astegolimab (RG 6149) / Amgen, Roche - LARVOL DELTA

Structural Basis for Inhibition of IL-33 Induced ST2 Activation by Astegolimab (ATS 2025) - "Biochemical and biophysical studies using recombinantly generated proteins show that astegolimab prevents IL33 from binding to ST2 in solution. A 2.6 Å cryo-EM structure of ST2 bound to the Fab fragment from astegolimab reveals that astegolimab binds to the IL33-binding interface on ST2, directly competes with IL33 binding, thereby prevents formation of the active signaling complex necessary for ST2 activation."

Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • IL1RAP • IL33

Serum Soluble ST2 (sST2) Is Associated With Chronic Obstructive Pulmonary Disease (COPD) Exacerbations and Enhanced Treatment Response to Astegolimab (Anti-ST2) (ATS 2025) - P2, P2b, P3 | "In the LEUKO study (NCT00493974), hospitalized COPD patients experiencing acute exacerbations received zileuton to assess the effect on hospital stay length. Our post-hoc analyses indicate sST2 levels: 1) are prognostic for exacerbations in placebo-treated COPD subjects, when measured at baseline, and 2) are elevated at the time of hospitalized exacerbation, suggesting NFκB signaling cytokines, such as IL-33, underlie COPD exacerbations. Notably, both COPD and asthma subjects with higher levels of sST2 at baseline derived greater astegolimab AERR treatment benefit."

Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IL33 • ST2

Astegolimab: NME submission in US for COPD in 2025 (Roche) - Q1 2025 Results: Regulatory submission in EU for COPD in 2025

EMA filing • FDA filing • Chronic Obstructive Pulmonary Disease • Immunology

ARNASA: A Study to Evaluate Astegolimab in Participants With Chronic Obstructive Pulmonary Disease (clinicaltrials.gov) - P3 | N=1290 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jun 2025 ➔ Dec 2026

Trial completion date • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

A Study to Evaluate the Effect of Injection Site on PK of Astegolimab in Healthy Subjects (clinicaltrials.gov) - P1 | N=78 | Completed | Sponsor: Genentech, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Apr 2025 ➔ Oct 2024 | Trial primary completion date: Apr 2025 ➔ Oct 2024

Trial completion • Trial completion date • Trial primary completion date

Targeting alarmins in asthma- From the bench to the clinic. (PubMed, J Allergy Clin Immunol) - "Tezepelumab, an anti-TSLP antibody has already been approved for the treatment of severe asthma. In this review we discuss our current understanding of alarmin biology with a primary focus on allergic airway diseases. We link the mechanistic corollaries to the clinical implications and advances in drug development targeting alarmins-focusing on currently approved treatments, those under study, as well as future potential targets in the alarmin signaling pathways."

Journal • Review • Allergy • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IL33 • IL5

Role of Monoclonal Antibodies in the Management of Eosinophilic COPD: A Meta-analysis of Randomized Controlled Trials. (PubMed, Ann Am Thorac Soc) - "In patients with eosinophilic COPD receiving standard of care therapy, the use of monoclonal antibodies led to a significant reduction in annualized COPD exacerbation rate compared to placebo. Monoclonal antibodies have an acceptable tolerability and safety profile."

Journal • Retrospective data • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Astegolimab: Data from P2 ALIENTO trial (NCT05037929) for COPD in 2025 (Roche) - Bernstein's 23rd Annual Pan European Premium Review Conference: Data from P3 ARNASA trial (NCT05595642) for COPD in 2025

P2 data • P3 data • Chronic Obstructive Pulmonary Disease • Immunology

Astegolimab: Data from P3 ARNASA trial (NCT05595642) for COPD in 2025 (Roche) - Q3 2024 Results

P3 data • Chronic Obstructive Pulmonary Disease • Immunology

Astegolimab: NME submission in US for COPD in 2025 (Roche) - Q3 2024 Results: Regulatory submission in EU for COPD in 2025

EMA filing • FDA filing • Chronic Obstructive Pulmonary Disease • Immunology

Pharmacokinetics (PK) of the anti-ST2 monoclonal antibody, astegolimab (ERS 2024) - P2, P2b, P3 | "Baseline sST2 levels were comparable in healthy volunteers and patients with asthma or COPD. PK in patients with COPD will be confirmed in pivotal studies (NCT05037929; NCT05595642)."

PK/PD data • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Respiratory Diseases • IL33

A Study to Evaluate the Effect of Injection Site on PK of Astegolimab in Healthy Subjects (clinicaltrials.gov) - P1 | N=78 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed

A Study to Evaluate the Efficacy and Safety of Astegolimab in Participants With Chronic Obstructive Pulmonary Disease (clinicaltrials.gov) - P2 | N=1440 | Recruiting | Sponsor: Genentech, Inc. | Active, not recruiting ➔ Recruiting

Enrollment open • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

A Study to Evaluate the Effect of Injection Site on PK of Astegolimab in Healthy Subjects (clinicaltrials.gov) - P1 | N=78 | Recruiting | Sponsor: Genentech, Inc.

New P1 trial

Role of Monoclonal Antibodies in Patients With Eosinophilic Subtype COPD: A Meta-analysis of Randomized Controlled Trials (ATS 2024) - "Monoclonal antibodies ranged from Astegolimab, Benralizumab, Dupilumab, Itepekimab, and Mepolizumab. To conclude, in patients with eosinophilic subtype of COPD, the use of monoclonal antibodies led to a significant reduction in annualized exacerbation rate compared to standard of care. Monoclonal antibodies have an acceptable tolerability and safety profile."

Retrospective data • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Safety Profile of Astegolimab, An Anti-ST2 Antibody: A Systematic Review (ATS 2024) - P2, P2b | "Astegolimab has been shown to be well tolerated in over 580 patients with asthma, atopic dermatitis, COPD, or COVID-19 pneumonia, with no safety concerns identified."

Clinical • Review • Asthma • Atopic Dermatitis • Cardiovascular • Chronic Obstructive Pulmonary Disease • Dermatitis • Dermatology • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • Septic Shock • IL33

Post Hoc Analysis of Quantitative HRCT Imaging Parameters in Astegolimab (anti-ST2) Treated COPD Patients Associates Airway Wall Thickness With Clinical Outcomes (ATS 2024) - "These post-hoc analyses associate baseline airway wall thickness with poor outcomes in placebo treated subjects and suggest it enriches for anti-ST2 treatment benefit for FEV1. However, a major limitation of this study is sample size limiting statistical power and will need to be validated in appropriately powered prospective studies. Future work will investigate the longitudinal imaging changes to better understand therapeutic effects."

Clinical • Clinical data • Retrospective data • Chronic Obstructive Pulmonary Disease • Cough • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IL33

Towards precision medicine in COPD: Targeting type 2 cytokines and alarmins. (PubMed, Eur J Intern Med) - "Two phase III randomized clinical trials (RCTs) showed a modest reduction in exacerbations in COPD patients with eosinophilic phenotype treated with mepolizumab (anti-IL-5) or benralizumab (anti-IL-5Rα). A phase III RCT showed a 30% reduction in exacerbations in COPD patients with ≥ 300 eosinophils/μL treated with dupilumab (anti-IL-4Rα)...Several ongoing RCTs are evaluating the efficacy and safety of anti-TSLP (tezepelumab), anti-IL-33 (itepekimab, tozorakimab), and anti-ST2 (astegolimab) in patients with COPD, who experience exacerbations. In conclusion, targeting T2 inflammation or epithelial-derived alarmins might represent a step forward in precision medicine for the treatment of a subset of COPD."

Clinical • Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IL13 • IL33 • IL4 • IL5

Mechanistic role of RND3-regulated IL33/ST2 signaling on cardiomyocyte senescence. (PubMed, Life Sci) - "NF-κB inhibitor pyrrolidinedithiocarbamate ammonium (PDTC) and ST2 antibody astegolimab treatments mitigated above effects...In contrast, RND3 overexpression in rats by injection of AAV9-CMV-RND3 particles inhibited IL33, ST2L, IL1α, IL6, and MCP1 expression in cardiac tissues, decreased serum IL33 levels, and increased sST2 levels. These results suggest that RND3 expression in cardiomyocytes modulates cell senescence by inhibiting the IL33/ST2/NF-κB signaling pathway, underscoring its potential as a therapeutic target in cardiovascular senescence."

Journal • Cardiovascular • Inflammation • Targeted Protein Degradation • IL1A • IL3 • IL33 • IL6

A Study to Evaluate the Efficacy and Safety of Astegolimab in Participants With Chronic Obstructive Pulmonary Disease (clinicaltrials.gov) - P2 | N=1440 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Approaches to COPD care: Targeting the ST2 receptor and IL-33 pathway as a potential option for patients at risk of exacerbating (ATS 2024) - "This educational event presents the latest scientific thinking in COPD care. Gain knowledge through educational presentations that bring to life: -The COPD patient: immunology, pathophysiology, and psychological burden -Astegolimab,* an investigational monoclonal antibody, potentially targeting the ST2 receptor and IL-33 pathway -The Genentech and Roche commitment to diversity in research *Astegolimab and its uses are investigational and have not been approved by the US Food and Drug Administration."

Clinical • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • IL33

Astegolimab: NME submission in US for COPD in 2025 (Roche) - Q1 2024 Results: Regulatory submission in EU for COPD in 2025

BLA • European regulatory • Chronic Obstructive Pulmonary Disease • Immunology

Astegolimab: Data readout from P3 ARNASA trial (NCT05595642) for COPD in 2025 (Roche) - FY2023 Results

P3 data • Chronic Obstructive Pulmonary Disease • Immunology

A Study to Evaluate the Efficacy and Safety of Astegolimab in Participants With Chronic Obstructive Pulmonary Disease (clinicaltrials.gov) - P2 | N=1440 | Recruiting | Sponsor: Genentech, Inc. | Phase classification: P2b ➔ P2

Phase classification • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Factors contributing to the nonlinear pharmacokinetics of astegolimab: a close examination of potential causes. (PubMed, Bioanalysis) - "Results & Our results demonstrate that there were two main contributors to PK nonlinearity: soluble target interference in the free PK assay, in addition to target-mediated drug disposition. Antidrug antibody status did not significantly impact PK."

Journal • PK/PD data