IntroductionMultiple biologic therapies are available for patients with severe asthma (SA) in the United States (US). The objective of this analysis was to describe trends in biologic initiation and switching among patients with SA.MethodsCHRONICLE is an ongoing, real-world, observational study of adults with SA receiving biologics, maintenance systemic corticosteroids, or uncontrolled on high-dosage inhaled corticosteroids with additional controllers. For patients enrolled between February 2018 and February 2023, biologic initiation and switching were described by time interval based on biologic approval dates. Switches were defined as stopping 1 biologic and starting a different biologic within 6 months.ResultsAmong 3574 enrolled patients, 2687 (73%) patients had any biologic use during the study period. From October 2018 through December 2021, dupilumab (32%) and benralizumab (27%) were most frequently initiated; from December 2021 through February 2023, dupilumab (32%) and tezepelumab (27%) were most frequently initiated (Figure). Overall, 531 (20%) patients had 680 biologic switches. Any switch was reported for 12.5% of patients from November 2017 to October 2018, 23.9% from October 2018 to December 2021, and 31.8% from December 2021 onward. In the most recent interval, there were 75 switches; the most frequent switches were to tezepelumab (45% of switches) and dupilumab (36% of switches).ConclusionBiologic initiations and switching frequency among patients with SA in the US have changed over time as new biologic therapies have been approved. In the most recent time interval, tezepelumab and dupilumab were the most commonly initiated biologics.

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.

IntroductionEosinophils are an important biomarker of type-2 inflammation in asthma. There are limited contemporary real-world data describing the effects of anti-IgE and anti–IL-4R biologics on blood eosinophil counts (BEC), relative to anti–IL-5/5R biologics. This analysis describes BEC before and after initiation of individual biologics in a real-world cohort of patients with severe asthma (SA).MethodsCHRONICLE is an ongoing, real-world, observational study of adults with SA receiving biologics, maintenance systemic corticosteroids, or uncontrolled on high-dosage inhaled corticosteroids with additional controllers. For patients enrolled between February 2018 and February 2023, we summarized means and medians of each patient's highest BECs collected before and 2–12 and ≥12 months after patients initiated omalizumab, mepolizumab, benralizumab, or dupilumab using a self-controlled analysis of those with BEC results before and after initiation.ResultsHighest BEC within 12 months prior to biologic initiation compared with after biologic initiation are shown in the Figure. More than 12 months following initiation, median highest BEC decreased 73% (300.0 to 80.5 cells/mcL) and 100% (366.3 to 0 cells/mcL) among patients who initiated mepolizumab (n=58) and benralizumab (n=104), respectively. In contrast, median BEC increased from before initiation to ≥12 months following biologic initiation in patients who initiated omalizumab (n=44; 32% increase from 139.0 to 182.8 cells/mcL) and dupilumab (n=49; 37% increase from 153.0 to 209.0 cells/mcL).ConclusionReductions in BECs were observed following initiation of anti–IL-5 biologics (mepolizumab and benralizumab), whereas increases were observed following initiation of anti–IL-4 (dupilumab) or anti–IgE (omalizumab) biologics.

IntroductionBiologics for severe asthma that target interleukin (IL)-4 and IL-13 signaling have been linked to hypereosinophilia. Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine involved in asthma pathogenesis. In the phase 2b PATHWAY (NCT02054130) and phase 3 NAVIGATOR (NCT03347279) studies, tezepelumab reduced IL-4, IL-5 and IL-13 activity compared with placebo in patients with severe, uncontrolled asthma, as evidenced by reduced immunoglobulin E levels, blood eosinophil counts and fractional exhaled nitric oxide levels. This post hoc analysis assessed the proportion of patients who experienced hypereosinophilia following tezepelumab treatment using pooled data from the PATHWAY and NAVIGATOR studies.MethodsPATHWAY and NAVIGATOR were multicenter, randomized, double-blind, placebo-controlled, parallel-group studies with similar designs. The proportion of patients (12–80 years old) with ≥ 1 occurrence of hypereosinophilia (defined as a blood eosinophil count of ≥ 1500 cells/µL) during the on-treatment period was assessed. The on-treatment period began on the date of the first dose of treatment and ended on either the date of the last dose of treatment plus 33 days, the date of death or the date of study withdrawal.ResultsOf the 1334 patients included in the analysis, one tezepelumab recipient (0.2%) and 17 placebo recipients (2.5%) had hypereosinophilia during the on-treatment period (Table).ConclusionThe incidence of hypereosinophilia was lower with tezepelumab than with placebo. This suggests that TSLP blockade, despite reducing IL-4 and IL-13 activity, is not associated with hypereosinophilia, which is consistent with the ability of tezepelumab to also reduce IL-5 activity.

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.

IntroductionMultiple biologic therapies are available for patients with severe asthma (SA) in the United States (US). However, effectiveness of biologics can vary by patient age at asthma onset, likely due to associations with allergic (earlier-onset) and eosinophilic (later-onset) inflammation. We examined real-world outcomes before and after biologic initiation among US subspecialist-treated adults with SA, as a function of asthma diagnosis age.MethodsCHRONICLE is an ongoing observational study of US adults with subspecialist-treated confirmed SA. Patients who started a biologic and had complete data for 6 months before and after biologic initiation from February 2018 to February 2022 were evaluated. A locally estimated scatterplot smoothing (LOESS) analysis was conducted to plot the correlation between percentage exacerbation rate reduction and age at asthma onset for each biologic class.ResultsThe analysis included patients with ≥1 exacerbation 6 months pre-biologic initiation (anti-IgE: n=64; anti–IL-5/5R/4R: n=198). Most patients were female, White, commercially insured, and had other comorbidities. LOESS plot curves showed generally similar rate reduction percentages between anti-IgE and anti–IL-5/5R/4R subgroups at younger asthma onset ages. However, reduced to no benefit was observed in the anti-IgE group who had asthma onset at age > 40 years (Figure).ConclusionAmong subspecialist-treated SA patients, reductions in exacerbations varied by patient age of onset and biologic class. Age of onset should be considered in biologic treatment decisions, particularly with use of anti-IgE in patients with asthma onset at age > 40 years.

IntroductionADP101, a pharmaceutical-grade, multifood oral immunotherapy (mOIT) under investigation to simultaneously treat allergy to one or more foods (almond, cashew, chicken's egg, codfish, cow's milk, hazelnut, peanut, pecan, pistachio, salmon, sesame, shrimp, soy, walnut, wheat), was evaluated in the phase 1/2 Harmony trial (NCT04856865).MethodsParticipants with qualifying allergy to 1-5 foods contained in ADP101, defined as dose-limiting symptoms at ≤100 mg protein on double-blind, placebo-controlled food challenge (DBPCFC) at screening, were randomized to low-dose ADP101 (100 mg protein/food/day; 1500 mg total/day) or high-dose ADP101 (300 mg protein/food/day; 4500 mg total/day) or placebo for 40 weeks (up-dosing followed by dose-maintenance). The primary endpoint was the proportion of participants tolerating ≥600 mg protein of ≥1 qualifying food without dose-limiting symptoms on exit DBPCFC. Secondary endpoints included evaluation of efficacy in multiallergic participants, including tolerance of ≥600 mg and ≥1000 mg for ≥2 foods. Safety analyses included rates and severity of anaphylaxis and epinephrine use.ResultsIn 61 pediatric participants, ADP101 demonstrated dose-dependent efficacy, with high-dose ADP101 demonstrating a greater response rate than placebo (55% vs 20%; P=0.048, alpha=0.025). Secondary endpoints demonstrated efficacy of high-dose ADP101 for simultaneous desensitization to ≥2 foods in multiallergic participants. Adverse events were mostly mild or moderate, with no life-threatening events or deaths. Severe anaphylaxis was infrequent and not attributed to ADP101; no ADP101-treated participants discontinued for anaphylaxis. Epinephrine was primarily used during up-dosing and for mild or moderate events.ConclusionA phase 3 program has been initiated based on ADP101’s efficacy, safety, and tolerability results.

Introduction (contexte de la recherche) Remibrutinib, a highly selective, covalent oral Bruton's tyrosine kinase inhibitor has demonstrated efficacy and safety as a treatment for chronic spontaneous urticaria (CSU). Objective Here, we report changes in total serum immunoglobulin (Ig) levels over time in a Phase 2b core (NCT03926611) and extension (NCT04109313) study. Methods Patients in the Phase 2b core study were randomized to receive remibrutinib 10mg once daily (q.d.), 35mg q.d., 100mg q.d., 10mg twice daily (b.i.d.), 25mg b.i.d., 100mg b.i.d. or placebo for up to 12 weeks. Eligible patients were enrolled in a 52-week open label extension study and received remibrutinib 100mg b.i.d. Total immunoglobulin A (IgA), IgE, IgG, and IgM at baseline and at the end of treatment (week 12 and week 52 in the core and extension studies, respectively) was assessed. Results In total, 309 patients were included in the Phase 2b core analysis (267 in any remibrutinib group and 42 in the placebo group), out of which 194 patients rolled-over to the 52-week extension analysis. No relevant numerical changes were observed in the total serum immunoglobulin levels (mean±standard deviation) at baseline vs. week 12 for the core study (in any remibrutinib group and the placebo group) and at baseline vs. week 52 for the extension study:– IgA (g/L): 2.2±0.98 vs. 2.3±1.0 (any remibrutinib dose); 2.4±1.3 vs. 2.4±1.6 (placebo); 2.3±1.0 vs. 2.3±1.0 (extension analysis);– IgE (μg/L): 688.1±1813.4 vs. 757.9±2020.6 (any remibrutinib dose); 1037.0±2835.8 vs. 873.1±2431.5 (placebo); 839.5±2530.3 vs. 699.2±1849.5 (extension analysis);– IgG (g/L): 11.0±2.4 vs. 10.9±2.3 (any remibrutinib dose); 10.9±2.7 vs. 11.1±2.6 (placebo); 11.0±2.4 vs. 10.5±2.5 (extension analysis);– IgM (g/L): 1.1±0.9 vs. 1.0±0.8 (any remibrutinib dose); 1.1±0.7 vs. 1.1±0.6 (placebo); 1.0±0.8 vs. 0.9±0.7 (extension analysis); Conclusions Remibrutinib treatment did not affect the total serum immunoglobulin levels in patients with CSU in phase 2 studies, including with long-term treatment up to 52 weeks.

Introduction We explored the effect of remibrutinib (LOU064), a novel oral Bruton's Tyrosine Kinase inhibitor, in chronic spontaneous urticaria (CSU) patients by baseline CU-index. Methods In this Phase 2b study (NCT03926611), 311 CSU patients were equally randomized to remibrutinib 10mg once-daily (q.d.)/35mg q.d./100mg q.d./10mg twice-daily (b.i.d.)/25mg b.i.d./100mg b.i.d. or placebo for 12 weeks. Outcomes included changes in weekly Urticaria Activity Score (UAS7) by baseline CU-index-positive (≥10) and -negative (<10) at Weeks 4 and 12, and patients achieving UAS7=0 and UAS7≤6 by CU-index at Week 12. Results Of 311 patients, 34.4% were CU-index-positive at baseline. Reductions of mean UAS7 from baseline were higher in CU-index-positive vs -negative patients in all remibrutinib arms at Weeks 4 (−18.64 to −30.15 vs −12.82 to −19.85) and 12 (−18.91 to −32.50 vs −13.56 to −18.29). In the placebo arm, mean UAS7 reduction was higher in CU-index-negative vs -positive patients at Weeks 4 (−6.68 vs −1.25) and 12 (−9.06 vs −5.81). At Week 12, higher proportions of CU-index-positive vs -negative patients achieved UAS7=0 (31.6–54.5% vs 18.5–34.5%) and UAS7≤6 (50.0–72.7% vs 32.1–48.3%) in all remibrutinib arms. In the placebo arm, more CU-index-positive vs -negative patients achieved UAS7=0 (21.4% vs 11.1%); UAS7≤6 response was similar between subgroups (28.6% vs 29.6%) Table 1. Conclusion Remibrutinib (all doses) improved UAS7 regardless of baseline CU-index, with greater improvements in CU-index-positive vs -negative patients. More patients on remibrutinib achieved UAS7=0 and UAS7≤6 vs placebo, irrespective of baseline CU-index. Larger studies are required to confirm the findings from Phase 2b study. UAS7, weekly Urticaria Activity Score.

Patient-reported disease triggers and their associated disease burden are not well-characterized among contemporary patients with severe asthma (SA).

Treatment of severe asthma (SA) necessitates subspecialist care and rigorous therapy. Patient and provider characteristics may influence use of biologics and maintenance systemic corticosteroids (mSCS), but such associations have not been evaluated in a large, contemporary sample of US SA patients.

AR101, an investigational oral biologic drug for peanut oral immunotherapy, was studied in PALISADE and ARTEMIS phase 3 trials. Efficacy and safety results are compared.

Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.

Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4/IL-13, key drivers of type 2 inflammation in multiple diseases. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), add-on dupilumab 200mg and 300mg every 2 weeks (q2w) vs placebo reduced severe exacerbations and improved pre-bronchodilator forced expiratory volume in 1 second FEV1 in patients with uncontrolled, moderate-to-severe asthma. Treatment effects were greater in patients with elevated baseline type 2 biomarkers. The new GINA report specifies baseline blood eosinophils ≥150cells/μL as a criterion for type 2 inflammatory asthma. This post hoc analysis assessed dupilumab's effect on asthma control in patients with baseline eosinophils ≥150cells/μL by baseline IgE levels (<100, 100–<500, ≥500IU/mL).

Introduction The treatment effect of beclomethasone dipropionate (BDP) delivered via a novel breath-actuated inhaler (BAI) was evaluated overall, and also according to pre-study therapy to see if the latter influenced efficacy. Methods This was a Phase 3, 6-week, double-blind, placebo-controlled study (NCT02513160) in 425 patients ≥12 years with persistent asthma previously treated with non-corticosteroids (NCS), inhaled corticosteroids (ICS), or ICS/long-acting beta-2 agonists. After a washout/inhaler training period, randomized patients received placebo (BAI), placebo metered-dose inhaler (MDI), BAI 320 mcg/day, BAI 640 mcg/day, or BDP MDI 320 mcg/day. Rescue medication (albuterol/salbutamol) MDI or equivalent was permitted throughout the study. Results In 425 patients, BDP BAI 320 and 640 mcg/day significantly improved baseline-adjusted trough morning forced expiratory volume in 1 second area under the effect curve from 0 to 6 weeks (FEV1AUEC0–6wk; p Conclusions Both BDP BAI doses demonstrated significant improvements in lung function overall according to the primary study endpoint; exploratory subanalysis suggests that efficacy is independent of prior asthma therapy. The safety profile of this new BDP BAI device was comparable to the established safety profile of BDP MDI, with no new safety signals.