Benralizumab: A Second Chance in Patients With COPD?

MADRID — Certain subgroups of patients with chronic obstructive pulmonary disease (COPD) may benefit from benralizumab (Fasenra) despite its overall failure to reduce acute exacerbations in phase III testing, pooled data from two of those studies indicated.

For patients with blood eosinophil counts of at least 220 cells/mL who were on so-called triple maintenance therapy, and who had three or more exacerbations in the prior year, benralizumab at 100 mg per injection was associated with a 30% reduced exacerbation rate versus placebo (95% CI 12%-44%), reported Gerard Criner, MD, of Temple University in Philadelphia.

This subgroup represented 19% of patients in the trial, he said here at the annual European Respiratory Society meeting. The findings were simultaneously reported in The Lancet Respiratory Medicine.

Another 6% — those at baseline showing either FEV₁ <40% of predicted normal after bronchodilator challenge or at least 15% improvement in FEV₁ with challenge — also benefited significantly from benralizumab, Criner reported.

“We believe the clinical history adds to the baseline eosinophil count to predict the patient population who may respond to this therapy,” Criner said while presenting the findings.

Patients in these subgroups receiving 30 mg benralizumab per injection in the trials did not show significant benefit with the drug, however.

Benralizumab, which was approved as an add­-on maintenance treatment for patients with severe eosinophilic asthma, is an eosinophil-depleting monoclonal antibody. Maintenance therapy in COPD typically involves some two- or three-drug combination including an inhaled corticosteroid (ICS), long-acting beta agonist (LABA), and/or long-acting muscarinic antagonist (LAMA).

In two prior phase III trials, GALATHEA and TERRANOVA, it failed to significantly reduce the exacerbation rate compared to placebo at both the 30- and 100-mg doses.

This post-hoc analysis identified baseline factors associated with a treatment response and ranked them in order of their relative influence on exacerbation rates. The authors emphasized this form of analysis does not require predefined thresholds for continuous parameters, and that the power to detect a treatment effect was low for some characteristics.

The findings are “to be viewed with caution” and “considered as hypothesis-generating,” wrote Richard Russell, MD, of the University of Oxford in England, in an accompanying editorial in the journal.

“However, the data generated might be invaluable for the future,” he wrote.

Russell, speculating on why only the 100-mg dose reduced COPD exacerbations in the subgroups, wrote that the higher dose may be required to prevent chemotaxis of eosinophils into the bronchial epithelium, particularly at the time of exacerbation.

Importantly, he also noted that the study did not classify COPD exacerbations, something that could inform future treatment options.

“Exacerbations are not homogenous events and should be phenotyped in order to understand their mechanisms,” he wrote. “The results might be that only eosinophilic COPD exacerbations are being suppressed by anti-IL5 therapy with non-eosinophilic events being unaffected.”

GALATHEA and TERRANOVA enrolled patients on dual therapy (ICS plus LABA or LABA plus LAMA) or triple therapy (ICS, LABA, and LAMA) with at least two exacerbations, defined as requiring corticosteroids or antibiotics, or one severe exacerbation, defined as hospitalization. The analysis was stratified by those with above or below 220 cells per microliter blood eosinophil counts. In the trials, patients assigned to benralizumab received treatment every eight weeks.

Overall, the 2,665 patients in this analysis had a mean age of 65.3 and 66% were male; 32% were current nicotine users. Two-thirds were on dual therapy (65%) and the rest were on triple maintenance therapy. Patients did not have concurrent asthma, although some displayed features of asthma and it’s possible others had eosinophilic inflammation, the authors reported.

There was a pattern towards a greater treatment effect with increasing baseline blood eosinophil counts, indicating this measure could be a biomarker identifying patients who could benefit from the therapy, the authors reported. However, there was no indication that varying blood eosinophil count thresholds influenced the null association found between benralizumab and both FEV₁ and quality of life.

Criner said his team is currently investigating the efficacy of benralizumab among patients with moderate to severe COPD and frequent exacerbations in a prospective trial called RESOLUTE that is expected to be completed in 2023.

“If confirmed prospectively in a future study, these easily identifiable clinical characteristics, together with an elevated blood eosinophil count, could potentially help to select patients with a greater probability of having a treatment effect with benralizumab,” he and his colleagues wrote.