Anti-Alarmin Therapy in COPD Exacerbations: Jadwiga A. Wedzicha, MD

Epithelial alarmins play an important role in driving exacerbations of chronic obstructive pulmonary disease (COPD), and future treatment is likely to rely on combinations of anti-alarmin therapies, according to Jadwiga A. Wedzicha, MD, professor of respiratory medicine at the National Heart and Lung Institute, Imperial College London.

In an interview with The American Journal of Managed Care^®, Wedzicha discussed how alarmins contribute to exacerbations, why results have differed across anti-alarmin trials, and which patients may be candidates for biologic therapy.

Why Alarmins Drive COPD Exacerbations

“Epithelial alarmins are important in driving COPD exacerbations,” Wedzicha said. Exacerbations are triggered by viruses, bacteria, pollutants, environmental factors, and allergens. Viruses in the airway stimulate epithelial cells to produce alarmins such as interleukin 33 (IL-33) and thymic stromal lymphopoietin (TSLP).

Those alarmins then act on a wide variety of immune cells, Wedzicha explained, including neutrophilic, non–type 2 (T2) pathways, and they can also stimulate T2 pathways.

Why Anti-Alarmin Trial Results Differ

Wedzicha noted that phase 2 and phase 3 trials of anti-alarmin therapies have produced different results. Of 2 trials of itepekimab, an anti–IL-33 antibody, one met its primary end point and one did not. Wedzicha pointed out that one study enrolled only former smokers, whereas other studies showed efficacy in both current and former smokers.

Astegolimab is an anti-ST2 agent that targets the receptor for IL-33. Wedzicha said the presence of a soluble form of ST2 could perhaps affect the drug’s efficacy. Some studies also took place during the COVID-19 pandemic, when exacerbations were reduced overall and people did not present with them, so several factors may be at play.

Tozorakimab also targets IL-33 but has properties against the receptor for advanced glycation end products (RAGE), which signals into the T2 population. “There are differences between the drugs,” Wedzicha said. For TSLP, the field is still waiting for phase 3 data, and TSLP has a distinct pathway from IL-33 with different downstream effects. “I think the future will be combinations of these alarmins,” Wedzicha said.

Where Biologics Fit in COPD Treatment

Standard treatment is dual bronchodilators or triple therapy, which adds inhaled corticosteroids to a dual bronchodilator, Wedzicha said. Patients who continue to exacerbate on these regimens become candidates for biologic therapy.

Those with an eosinophil count above 300 would go to T2 biologics, an approach Wedzicha described as comparatively well worked out and simpler. For patients with counts below 300 but above 150, a TSLP-targeting agent may be a candidate if trials confirm benefit. Other patients are suitable for anti-alarmin therapy.

The main problem is the lack of biomarkers for these specific pathways. “We’re almost studying them in the dark at the moment,” Wedzicha said.

Available data suggest dupilumab affects lung function in patients with high eosinophil counts, probably by reducing mucus plugs, Wedzicha said. Tozorakimab also reduces mucus plugs but has less effect on lung function. In neutrophilic patients with lower eosinophil counts, the effect seems to be more on exacerbations. Wedzicha said the system is complex and that differences between studies will teach more about how to target these compounds.