Michael E. Wechsler

Background: Rademikibart, an IL‐4Rα‐targeting antibody, demonstrated efficacy in a Phase 2b trial of adults with moderate‐to‐severe uncontrolled asthma (NCT04773678). We report exploratory and predominantly post hoc subgroup analyses, according to baseline eosinophil count (EOS) and fractional exhaled nitric oxide (FeNO). Methods: Patients were randomized, double‐blind, to rademikibart 150 mg or 300 mg Q2W (600‐mg loading) or placebo, with medium‐to‐high dose inhaled corticosteroids and ≥ 1 reliever/controller. Up to eight EOS/FeNO subgroups were investigated, focusing on the following five: ≥ 300 cells/μL and ≥ 25 ppb ( N = 80); ≥ 25 ppb ( N = 142); ≥ 300 cells/μL ( N = 129); ≥ 150 cells/μL ( N = 247); 150– < 300 cells/μL ( N = 118). Results: Prebronchodilator FEV ₁ increased significantly at first assessment (Week 1) and was sustained throughout the 24‐week treatment period. FEV ₁ and asthma control (ACQ‐6) improvements were greatest when baseline EOS and FeNO were both elevated. At Week 1, after a 600‐mg loading dose, placebo‐adjusted FEV ₁ increased by 422 mL (≥ 300 cells/μL and ≥ 25 ppb), 339 mL (≥ 25 ppb), 324 mL (≥ 300 cells/μL), 227 mL (≥ 150 cells/μL), and 141 mL (150– < 300 cells/μL). At Week 24, with 300 mg Q2W, placebo‐adjusted FEV ₁ increased by 519 mL (≥ 300 cells/μL and ≥ 25 ppb), 401 mL (≥ 25 ppb), 394 mL (≥ 300 cells/μL), 287 mL (≥ 150 cells/μL), and 159 mL (150– < 300 cells/μL). Exacerbations decreased by ≥ 63% per subgroup. Rademikibart was well tolerated. No eosinophilia (Preferred Term) was reported. Grade 1 eosinophil count increased did not lead to treatment discontinuation ( n = 2). Conclusions: Rapid and sustained improvements were more pronounced in patients with type 2‐high biomarkers than previously reported in the overall study population.

Introduction: Verekitug is a novel, fully human monoclonal antibody with extended dosing interval targeting the receptor for TSLP, a key epithelial alarmin in severe asthma. Aim: Assess verekitug efficacy and safety in participants (pts) with severe asthma. Methods: VALIANT, a ph2, dose-ranging study, randomized adults with severe asthma 1:1:1:1 to subcutaneous verekitug (100mg every [q] 12 weeks [w]; 400mg q24w; 100mg q24w) or placebo (PBO), with a variable 24–60w treatment period. The primary endpoint was annualized asthma exacerbation rate (AAER) over 60w. Secondary endpoints included w24 and w60 change from baseline in prebronchodilator FEV₁, FeNO and ACQ-6. Results: 478 pts were randomized. Median treatment duration for efficacy analysis was 37w; 436 (91%) received ≥3 doses of study drug. All verekitug arms reduced AAER vs PBO: rate ratio (95% CI) 0.44 (0.28–0.69), P=0.0003 [100mg q12w]; 0.61 (0.40–0.93), P=0.02 [400mg q24w]; 0.51 (0.33–0.79), P=0.003 [100mg q24w], with up to 87% reduction for pts with high baseline eosinophil counts (Table). All verekitug arms improved w24 FEV₁, FeNO and ACQ-6, and w60 FEV₁ and FeNO vs PBO. Treatment-emergent adverse event incidence was similar with verekitug (58–62%) vs PBO (66%). Conclusion: In pts with severe asthma on standard background therapy, verekitug q12w or q24w led to statistically significant, clinically meaningful AAER reductions, early lung function and asthma symptom improvements, and a similar safety profile to PBO. Funding: Upstream Bio, Inc. NCT06196879. erj;68/suppl_70/OA5553/F1 F1 F1

Purpose: Time to biologic initiation for the treatment of severe asthma (SA) is affected by many factors, including ease of access to biologics, which is often subject to approval by regulatory authorities and reimbursement criteria by relevant agencies. We investigated the association between ease of biologic access (using the biologic accessibility score [BACS] as a proxy) and post-biologic asthma outcomes, including remission. Methods: This ecological study, using data from CHRONICLE (a US severe asthma registry), the International Severe Asthma Registry (ISAR), and the Optimum Patient Care Research Database (OPCRD), included patients with SA from 21 countries. Associations at the country level, between BACS, a composite score of prescription criteria for biologics in SA, and the proportion of patients with a favorable asthma outcome 1-year post-biologic in each setting (ie ISAR country or in the CHRONICLE or OPCRD datasets) were tested. Several definitions of favorable outcome were used, including proportion of patients who achieved clinical remission (defined using 2, 3 and 4 domains), experienced no exacerbations, had well- or partly controlled asthma, a percent predicted forced expiratory volume in 1 second (ppFEV₁) or percent predicted peak expiratory flow rate (ppPEFR) ≥ 80%, and no long-term oral corticosteroid (LTOCS) use. Results: A total of 9,183 patients were included. A higher BACS (as a proxy of easier access to biologics) was associated with a higher likelihood of achieving clinical remission (p≤ 0.001), no exacerbations (p< 0.001), well- or partly controlled asthma (p=0.047), a ppFEV₁ or ppPEFR ≥ 80% (p=0.004), and no need for LTOCS (p=0.045) 1 year post-biologic initiation. Conclusion: Easier access to biologics for patients with SA, a prerequisite for shorter time-to-initiation, was associated with a greater probability of achieving clinical remission and other favorable asthma outcomes. Initiating biologics earlier in the asthma disease course may help unlock greater therapeutic potential in SA. These findings warrant confirmation in additional studies to further establish the causal relationship between biologic accessibility, timing of initiation, and clinical outcomes in SA.

Purpose of review: Severe asthma continues to be a significant cause of global morbidity and mortality despite the dramatic change in landscape of asthma management dramatically over the last two decades, However, there are a variety of novel therapeutic agents under investigation whose goals are to enable patients with severe asthma to achieve remission. Recent findings: New strategies in drug development include an ultra-long-acting mechanism with reduced administration frequency, biologics used in combinations, oral therapies and novel therapeutic targets. These targets include bruton tyrosine kinase, OX-40 ligand, janus kinase, CC-chemokine receptor4 (CCR4), and GATA-3, among others reviewed here. Summary: Many patients have benefited tremendously from the currently available asthma biologics in achieving better symptoms control, improved quality of life, and reduced cumulative dose of systemic steroids. Despite this, most patients are unable to achieve remission, potentially related to shortcomings of these therapies in addressing asthma's heterogeneous pathophysiology. As such, a variety of novel therapeutic mechanisms and targets are being investigated and are discussed in this review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare and potentially life‐threatening systemic, inflammatory disease with multi‐organ manifestations, variable presentation and complex pathology. Multiple interconnected immunological pathways are implicated in EGPA pathology, including a type‐2 immune response driving predominantly eosinophilic inflammation, B‐cell mediated autoimmunity, neutrophil activation, and the generation of pathogenic anti‐neutrophil cytoplasmic antibodies, all of which can contribute to tissue/organ damage. High‐dose glucocorticoids are the mainstay treatment for EGPA, but over the past two decades the development of biologic treatments targeting interleukin (IL)‐5, eosinophils and B‐cells has revitalized the treatment landscape. Mepolizumab, a humanized monoclonal antibody that specifically targets IL‐5, and benralizumab, which targets the IL‐5 receptor (IL‐5Rα), are both approved for the treatment of patients with non‐severe relapsing or refractory EGPA. In Phase III trials, these biologics have demonstrated favorable safety profiles and efficacy, with treatment leading to remission induction, remission maintenance, and oral glucocorticoid sparing benefits. However, as understanding of the full complexity of EGPA pathogenesis improves, new treatment targets are emerging. Consequently, understanding key pathogenic mechanisms at the patient level, enabling a more tailored treatment approach, is an important goal for future research.

For people living with eosinophilic granulomatosis with polyangiitis (EGPA), the journey to diagnosis can be long and complicated. EGPA is a rare inflammatory disorder, typically characterized by high levels of blood eosinophils and vasculitis in the lungs and/or other end organ(s). It is associated with asthma, pulmonary infiltrates, neuropathy, sinus disease and the presence of anti-neutrophil cytoplasmic antibodies. Patients can present with a number of symptoms and complications, which often go unrecognized or misdiagnosed and can result in considerable delays in appropriate treatment and worsening of underlying disease. Following correct diagnosis, patients are often treated with oral corticosteroids and other immunosuppressive drugs. While these treatments can be effective at controlling disease, they are also associated with significant side effects, which can lead to diminished quality of life. The emergence in recent years of anti-interleukin-5/receptor (anti-IL-5/R) therapies, such as benralizumab and mepolizumab, has revolutionized the management of EGPA. Interleukin-5 (IL-5) is a key cytokine in the maturation, proliferation and activation of eosinophils. Anti-IL-5/R therapies work by binding IL-5 or the receptor for IL-5, thereby significantly decreasing eosinophilic inflammation, the key pathogenic driver in EPGA. Not only are anti-IL-5/R therapies effective at controlling disease, but they are also well tolerated and can facilitate corticosteroid tapering. In this podcast, a patient and physician discuss the lived experience of EGPA, including difficulties with diagnosis, impact of disease on daily life and disease management with both traditional treatments and with the newer anti-IL-5/R therapies. The discussion highlights the importance of EGPA awareness and of physicians recognizing seemingly unconnected symptoms and different disease components, as well as the need to minimize corticosteroid use because of long-term risks. Furthermore, access to an experienced and coordinated healthcare team and establishing a strong support network are emphasized as essential to help patients manage this complex and rare disease. Podcast Audio (MP4 168118 KB)