDING: Sanofi and Regeneron Pharmaceuticals.

Real-world severe asthma biologic administration and adherence differs by biologic: CHRONICLE study results.

BACKGROUND: Patient adherence to biologic therapies is crucial for clinical benefits. Previous assessments of US patient adherence to severe asthma (SA) biologic therapies have relied on health care insurance claims data that have limitations. OBJECTIVE: To describe real-world, specialist-reported, biologic administration and adherence among US adults with SA. METHODS: CHRONICLE (ClinicalTrials.gov identifier: NCT03373045) is an ongoing real-world, noninterventional study of patients with SA treated by US subspecialists. Sites report date and location for all biologic administrations. We evaluated biologic (benralizumab, dupilumab, mepolizumab, omalizumab, reslizumab) adherence as the proportion of days covered (PDC) during the first 52 weeks and the mean number of days until patients received the expected number of doses for 13, 26, and 52 weeks of treatment. RESULTS: A total of 2117 patients received biologic administrations between February 2018 and February 2022. Most patients (84%) received biologic administrations at a subspecialist site. Over time, administrations at specialist sites decreased, whereas at-home administrations increased. The median PDC was 87%; the mean number of days to receive a 52-week (364-day) equivalent number of doses was 423 for all biologics (average delay of 58 days). Dupilumab had the lowest PDC and highest mean delays in dosing across all intervals; better adherence was observed among commercially insured patients. CONCLUSION: Patients with SA are mostly adherent to biologic therapies. Biologics with shorter dosing intervals and at-home administration had worse adherence, likely because of greater opportunities for delays. Specialist-reported administration data provide a unique perspective on biologic adherence, which may be overestimated for at-home administrations by insurance claims data. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03373045.

Number of patient-reported asthma triggers predicts uncontrolled disease among specialist-treated patients with severe asthma.

BACKGROUND: Patients with severe asthma (SA) experience a high disease burden, often precipitated by exposure to disease triggers. OBJECTIVE: To evaluate the prevalence and effects of patient-reported triggers on asthma disease burden in a cohort of subspecialist-treated patients with SA in the United States. METHODS: CHRONICLE is an observational study of adults with SA receiving biologics or maintenance systemic corticosteroids or whose disease is uncontrolled on high-dosage inhaled corticosteroids and additional controllers. Data were analyzed for patients enrolled between February 2018 and February 2021. This analysis evaluated patient-reported triggers from a 17-category survey and associations with multiple measures of disease burden. RESULTS: Among 2793 enrolled patients, 1434 (51%) completed the trigger questionnaire. The median trigger number per patient was 8 (interquartile range, 5-10). The most frequent triggers were weather or air changes, viral infections, seasonal allergies, perennial allergies, and exercise. Patients reporting more triggers experienced more poorly controlled disease, worse quality of life, and reduced work productivity. The annualized rates of exacerbations and asthma hospitalizations increased by 7% and 17%, respectively, for each additional trigger (both P < .001). For all measures, trigger number was a stronger predictor of disease burden than blood eosinophil count. CONCLUSION: Among US specialist-treated patients with SA, asthma trigger number was positively and significantly associated with greater uncontrolled disease burden across multiple measures, which highlights the importance of understanding patient-reported triggers in SA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Phase 2 randomized clinical trial of astegolimab in patients with moderate to severe atopic dermatitis.

BACKGROUND: The binding of IL-33 to its receptor ST2 (alias of IL1RL1) leads to the release of inflammatory mediators and may play a role in the pathogenesis of atopic dermatitis. Astegolimab is a fully human, IgG2 mAb that binds to ST2 and inhibits IL-33 signaling. OBJECTIVES: This study sought to assess the efficacy, safety, and pharmacokinetics of astegolimab in patients with atopic dermatitis. METHODS: This was a randomized, placebo-controlled, phase 2 study in which adults with chronic atopic dermatitis were randomized 1:1 to receive astegolimab 490 mg every 4 weeks or placebo, for 16 weeks. The primary outcome was the percentage of change from baseline to week 16 of the Eczema Area and Severity Index score. RESULTS: A total of 65 patients were enrolled in the study (placebo, n = 32; astegolimab, n = 33). The adjusted mean percentage of change from baseline to week 16 in the Eczema Area and Severity Index score was -51.47% for astegolimab compared with -58.24% for placebo, with a nonsignificant treatment difference of 6.77% (95% CI: -16.57-30.11; P = .5624). No differences were observed between treatment groups for secondary efficacy outcomes and in exploratory biomarkers (blood eosinophils, serum IL-5, serum CCL13). With the use of loading dose, pharmacokinetic exposure was sufficient from week 1. Astegolimab was well-tolerated, with a safety profile consistent with that observed in previous clinical trials. CONCLUSIONS: In patients with atopic dermatitis, astegolimab did not show a significant difference compared to placebo for the primary or secondary outcomes.

Upadacitinib plus topical corticosteroids in atopic dermatitis: Week 52 AD Up study results.

BACKGROUND: Primary (week 16) results from the ongoing phase 3, double-blind AD Up study (NCT03568318) demonstrate a positive benefit-risk profile for upadacitinib + topical corticosteroid (TCS) in patients with moderate-to-severe atopic dermatitis. OBJECTIVE: We evaluated the efficacy and safety of upadacitinib + TCS through 52 weeks. METHODS: Patients aged 12 to 75 years with chronic moderate-to-severe atopic dermatitis (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] ≥16, Validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] ≥3, and Worst Pruritus Numerical Rating Scale [WP-NRS] score ≥4) were randomized 1:1:1 to once-daily upadacitinib 15 mg + TCS, upadacitinib 30 mg + TCS, or placebo (PBO) + TCS (rerandomized at week 16 to upadacitinib + TCS). Safety and efficacy, including proportion of patients experiencing ≥75% improvement in EASI (EASI-75), vIGA-AD of clear/almost clear with improvement ≥2 grades (vIGA-AD 0/1), and WP-NRS improvement ≥4, were assessed through week 52. Missing data were primarily handled by nonresponse imputation incorporating multiple imputation for missing values due to coronavirus disease 2019 (COVID-19). RESULTS: Of 901 patients, 300 were randomized to upadacitinib 15 mg + TCS, 297 to upadacitinib 30 mg + TCS, and 304 to PBO + TCS. For all end points, efficacy for upadacitinib 15 mg + TCS and upadacitinib 30 mg + TCS at week 16 was maintained through week 52. At week 52, the proportions of patients treated with upadacitinib 15 mg + TCS and upadacitinib 30 mg + TCS who experienced EASI-75 were 50.8% and 69.0%, respectively; 33.5% and 45.2%, respectively, experienced vIGA-AD 0/1; and 45.3% and 57.5%, respectively, experienced WP-NRS improvement ≥4. Upadacitinib + TCS was well tolerated through 52 weeks; no new important safety risks beyond the current label were observed. No deaths were reported; major adverse cardiovascular events and venous thromboembolic events were infrequent (≤0.2/100 patient-years). CONCLUSIONS: Results through 52 weeks demonstrate long-term maintenance of efficacy and a favorable safety profile of upadacitinib + TCS in patients with moderate-to-severe AD.

Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting. FINDINGS: Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group. INTERPRETATION: Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis. FUNDING: AbbVie.

Sustained safety and efficacy of ligelizumab in patients with chronic spontaneous urticaria: A one-year extension study.

BACKGROUND: Ligelizumab, a next-generation, humanized anti-immunoglobulin E (IgE) monoclonal antibody is in development as a treatment for patients with chronic spontaneous urticaria, whose symptoms are inadequately controlled with standard-of-care therapy. OBJECTIVE: To evaluate the long-term safety and re-treatment efficacy of ligelizumab 240 mg in patients who completed the core study and extension study. METHODS: This open-label, single-arm, long-term Phase 2b extension study was designed to assess patients who were previously administered various doses of ligelizumab, omalizumab or placebo in the Phase 2b, dose-finding core study and who presented with active disease after Week 32. In the extension study, patients received ligelizumab 240 mg subcutaneously every 4 weeks, for 52 weeks and were monitored post-treatment for 48 weeks. RESULTS: Overall, ligelizumab was well-tolerated with no newly identified safety signals. A total of 95.4% (226/237) screened patients received ligelizumab 240 mg in the extension study; 84.1% (190/226) of patients experienced at least one treatment-emergent adverse event. Most reported events were mild (41.6%) or moderate (35.8%) and mostly unrelated to the study treatment. At Week 12, 46.5% of patients had a complete response increasing to 53.1% after 52 weeks. Following 52 weeks of extension study treatment, 75.8% (95% confidence interval, 69.9, 81.3) of patients had cumulative complete responses. The median time to relapse in complete responders was 38 weeks. CONCLUSION: The long-term safety profile of ligelizumab 240 mg in patients with chronic spontaneous urticaria was consistent with the core study and re-treatment efficacy was shown. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02477332 and NCT02649218.

Patient-oriented measures for phase 3 studies of tralokinumab for the treatment of atopic dermatitis (ECZTRA 1, 2, and 3).

BACKGROUND: Tralokinumab, as monotherapy or in combination with topical corticosteroids (TCS), has exhibited marked efficacy through 52 weeks in phase 3 trials of adults with moderate-to-severe atopic dermatitis and additional efficacy in a long-term extension trial. Early changes in patient-reported symptoms have not been communicated. OBJECTIVE: To evaluate early changes in patient-reported outcomes (PROs) across the ECZTRA 1, 2, and 3 tralokinumab trials. METHODS: Monotherapy data (ECZTRA 1 + 2) was pooled; ECZTRA 3 evaluated tralokinumab plus optional TCS. The PROs were assessed through the trials. RESULTS: A total of 1596 and 380 patients were randomized in ECZTRA 1 and 2 and ECZTRA 3, respectively. Baseline demographics and clinical characteristics were similar between groups. Early separation from placebo was observed in percentage improvement in worst average daily pruritus numerical rating score (NRS) (week 1, ECZTRA 1 + 2; week 2, ECZTRA 3) and from day 2 in ECZTRA 1 and 2 daily data. More tralokinumab-treated patients achieved clinically meaningful improvements (≥ 4 points) in NRS by week 2 (ECZTRA 1 + 2) or week 3 (ECZTRA 3) vs placebo. Improvements in eczema-related sleep NRS were seen within 2 weeks (week 1, ECZTRA 1 + 2; week 2, ECZTRA 3), supported by similar improvements in other sleep measures. Meaningful changes in Dermatology Life Quality Index were observed from week 2 (ECZTRA 1 + 2). Results were supported by numerical differences from placebo in Patient-Oriented Eczema Measure total score (week 2, both data sets). CONCLUSION: Tralokinumab with or without TCS exhibited early and clinically meaningful improvements vs placebo in several PROs, which may be beneficial to patients because atopic dermatitis symptom relief is a key treatment concern for patients.

Biologic use and outcomes among adults with severe asthma treated by US subspecialists.

BACKGROUND: Multiple biologics are now available for severe asthma (SA) treatment and can improve outcomes for patients. However, few available data describe the real-world use and effectiveness of multiple approved biologics, including biologic switching, among subspecialists in the United States. OBJECTIVE: To evaluate biologic use and associated exacerbation outcomes in a large cohort of subspecialist-treated US adults with SA. METHODS: CHRONICLE is an ongoing, noninterventional study of subspecialist-treated US adults with SA receiving biologics, maintenance systemic corticosteroids, or those persistently uncontrolled by high-dose inhaled corticosteroids with additional controllers. For enrolled patients, sites report asthma exacerbations and medication use starting 12 months before enrollment. For patients enrolled between February 2018 and February 2021, biologic use and exacerbation outcomes before and after biologic initiation are described. RESULTS: Among 2793 enrolled patients, 66% (n = 1832) were receiving biologics. The most used biologic (> 1 biologic use per patient allowed) was omalizumab (47%), followed by benralizumab (27%), mepolizumab (26%), dupilumab (18%), and reslizumab (3%). Overall, 16% of patients had biologic switches, 13% had stops, and 89% had ongoing biologic use. Patients starting and switching biologics experienced a 58% (1.80 vs 0.76 per patient-year) and 49% (1.47 vs 0.75 per patient-year) reduction in exacerbations, respectively (both P < .001), with a numerically greater reduction observed among those starting non-anti-immunoglobulin E biologics compared with anti-immunoglobulin E. CONCLUSION: Real-world starting and switching of biologic therapies for SA were associated with meaningful reductions in exacerbations. With increasing biologic options available, individualized approaches to therapy may improve patient outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03373045.

Differing perceptions of asthma control and treatment effectiveness by patients with severe asthma and treating subspecialists in the United States.

OBJECTIVE: For patients with severe asthma (SA), overestimation of asthma control may lead to poorer outcomes. The objective of this study was to assess concurrent patient and specialist assessments of asthma control and treatment effectiveness among a large US cohort of SA patients. METHODS: CHRONICLE is an ongoing observational study of patients with SA treated by US subspecialists. Asthma control was assessed using the patient-completed Asthma Control Test™ (ACT™) and specialist clinical assessment of control. Treatment effectiveness was measured using the Global Evaluation of Treatment Effectiveness (GETE) completed by patients and specialists. RESULTS: 1109 patients who completed online surveys at enrollment were included. 14%, 28%, 25%, and 33% of patients had ACT™ scores of 5-9, 10-15, 16-19, and 20-25, respectively. Compared with 67% of patients with uncontrolled asthma by ACT™, 44% were uncontrolled by specialist assessment. 54% of patients who were uncontrolled according to the ACT™ were rated as controlled by specialists, demonstrating overestimation of asthma control. Based on ACT™ score, asthma control was more frequent among patients treated with biologics compared to other treatments. Using the GETE, 90% of patients reported treatment effectiveness compared with 71% of specialists. Patient and specialist treatment effectiveness categorizations agreed 73% of the time. CONCLUSION: Specialists commonly overestimated asthma control relative to ACT™ scores. Patients reported treatment effectiveness more frequently than specialists. These findings emphasize the importance of validated instruments to assess asthma control and reduce potential treatment gaps associated with patient-specialist discordance. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial.

BACKGROUND: The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. OBJECTIVES: This study evaluated astegolimab efficacy and safety in patients with severe asthma. METHODS: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/µL) and ∼95 patients who were eosinophil-low (<300 cells/µL) per arm. RESULTS: Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups. CONCLUSIONS: Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.

Omalizumab response in patients with asthma by number and type of allergen.

BACKGROUND: The anti-immunoglobulin E therapy, omalizumab, improves asthma control and reduces exacerbations in patients with moderate-to-severe allergic asthma. However, it has been suggested that omalizumab should be reserved for highly allergic patients with multiple allergen sensitivities or perennial-only sensitivities. OBJECTIVE: To examine impact of allergy burden, including number and type of allergen sensitivities, on omalizumab response in a real-world setting. METHODS: This post hoc analysis evaluated a subset of omalizumab-treated patients from the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (NCT01922037) who had completed 13 allergen assessments (N=478). Patients were classified by allergen burden (nonsensitized, 1, 2-4, or ≥5 allergen sensitivities) and type of allergen (nonsensitized, seasonal, perennial, or both). Outcome measures included exacerbation rate vs previous year and improvements in lung function and Asthma Quality of Life Questionnaire (AQLQ). RESULTS: Comparable adjusted exacerbation rates were observed after omalizumab initiation, regardless of number or type of allergen sensitizations (0.56-0.85/y). Improvements in forced expiratory volume in 1 second from baseline at months 6 (0.03-0.09 L) and 12 (-0.08 to 0.08 L) were also similar across subgroups. Least squares mean change in AQLQ from baseline at months 6 (1.0-1.2) and 12 (1.1-1.4) was comparable across patient subgroups, and similar percentages of patients achieved AQLQ minimal clinically important difference of at least a 0.5-point improvement at month 6 (71%-75%), which was maintained or improved to month 12 (71%-89%). In all analyses, 95% confidence intervals overlapped. CONCLUSION: Overall findings suggest that patients with allergic asthma achieved comparable improvements across distinct outcome measures after omalizumab therapy in a real-world setting, regardless of number and type of allergen sensitizations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01922037.

Severe asthma exacerbations in the United States:: Incidence, characteristics, predictors, and effects of biologic treatments.

BACKGROUND: Patients with severe asthma (SA) have a heightened risk of exacerbations including hospitalization. The real-world, specialist-verified incidence and characteristics of exacerbations among patients with SA in the United States have not been described. OBJECTIVE: To describe the real-world incidence, characteristics, and predictors of exacerbations among patients with SA in the United States. METHODS: The CHRONICLE study is an ongoing observational study of specialist-treated adults with SA in the United States receiving biologic treatment or maintenance systemic corticosteroids or uncontrolled by high-dosage inhaled corticosteroids with additional controllers. For patients enrolled from February 2018 to February 2020, annualized rates and characteristics of exacerbation-related events were summarized by treatment category for 12 months before enrollment and after enrollment through the latest data collection. Results were further analyzed for subgroups of interest. RESULTS: Among 1884 enrolled patients, 53.5% and 12.3% experienced an exacerbation and asthma hospitalization, respectively (0.81 and 0.14 per person-year). Of all exacerbations, 36%, 9%, and 15% required an unscheduled health care provider visit, emergency department visit without hospitalization, and hospitalization, respectively. Among patients not receiving biologics or systemic corticosteroids, higher blood eosinophil count, higher fractional exhaled nitric oxide, and lower total immunoglobulin E level were associated with higher exacerbation rates. Exacerbation rates decreased after starting or switching biologics (n = 1299). Multivariate analyses of enrolled patients revealed previous-year exacerbations or hospitalizations, lack of asthma control, and the geographic region also predicted event risk. CONCLUSION: In this real-world cohort of specialist-treated adults with SA in the United States, there was a substantial burden of exacerbations and associated health care resource utilization. Patients receiving biologics had a lower exacerbation burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Biologic and maintenance systemic corticosteroid therapy among US subspecialist-treated patients with severe asthma.

BACKGROUND: Severe asthma (SA) often requires subspecialist management and treatment with biologic therapies or maintenance systemic corticosteroids (mSCS). OBJECTIVE: To describe contemporary, real-world biologic and mSCS use among US subspecialist-treated patients with SA. METHODS: CHRONICLE is an ongoing, noninterventional study of US adults with SA treated by allergists/immunologists or pulmonologists. Eligible patients are receiving biologics or mSCS or are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Biologic and mSCS use patterns and patient characteristics were summarized for patients enrolled between February 2018 and February 2019. RESULTS: Among protocol-eligible patients, 58% and 12% were receiving biologics and mSCS, respectively, with 7% receiving both. Among 796 enrolled, most were women (67%), non-Hispanic white (71%), of suburban residence (50%), and had elevated body mass index (median: 31). Respiratory and nonrespiratory comorbidities were highly prevalent. With biologics (n = 557), 51% were anti-immunoglobulin E and 48% were anti-interleukin (IL)-5/IL-5Rα; from May 2018, 76% of initiations were anti-IL-5/IL-5Rα. In patients receiving mSCS, median prednisone-equivalent daily dose was 10 mg. Multivariate logistic regression found that patients of hospital clinics, sites with fewer nonphysician staff, and with a recorded concurrent chronic obstructive pulmonary disease diagnosis were less likely to receive biologics and more likely to receive mSCS. CONCLUSION: In this real-world sample of US subspecialist-treated patients with SA not controlled by high-dosage inhaled corticosteroids with additional controllers, mSCS use was infrequent and biologic use was common, with similar prevalence of anti-immunoglobulin E and anti-IL-5/IL-5Rα biologics. Treatment differences associated with patient and site characteristics should be investigated to ensure equitable access to biologics and minimize mSCS use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study.

BACKGROUND: Significant unmet need exists for long-term treatment of moderate to severe atopic dermatitis (AD). OBJECTIVE: To assess the long-term safety and efficacy of dupilumab in patients with AD. METHODS: This ongoing, multicenter, open-label extension study (NCT01949311) evaluated long-term dupilumab treatment in adults who had previously participated in phase 1 through 3 clinical trials of dupilumab for AD. This analysis examined patients given 300 mg dupilumab weekly for up to 76 weeks at data cutoff (April 2016). Safety was the primary outcome; efficacy was also evaluated. RESULTS: Of 1491 enrolled patients (1042.9 patient-years), 92.9% were receiving treatment at cutoff. The safety profile was consistent with previously reported trials (420.4 adverse events/100 patient-years and 8.5 serious adverse events/100 patient-years), with no new safety signals; common adverse events included nasopharyngitis, conjunctivitis, and injection-site reactions. Sustained improvement was seen up to 76 weeks in all efficacy outcomes, including measures of skin inflammation, pruritus, and quality of life. LIMITATIONS: Lack of control arm, limited number of patients with 76 weeks or longer of treatment (median follow-up, 24 weeks), and patients not receiving the approved dose regimen of 300 mg every 2 weeks. CONCLUSION: The safety and efficacy profile from this study supports the role of dupilumab as continuous long-term treatment for patients with moderate to severe AD.

Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.

BACKGROUND: Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. METHODS: In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. FINDINGS: Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (-74% [SE 5·16]), 300 mg every 2 weeks (-68% [5·12]), 200 mg every 2 weeks (-65% [5·19]), 300 mg every 4 weeks (-64% [4·94]), 100 mg every 4 weeks (-45% [4·99]); placebo (-18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). INTERPRETATION: Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. FUNDING: Sanofi and Regeneron Pharmaceuticals.

A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma.

BACKGROUND: Quilizumab, a humanized IgG1 monoclonal antibody, targets the M1-prime segment of membrane-expressed IgE, leading to depletion of IgE-switched and memory B cells. In patients with mild asthma, quilizumab reduced serum IgE and attenuated the early and late asthmatic reaction following whole lung allergen challenge. This study evaluated the efficacy and safety of quilizumab in adults with allergic asthma, inadequately controlled despite high-dose inhaled corticosteroids (ICS) and a second controller. METHODS: Five hundred seventy-eight patients were randomized to monthly or quarterly dosing regimens of subcutaneous quilizumab or placebo for 36 weeks, with a 48-week safety follow-up. Quilizumab was evaluated for effects on the rate of asthma exacerbations, lung function, patient symptoms, serum IgE, and pharmacokinetics. Exploratory analyses were conducted on biomarker subgroups (periostin, blood eosinophils, serum IgE, and exhaled nitric oxide). RESULTS: Quilizumab was well tolerated and reduced serum total and allergen-specific IgE by 30-40 %, but had no impact on asthma exacerbations, lung function, or patient-reported symptom measures. At Week 36, the 300 mg monthly quilizumab group showed a 19.6 % reduction (p = 0.38) in the asthma exacerbation rate relative to placebo, but this was neither statistically nor clinically significant. Biomarker subgroups did not reveal meaningful efficacy benefits following quilizumab treatment. CONCLUSIONS: Quilizumab had an acceptable safety profile and reduced serum IgE. However, targeting the IgE pathway via depletion of IgE-switched and memory B cells was not sufficient for a clinically meaningful benefit for adults with allergic asthma uncontrolled by standard therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01582503.

Dupilumab therapy provides clinically meaningful improvement in patient-reported outcomes (PROs): A phase IIb, randomized, placebo-controlled, clinical trial in adult patients with moderate to severe atopic dermatitis (AD).

BACKGROUND: Moderate to severe atopic dermatitis (AD) is associated with substantial patient burden despite current therapies. OBJECTIVE: We sought to evaluate dupilumab treatment on patient-reported outcomes in adults with moderate to severe AD. METHODS: Adults (N = 380) with moderate to severe AD inadequately controlled by topical medications were randomized to 16 weeks of double-blind, subcutaneous treatment with dupilumab 100 mg every 4 weeks, 200 mg every 2 weeks, 300 mg every 2 weeks, 300 mg once weekly, or placebo. Patient-reported outcomes included pruritus numeric rating scale; patient-reported sleep item on Scoring AD scale; Patient-Oriented Eczema Measure; Hospital Anxiety and Depression Scale; Dermatology Life Quality Index; and 5-dimension 3-level EuroQol. RESULTS: Dupilumab reduced peak itch at 16 weeks relative to placebo by 1.1 to 3.2 points on numeric rating scale (P < .0001 all doses, except 100 mg every 4 weeks P < .05); improved sleep and health-related quality of life on Dermatology Life Quality Index and 5-dimension 3-level EuroQol (P < .05 all doses, except 100 mg every 4 weeks); and reduced anxiety and depression symptoms (P < .05 all doses). Dupilumab's effects appeared early and achieved clinically relevant improvements without significant safety concerns. LIMITATIONS: There are potential cultural differences affecting patient-reported outcome responses. Outcomes were secondary or exploratory end points. CONCLUSION: Dupilumab produced early and sustained patient-reported and clinically relevant improvements in sleep, mental health, and health-related quality of life; the two 300-mg dose regimens resulted in greatest benefits.

Quality of Life Improvements with Biologic Initiation Among Subspecialist-Treated US Patients with Severe Asthma.

Purpose: Patients living with severe asthma (SA) experience multiple health-related quality of life (HRQoL) impairments. This study examined HRQoL changes after biologic treatment initiation among a large, real-world cohort of patients with SA. Patients and methods: CHRONICLE is an ongoing observational study of subspecialist-treated adults with SA who receive biologics or maintenance systemic corticosteroids or are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Patients enrolled February 2018-February 2023 were asked to complete the St. George's Respiratory Questionnaire (SGRQ) every 6 months (total score range of 0-100 [0=best possible health], meaningful change threshold is a 4-unit reduction in the total score). Changes in SGRQ responses from 6 months before initiation to 12 to 18 months after initiation were summarized. Results: A total of 76 patients completed the SGRQ 0 to 6 months before and 12 to 18 months after biologic initiation. The mean (SD) SGRQ total score decreased from 52.2 (20.6) to 41.9 (23.8), with improvement across the symptoms (-14.5), activity (-11.0), and impacts (-8.3) components. For specific impairments reported by ≥50% of patients before biologic initiation, fewer reported each impairment after biologic initiation; the largest reductions were for "Questions about what activities usually make you feel short of breath these days [Walking outside on level ground]" (67% to 43%), "Questions about other effects that your respiratory problems may have on you these days [I feel that I am not in control of my respiratory problems]" (55% to 34%), and "Questions about your cough and shortness of breath these days [My coughing or breathing disturbs my sleep]" (63% to 45%). Conclusion: In this real-world cohort of adults with SA, biologic initiation was associated with meaningful improvements in asthma-related HRQoL. These data provide further insight into the burden SA places on patients and the benefits of biologic treatment.