The primary aims of COPD drug research are to develop agents capable of either inhibiting COPD-mediating inflammatory cell recruitment and activation directly, or indirectly - by targeting inflammatory mediators and blocking them from interacting with inflammatory cells. As neutrophilic inflammation is present in most COPD cases, so first attempts at developing biologics for COPD therapy have focused on targeting the mechanisms of T1 inflammation. Attempts at safe and effective mAb-mediated CXCR2 inhibition and TNF-a inhibition have also been unsuccessful, with high incidence of adverse effects and no improvements in patient health found in clinical trials. Thus, further attempts at COPD biologics have turned their attention to primarily treating COPD related eosinophilia.

1. Senior Consultant Physician,
Division of Allergy & Pulmonary Medicine,
Department of Medicine SMS Medical College Jaipur

2. GOLD 2023
New definition of COPD
and COPD exacerbation,
emphasizes combined
bronchodilator therapy,
and minimizes use of
inhaled corticosteroids
2023
Milestones in Current Management of COPD

3. Gold 2023
Treatment guidelines for COPD

4.  The primary aims of COPD drug research are to develop agents
capable of either inhibiting COPD-mediating inflammatory cell
recruitment and activation directly, or indirectly - by targeting
inflammatory mediators and blocking them from interacting with
inflammatory cells.
 As neutrophilic inflammation is present in most COPD cases, so
first attempts at developing biologics for COPD therapy have
focused on targeting the mechanisms of T1 inflammation.
 Attempts at safe and effective mAb-mediated CXCR2 inhibition
and TNF-a inhibition have also been unsuccessful, with high
incidence of adverse effects and no improvements in patient
health found in clinical trials.
 Thus, further attempts at COPD biologics have turned their
attention to primarily treating COPD related eosinophilia.
COPD
Treatment
Old Protocol Newer Protocol
Bronchodilators,
ICS
Monoclonal
antibodies
Neutrophil
mediated
Eosinophil
mediated

5. Global Causes of Death (WHO 2019-2020)
COPD is the 3rd most common cause of death worldwide

6. “It is essential to find drugs capable of suppressing the inflammation associated
with COPD and preventing the progression of the disease. Several new potential
targets have recently been identified, and new agents have been developed for
these targets.”
Drugs capable of
1. Inhibiting recruitment and activation of the cellular components of inflammation or
2. Able to antagonize their products are new interesting therapeutic possibilities

7.  biologics targeting T2 inflammation have shown some small but promising effects in the
eosinophilic phenotype subgroup of COPD.
 This suggests that targeting biologics according to a particular phenotype of the disease may
improve outcomes.

8.  The results of the BOREAS trial should be most welcome because they finally open a new era
in the treatment of patients with COPD.
 Hopefully, new biologic therapies will be illuminated soon, and this new era will offer patients
with COPD new and more effective remedies for their disease.
Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med 2023;389:205-14

9. July 20, 2023 N Engl J Med 2023; 389:205-214 DOI: 10.1056/NEJMoa2303951
 BOREAS TRIAL- a phase 3, double-blind, randomized trial, patients with COPD with blood eosinophil count of at
least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy assigned to
receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks.
 The primary end point was the annualized rate of moderate or severe exacerbations of COPD.
 Key secondary and other end points that were corrected for multiplicity were the change in the pre bronchodilator
forced expiratory volume in 1 second (FEV1) and in the scores on the St. George’s Respiratory Questionnaire
(SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory
Symptoms in COPD (E-RS–COPD; range, 0 to 40, with lower scores indicating less severe symptoms)

10. Characteristics
Dupilumab
Group
Placebo
Group
P-Value
Number of Participants-(939) 468 471
Annualized rate of moderate or severe exacerbation 0.78 1.10 <0.01
Increased in Prebronchodilator FEV1 from baseline 160 mL 77 mL <0.01
Improvement in SGRQ score at 52 weeks -9.7 -6.4 0.002
Improvement in E-RS-COPD Score at 52 weeks -2.7 -1.6 0.001

12. Graph: A. Moderate or Severe COPD Exacerbations and
B. Change in Prebronchodilator FEV1 over Time.
I bars indicate 95% confidence intervals.
COPD denotes chronic obstructive pulmonary disease, FEV1 forced expiratory volume in 1
second, and LS least squares.
Table: Adverse Events:
No significant difference

13. Among patients with COPD who had type 2 inflammation as indicated by elevated blood
eosinophil counts, those who received dupilumab had
1. Fewer exacerbations,
2. Better lung function and quality of life, and
3. Less severe respiratory symptoms than those who received placebo.

14. Drug Target Biological effect Clinical effects Other FDA approved
indications
Clinical trails
Mepolizumab IL-5 Significant reductions in eosinophil activation and
increases in IL-5 and IL-5 receptor expression
levels ex vivo (90)
Significant reductions in
annual disease
exacerbation rates in
Phase III trials (81)
Severe eosinophilic asthma,
inadequately controlled
CRSwNP, Churg-Strauss
syndrome, hypereosinophilic
syndrome
NCT02105948 (79),
NCT02105961 (80)
Benralizumab IL5-Ra Rapid depletion of peripheral eosinophil count in
cynomolgus monkeys (91)
Did not significantly reduce
exacerbation and adverse
event rates in previous
COPD studies (92, 93)
Severe eosinophilic asthma NCT04053634 (82)
Astegolimab ST2 None published Significant improvements in
QoL questionnaire scores,
FEV1 and reductions in
blood eosinophils in Phase
IIa trial (84)
None NCT05037929
(85),
NCT05595642 (86)
Tozorakimab IL-33 Potent inhibition of ST2-dependent inflammation in
primary human cells and a humanised IL-33 mouse
model of airway inflammation, exhibited 3x higher
binding affinity for IL-33 than sST2 (94)
Favourable safety and
pharmacokinetics profiles
shown in Phase I clinical
trial (89)
None NCT05158387
(87),
NCT05166889 (87)
Summary of biologics currently undergoing clinical trials in the treatment of COPD

15. Mepolizumab at a dose of 100 mg was associated with a lower annual rate of
moderate or severe exacerbations than placebo among patients with COPD and an
eosinophilic phenotype.

16. Mepolizumab and benralizumab, previously approved for asthma treatment, have been shown to reduce exacerbation rates in COPD patients
exhibiting eosinophilia.
METREX (NCT02105948) and METREO (NCT02105961) are two phase III clinical trials of mepolizumab in moderate to severe COPD which
concluded in 2018.
 METREX Trial: 100 mg mepolizumab arm or placebo arm at a 1:1 ratio, and received respective treatments every 4 weeks for 52 weeks.
 METREO Trial: 100 mg or 300 mg mepolizumab, or placebo at a 1:1:1 ratio, also every 4 weeks over 52 weeks.
 Subjects were grouped into eosinophilic and non-eosinophilic disease endotypes based on blood eosinophil count screenings and blood
eosinophil count history over the previous year.
 METREX included both disease endotypes, while METREO examined only patients with eosinophilic inflammation.
 Analysis of both studies found that annual rates of disease exacerbation in patients with eosinophilia treated with 100 mg mepolizumab were
18 to 20% lower than in the placebo arm. Non-eosinophilic patients who received mepolizumab had poorer clinical outcomes than those in
the placebo arm.

17. 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.

18. Trial Design. The trials had 90% power to detect a 30% lower annual exacerbation rate (under
multiple-testing procedures) in the 30-mg and 100-mg groups than in the placebo group

19.  Annualized Exacerbation Rates among Patients with Baseline Blood Eosinophil Counts > 220 per
Cubic Millimeter.
 Higher doses of Benralizumab reduces the exacerbation rate in patients of COPD but not statistically
significant.
The percentages and corresponding 95% confidence intervals reflect the degree to which the rate is lower in the benralizumab group than in the placebo group (i.e., a positive percentage
indicates a lower rate in the benralizumab group than in the placebo group) and are based on the annualized exacerbation rate ratios (benralizumab vs. placebo); for example, a rate ratio of
0.96 corresponds to a 4% lower annualized exacerbation rate in the 30-mg benralizumab group than in the placebo group.
GALATHEA
(1:1:1)
1. Benralizumab 30 mg
2. Benralizumab 100 mg
3. Placebo
TERRANOVA
(1:1:1:1)
1. Benralizumab 10 mg
2. Benralizumab 30 mg
3. Benralizumab 1000 mg
4. Placebo
Criner GJ, Celli BR, Brightling CE, Agusti A, Papi A, Singh D, Sin DD, Vogelmeier CF, Sciurba FC, Bafadhel M, Backer V, Kato M, Ramírez-Venegas A, Wei YF, Bjermer L, Shih VH, Jison M, O'Quinn S, Makulova N, Newbold P, Goldman M, Martin UJ;

20. Received: 24 May 2023 Accepted: 18 July 2023 Published: 27 July 2023
In the exploratory post hoc analysis of the GALATHEA and TERRANOVA trials a potential responder population
identified in which treatment with benralizumab prevents recurrent COPD exacerbations during 30- and 90-day
periods following an initial exacerbation, a vulnerable period for an exacerbation to occur.

21.  Benralizumab under the trade name Fasenra is currently being tested for COPD in the
AstraZeneca-funded Phase III RESOLUTE trial (NCT04053634).
 Randomised 1:1 to either the placebo arm or 100 mg benralizumab arm of the study.
 Both treatments will be administered subcutaneously every 4 weeks for the first 3
doses, then every 8 weeks over a period of 56 weeks.
 The results of the RESOLUTE trial are to be published in 2025.
Yousuf AJ, Mohammed S, Carr L, Ramsheh MY, Micieli C, Mistry V, et al. Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease
(COPD-ST2OP): a phase 2a, placebo-controlled trial. Lancet Respir Med (2022) 10(5):469–77. doi: 10.1016/S2213-2600(21)00556-7

22.  Astegolimab is an anti-ST2 mAb which has been tested in a randomised Phase IIa clinical trial named COPD-
ST2OP (NCT03615040).
 Randomised to receive either 490 mg of astegolimab subcutaneously or placebo, every 4 weeks for 44 weeks.
 Astegolimab treatment within the clinical trial did not reduce exacerbation rates as compared to placebo,
however it did improve patient health status as measured by eosinophil counts, FEV1 and St.GRQ score.
 These results served as the basis for further Phase IIb (NCT05037929) and Phase III (NCT05595642)
randomised clinical trials at a much larger scale, each recruiting 1290 patients. This pair of astegolimab clinical
trials is slated to complete in 2025.

23.  TITANIA (NCT05158387) and OBERON (NCT05166889) are a pair of parallel
Phase III randomised clinical trials evaluating the efficacy and safety of
tozorakimab administered subcutaneously in adult participants with symptomatic
COPD and a history of COPD exacerbations in the previous 12 months.
 Tozorakimab is an anti-IL-33 mAb which has shown a favourable safety and
pharmacokinetics profile in earlier, small scale clinical trials (NCT04631016) (89).
 The results of these clinical trials are to be published in late 2025 (87, 88).
AstraZeneca. Phase III, multicentre, randomised, double-blind, chronic-dosing, parallel-group, placebo-controlled study to evaluate the efficacy and safety of two dose
regimens of tozorakimab in participants with symptomatic chronic obstructive pulmonary disease (COPD) with a history of COPD exacerbations (OBERON) (2023). Available
at: https://clinicaltrials.gov/ct2/show/NCT05166889.

24. The various biologics conti….
Lebrikizumab And Tralokinumab -
 Both are monoclonal antibodies that target IL-3 - a protein that functionally
activates neutrophils, macrophages, and other immune cells, all of which
promote inflammation.
 These drugs have initially yielded benefits with respect to airway function
but are still being studied further in regard to their application in COPD.

25. The various biologics conti….
Tezepelumab (AMG-157)
 It targets thymic stromal lipoprotein, which is a relatively novel target for
COPD.
 It is an epithelial-derived cytokine that drives allergic inflammatory responses
by activating dendritic cells and mast cells.
 Tezepelumab lowers the rates of exacerbation by binding to the thymic stromal
lipoprotein.

26. The various biologics conti….
Brodalumab
 It binds to IL-17- a cytokine that plays an important role in the immunologic
responses seen in COPD and asthma.
 IL-17 receptor activation leads to the secretion of inflammatory mediators like
tumor necrosis factor-alpha (TNF-ɑ) and granulocyte-macrophage colony-
stimulating factor, both of which ultimately lead to neutrophil recruitment.
 Brodalumab binds to the IL-17 receptor and inhibits the activation of inflammatory
mediators.

27. Completed Clinical trials of Mab in COPD

29. Ongoing Clinical trials of Mab in COPD

30.  Due to heterogeneity of the disease, the current management of the COPD, which mainly
relies on bronchodilators and corticosteroids can not be consider for all CODP population.
 Use of targeted biotherapy may obtain better results by increasing understanding of the
underlying inflammatory process and identifying new biomarkers.
 However Biologics targeting T2 inflammation have some small but promising effects in the
eosinophilic phenotype subgroup of COPD.
 We need more trials that should look into the best route of administration, optimal dose and
duration of treatment, appropriate out come measures, and patient selection to determine the
efficacy of biologics in managing COPD.