recent Biologicals in COPD management

COPD
Biologicals

1. Biologicals In COPD Prof Dr A Sundararajaperumal Professor – Respiratory Medicine Institute Of Thoracic Medicine Madras Medical College & RGGGH

2. COPD: The Need For New Treatments Major health impact world-wide - High mortality and morbidity - High health care costs - High welfare costs Quiting S moking difficult ~10% unrelated to smoking - air pollution, biomass exposure, genetic, idiopathic No currently available treatment slows progression or reverse the damage

3. Where we stand Current therapy is merely palliative. Lack of disease modifying properties. More focus should be on preventive and regenerative therapies However, these are ambitious targets for new drugs… A Peep into the future

4. Cigarette smoke induces lung epithelial cells to produce high levels of IL-33 that will be released after cell damage, such as viral or bacterial infections. On the one hand, exposure to smoke inhibits the expression of the IL-33 (ST2) receptor in type 2 innate lymphoid cells (ILC2), which leads to the inhibition of ILC2 responses and the synthesis of cytokines induced by the IL-33. Moreover, tobacco smoke favors the expression of the ST2 in macrophages (M0) and natural killer (NK) cells. This leads to NK cell proliferation and increased production of the pro-inflammatory cytokine IFN- gamma leading to exacerbated COPD

5. Pathogenesis – What we need to know more Inflammatory and structural changes seen in patients with more advanced COPD persist even after smoking cessation, possibly because of the development of autoantigens and perturbations in the lung microbiome

6. Role Of Biologics in COPD Management B iologics represent a promising therapeutic approach in COPD management, particularly for patients with severe disease and frequent exacerbations who may benefit from targeted anti-inflammatory therapy.

7. Overall, tozorakimab was well-tolerated, with a linear, time-independent serum pharmacokinetic profile. Additionally, biomarker studies demonstrated proof of mechanism. Overall, these data support the further clinical development of tozorakimab in COPD and other inflammatory diseases. Phase II POC clinical study - to assess efficacy, safety and tolerability of 600mg Q4W Tozorakimab in COPD & chronic bronchitis ongoing . Phase III studies with dose of 300mg Q8W/Q4W ongoing , 300mg Q2W ongoing.

8. A recent phase 2 study demonstrated that itepekimab 300 mg every 2 weeks (q2w) vs placebo reduced exacerbation rates & improved lung function in the subgroup of former smokers with moderate-to-severe COPD during the 24–52-week treatment period.

9. ANTI-IL-4/IL-13 Biologics (Dupilumab) The LIBERTY COPD program investigated dupilumab, a dual inhibitor of IL-4 and IL-13 receptors, in COPD patients with raised blood eosinophil levels. Results from the LIBERTY COPD trials showed improvements in lung function and symptoms compared to placebo in patients with moderate-to-severe COPD and raised blood eosinophil levels

10. P hase 3, double-blind, randomized trial W ho had a blood eosinophil count of at least 300 per microliter & an elevated exacerbation risk despite the use of standard triple therapy Dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. CONCLUSION: Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo .

11. ANTI-IL-5 Biologics (Mepolizumab, Reslizumab ) The MENSA trial evaluated mepolizumab, an anti-IL-5 monoclonal antibody, in COPD patients with eosinophilia. Results showed a reduction in exacerbation rates compared to placebo. The COSMOS trial investigated reslizumab , another anti-IL-5 monoclonal antibody, in COPD patients with eosinophilia. It showed a reduction in exacerbation rates but did not meet its primary endpoint of improved lung function.

12. Astegolimab Astegolimab  is a selective  ST2   IgG2   monoclonal antibody  developed to treat  asthma  and  chronic obstructive pulmonary disease

13. Astegolimab , an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial Single- centre , randomised , double-blinded, placebo-controlled phase 2a trial in moderate-to-very severe COPD Participants were randomly assigned (1:1) with a web-based system 490 mg subcutaneous astegolimab or subcutaneous placebo every 4 weeks for 44 weeks.  In patients with moderate-to-very severe COPD, astegolimab did not significantly reduce exacerbation rate, but did improve health status compared with placebo. S ubgroup analyses suggested more benefit in subjects with lower blood eosinophil counts.

14. At a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) W ho had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo.  Conclusion: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater.

15. Administered intravenously and subcutaneously in the form of suspension & solution

16. ANTI-TNF Biologics (Infliximab) The RENEW trial examined infliximab, an anti- tumor necrosis factor-alpha (TNF-α) monoclonal antibody, in COPD patients with emphysema. There were improvements in some secondary endpoints such as exercise capacity, the trial did not demonstrate a significant reduction in the rate of lung function decline compared to placebo

17. ANTI-IL-13 Biologics (Lebrikizumab, Tralokinumab) Lebrikizumab, an anti-IL-13 monoclonal antibody, was studied in the LUTE and TALENT trials. While these trials did not meet their primary endpoints, some subgroup analyses suggested potential benefits in specific patient populations. Tralokinumab, another anti-IL-13 monoclonal antibody, was evaluated in the STRATOS 1 and STRATOS 2 trials. These trials also did not meet their primary endpoints of reducing exacerbation rates, although post-hoc analyses suggested potential benefits in certain patient subgroups

18. Biologics in COPD Anti-inflammatory Effects T arget specific inflammatory mediators implicated in COPD, such as interleukin (IL)-5, IL-13, and tumor necrosis factor-alpha (TNF-α). Reduction of Exacerbations D ecrease the frequency and severity of COPD exacerbations. IL-5 inhibitors like mepolizumab has shown efficacy in reducing exacerbation rates in COPD patients with eosinophilia . Improvement in Lung Function T argeting the IL-4/IL-13 pathway with dupilumab has demonstrated improvements in lung function and symptoms Personalized Medicine Adjunct to Standard Therapy Potential for Disease Modification

19. Conclusion Overall, biologics represent a promising therapeutic approach in COPD management, particularly for patients with severe disease and frequent exacerbations who may benefit from targeted anti-inflammatory therapy. However, further research is needed to optimize their use, identify ideal candidate populations, and determine long-term efficacy and safety.

20. Trait Biomarker Treatments Likely outcome Comments           Airflow limitation FEV 1 /FVC ratio < 0.7 b 2 -Agonists, antimuscarinic agents, theophylline Improved symptoms, lung function, and Caused by multiple factors, including airway smooth muscle contraction,       exercise capacity mucus plugging, airway wall edema,         small-airway fibrosis, and loss of         airway support; components not         readily distinguishable and likely to         respond to treatments differently Eosinophilic airway ICSs; oral CSs; anti–IL-5, Reduced exacerbations Well-defined, identifiable, and treatable; inflammation anti–IL-4, and anti–IL-13; and variable and smaller likely the results of different pathways     anti-TSLP improvement in symptoms       and lung function   Neutrophilic airway Induced sputum ? Macrolides; CXCR2 ? Reduced exacerbations; Not at all well-defined; might be multiple inflammation neutrophil count; antagonists ? Reduced rate of decrease pathways, including infection-associated   ? CRP   in lung function; ? reduced pathways, caused by exogenous stimuli       cough and sputum (ie, smoking) and autoimmune processes         (ie, rheumatoid-associated airway disease) Cough reflex 24-h Cough counts, Gabapentin; ? P2X3 Improved cough Recent progress with new measurement hypersensitivity Leicester Cough antagonists   techniques and treatments   Questionnaire       Mucus CT-based assessment; Carbocysteine; no other Improved sputum; ? reduced Unclear whether independent of airway overproduction sputum production well-established exacerbations inflammation     treatments in patients         with COPD              

21. 11 and YY , Marked effect; , no effect; ? , no information. OCS , Oral corticosteroid; TSLP , thymic stromal lymphopoietin.

22. ANTI-IL-5 Biologics (Mepolizumab, Reslizumab ):

23. Overall, tozorakimab was well-tolerated, with a linear, time-independent serum pharmacokinetic profile. Additionally, biomarker studies demonstrated proof of mechanism. Overall, these data support the further clinical development of tozorakimab in COPD and other inflammatory diseases. Phase II POC clinical study - to assess efficacy, safety and tolerability of 600mg Q4W Tozorakimab in COPD & chronic bronchitis ongoing . Phase III studies with dose of 300mg Q8W/Q4W ongoing , 300mg Q2W ongoing.

24. IL-33 & the Lung

25. IL-33 in COPD Increased expression of IL-33 and ST2 receptors has been observed in COPD ; however, unlike in allergic diseases where it induces classic type 2 responses, the role and mechanisms are more complex. Cigarette smoke (CS) is a major driver of COPD development, and exposure to cigarette smoke can induce a chain of systemic responses that not only increase IL-33 production in epithelial and endothelial cells but also cause increased IL-33 expression in peripheral blood mononuclear cells , which induces persistent activation of the immune system favoring COPD progression . CS also alters ST2 receptor expression, which implies an increased type 1 pro-inflammatory response in the lungs, intensifying exacerbation-induced inflammation in COPD. It has been reported that IL-33 increases mucus production and vascular endothelial permeability, which further aggravates inflammation Infections might increase IL-33 expression and secretion in the epithelium and enhance IL-33 in PBMC and peripheral blood lymphocytes.

26. Other biologics targeting various inflammatory pathways, such as IL-1β inhibitors (e.g., canakinumab), are also being explored in COPD, although clinical trial data in this area are limited