**5. Use of biologics in refractory therapy of COPD**

Drug therapy of COPD includes various pharmaceuticals, some of which are inhaled and some orally used, in various combinations. These include muscarinic antagonists, ß2-sympathomimetics, corticosteroids, mucolytics, antitussives, betablocker, N-acetyl-L-cysteine, antibiotics, oxygen, and vaccinations against pneumococcus infection, pertussis, influenza, and COVID-19. The administration of the phosphodiesterase-4 inhibitor roflumilast is possible as add-on therapy in patients with COPD who repeatedly exacerbate despite therapy, who are assigned to the chronic bronchitis phenotype, and who have an FEV1 (forced expiratory pressure in 1 s) <50% [2, 3, 15].

Furthermore, there are several biologics which could be used in the case of refractory therapy of COPD, especially if there is a combination with bronchial asthma. The following shows a representative selection of biologics, which are mostly used in the treatment of other inflammatory diseases, but which can be considered in individual cases of COPD in particularly severe courses that are resistant to conventional treatment options:


psoriasis and rheumatic diseases. The solution for injection is administered subcutaneously [1, 6, 15].


Other biologics are currently in clinical trials and will be launched in near future. An example is itepekimab, which is under investigation in a phase 3 study. In a current study, the researchers first carried out genetic investigations to determine whether genetic variants within the IL-33 signaling pathways are associated with the risk of COPD. They found that genetic variants that resulted in loss of IL-33 function reduced the risk of COPD. Variants that caused IL-33 to be more active increased the risk of COPD. In addition, they examined the safety and effectiveness of the IL-33 antibody itepekimab in moderate to severe COPD. Itepekimab targets IL-33, thereby inhibiting the activity of the protein. 343 patients between the ages of 40 and 75 were included in the study. All were current or former smokers with a COPD diagnosis of at least 1 year. They were randomly assigned either to the itepekimab or placebo group. In addition to standard therapy, people in the itepekimab group received the

antibody as injections every 2 weeks. The other group received a drug-free placebo instead of the antibody. The effect of itepekimab on the annual rate of acute COPD exacerbations and lung function was analyzed. When both groups were compared, there were initially no significant differences. However, a subgroup analysis found that itepekimab significantly reduced exacerbation rates and improved lung function in ex-smokers with COPD. The positive effects also persisted during the 20-week follow-up period after treatment. The side effects were about the same in both groups. According to the researchers, the study does not show any advantage of itepekimab for current smokers with COPD. However, for ex-smokers with COPD, this biological therapy could be an option to improve the rate of disease worsening and lung function. Future studies should therefore focus even more on this subgroup of patients. Two-phase three clinical trials are already underway to confirm and better understand the potential of the novel therapy in ex-smokers with COPD [3, 6, 23, 24].
