Biologics targeting different antigens are being investigated for the treatment of chronic obstructive pulmonary disease (COPD) with eosinophilic signs of inflammation. Professor Dr. Christopher E. Brightling, Director of the Institute of Lung Health at the University of Leicester, UK, explained the following approaches at the ERS Congress 2024 in Vienna:
- Blockade of interleukin (IL)-5 or its receptor,
- Activation of the IL-4 receptor,
- Inhibition of IL-33 or its receptor ST2 (Suppression of Tumorigenicity 2),
- Blockade des Zytokins Thymic Stromal Lymphopoietin (TSLP).
IL-5 inhibition: Benefits only evident for subgroups
Early on, the antibody benralizumab, which is directed against the IL-5 receptor alpha, was studied in patients with moderate to severe COPD with at least one acute exacerbation in the last year and at least 3% eosinophils in the sputum.
In the randomized, placebo-controlled, double-blind Phase IIa study, the antibody reduced eosinophils in both blood and sputum, but only led to a reduction in exacerbations compared to placebo when eosinophil counts in blood (≥200 cells/µl) or sputum (≥3%) were higher.
However, two placebo-controlled phase III trials failed to demonstrate a significant effect of benralizumab on the exacerbation rate of patients with frequently exacerbating COPD receiving guideline-based therapy. The endpoint was not reached even with ≥200 eosinophils/µl in serum.
However, subgroup analyses provided evidence of a potential benefit for patients with three or more exacerbations in the year prior to study entry, where a 39% reduction in annualized exacerbation rate (AER) was observed, and for patients on triple therapy, where an 18% reduction in AER was observed, Brightling explained.
The antibody mepolizumab, which is directed against IL-5, also failed to achieve the goal of reducing AER compared to placebo in two phase III trials. These trials included patients with COPD who continued to suffer from moderate to severe exacerbations despite triple therapy.
However, in the subgroup of patients with eosinophilia (≥150 eosinophils/µl at screening or ≥300/µl in the previous year), a significant benefit was seen with a reduction in the exacerbation rate of approximately 20%.
The breakthrough: antibodies against IL4 receptor alpha
Brightling highlighted the positive results for dupilumab in the BOREAS study, which led to the approval of the antibody against the IL-4 receptor alpha (IL4Rα). The study included smokers and ex-smokers with COPD, a serum eosinophil count of at least 300/µl and a high risk of exacerbation despite triple therapy.
Treatment with 300 mg dupilumab administered subcutaneously every two weeks resulted in a 30% reduction in the annualized exacerbation rate compared to placebo. In addition, there was a significant improvement in pre-bronchodilation forced expiratory volume in one second (FEV1) by 83 ml after 12 weeks and after 52 weeks.
Respiratory-related quality of life, measured with the St. George’s Respiratory Questionnaire (SGRQ), also improved by 3.4 points. These positive results were confirmed in the NOTUS study.
Light and shadow with anti-IL33/ST2 antibodies
The anti-IL-33 antibody itepekimab was investigated in a phase II study in smokers and ex-smokers with COPD, impaired lung function and exacerbations despite stable medication. A significant effect of the antibody on the exacerbation rate was only seen in ex-smokers.
The anti-ST2 antibody astegolimab also failed to meet the primary endpoint of reducing the exacerbation rate compared to placebo in addition to background therapy in a phase II study.
Interestingly, however, an effect on exacerbations was seen in patients with low blood and sputum eosinophilia. In addition, in the overall cohort, health-related quality of life and lung function improved in the astegolimab group compared to the placebo group.
It remains to be seen whether these results will be confirmed in Phase III trials, Brightling said.
TSLP is promising as a therapeutic target
Brightling sees good development prospects for the antibody tezelizumab, which is directed against TSLP. In the Phase IIa study COURSE, treatment with the antibody (420 mg sc every four weeks) in addition to triple therapy led to a non-significant reduction in moderate to severe exacerbations by 17% compared to placebo in a patient cohort with COPD and at least two exacerbations in the previous year.
However, the rate of severe exacerbations was reduced by 48% over 52 weeks. Patients with at least 150 eosinophils/µl and those with a high FeNO value at baseline benefited particularly significantly.
Towards precision medicine
Biologics are not therapeutics for COPD that benefit all patients equally. “We need to move to precision medicine,” Brightling stressed.
Phase II trials of biologics in COPD aim to identify the patient groups that will benefit most from the therapies. Phase III trials must then confirm the efficacy and safety in these specific subgroups.
This has already been achieved for dupilumab, and for tezelizumab, Brightling expects the primary results of a Phase III study in patients with moderate to severe COPD at the end of next year.
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