GSK, AstraZeneca, Sanofi, Roche: The Battle for COPD Biologics Dominance

Sep 20, 2024 18:25 CST Updated 18:25

GSK

Pharmaceutical R&D Manufacturer

AstraZeneca

Pharmaceutical Technology Research and Development Provider

Both being respiratory system diseases, when monoclonal antibody drugs are making significant progress in the asthma field, they are facing challenges in chronic obstructive pulmonary disease (COPD) The deadlock in this field has been difficult to break for a long time.

Recently, GSK announced positive results from the Phase III MATINEE clinical trial of IL-5 monoclonal antibody Nucala for the treatment of COPD, which can reduce exacerbations in COPD patients and is expected to successfully expand its indications. Monoclonal antibody biologics targeting interleukin-4 receptor alpha subunit (IL-4Rα), IL-5, IL-33, and thymic stromal lymphopoietin (TSLP) are gradually forming a four-way competition.

Numerous studies have shown that chronic inflammation exists throughout the airways, lung parenchyma, and pulmonary vasculature of COPD patients. This includes type 1 cytokines such as tumor necrosis factor-alpha (TNF-α), type 2 cytokines like IL-4, IL-5, IL-13, as well as alarmins such as IL-33 and TSLP, all of which are involved in the pathophysiology of COPD.

Although some preclinical studies have shown that TNF-α inhibitors can synergize with glucocorticoids to control airway remodeling and reduce glucocorticoid insensitivity to inflammation, the clinical efficacy of TNF-α inhibitor monoclonal antibodies in the actual treatment of COPD is limited.

Thus, research on biologics for COPD began to shift toward type 2 inflammation. Bronchial epithelial cells produce alarmin cytokines such as IL-33, IL-25, and TSLP when exposed to harmful environments (including smoking). These cytokines can lead to the differentiation of naïve T cells into helper T (Th) cells, thereby triggering the production of type 2 inflammatory cytokines such as IL-5, IL-13, and IL-4 through the initiation of adaptive immune responses.

IL-5（R）：A Reversal After a Setback

Many studies have shown that IL-5 and IL-5R are elevated in the sputum of COPD patients, and they have been identified as potential targets for treatment with biologics.

AstraZeneca's IL-5R monoclonal antibody Fasenra and GSK's Nucala were approved by the U.S. FDA for marketing in 2015 and 2017, respectively, both for add-on maintenance treatment of severe asthma with an eosinophilic phenotype. Both work by blocking the interaction between IL-5 and IL-5R, thereby reducing eosinophil maturation and survival and lowering airway inflammation levels in severe asthma.

Despite AstraZeneca and GSK both aiming to expand their drug indications to COPD, they both encountered setbacks in 2018.

After the setback, the two companies did not give up. They redesigned and launched a new COPD clinical study based on the analysis of the trial data. Recently, GSK's Nucala achieved positive results in the Phase III MATINEE clinical trial for COPD treatment.

Although GSK did not provide specific data in the statement, it only revealed that after two years of patient follow-up, compared with placebo, Nucala "significantly reduced the annual rate of moderate or severe exacerbations with clinical significance." In terms of safety, the adverse events of Nucala in MATINEE were consistent with its known profile.

Further analysis of the MATINEE study is ongoing, and the company hopes this research will create new opportunities for Nucala to enter the COPD field.

IL-4Ra: First to Emerge

In July this year, Dupixent (IL-4Ra monoclonal antibody) co-developed by Sanofi and Regeneron was the first in the world to receive approval from the European Medicines Agency (EMA) for the treatment of adult patients with chronic obstructive pulmonary disease (COPD) who have elevated blood eosinophils (BEC) and are not adequately controlled, thereby earning the title of "the first biologic for COPD." The application for the U.S. market approval of Dupixent for this indication is currently under review.

Dupixent was first approved by the FDA for the treatment of atopic dermatitis in 2017. The drug can inhibit IL-4 and IL-13 cytokine-induced inflammatory responses by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes.

Previously, Dupixent reported positive results in two Phase III clinical trials (BOREAS and NOTUS) involving adult patients with uncontrolled COPD and evidence of type 2 inflammation (i.e., BEC≥300/μL).

Dupixent can target the shared subunit of the IL-4 and IL-13 receptors. In contrast, Nucala and Fasenra only target IL-5 or IL-5R. However, the benefits of Dupixent in COPD are limited to patients receiving triple therapy with long-acting muscarinic antagonists (LAMA), long-acting β2-agonists (LABA), and inhaled corticosteroids (ICS) (or with contraindications to ICS), who have bronchitis symptoms and a BEC ≥ 300/μL.

In the design of Dupixent clinical trials, eosinophils were considered to select the subgroup of COPD patients with type 2 immune dysfunction who were most likely to benefit from the drug. The success of the drug further validated the role of IL-4 and IL-13 signaling in COPD through trials.

IL-33: Research and Development in Hot Pursuit

IL-33 is an alarmin that acts as a pro-inflammatory endogenous danger signal, expressed by many cells and tissues, including bronchial epithelium, fibroblasts, smooth muscle, macrophages, and dendritic cells. The biological activity of IL-33 is mediated by its interaction with the ST2 receptor and the IL-1 receptor accessory protein.

IL-33 binding to its specific receptor ST2 stimulates the release of various cytokines, most importantly IL-5 and IL-13, as well as mediators of vascular and airway smooth muscle tone. Recent studies have shown that IL-33 is a key cytokine driving viral infections and inducing AECOPD. Additionally, overexpression of IL-33 has been observed in the plasma and bronchial epithelium of COPD patients.

Currently, three monoclonal antibodies targeting IL-33/ST2 are in Phase III clinical trials for COPD: Sanofi's itepekimab targets IL-33. Sanofi predicts that the peak annual sales of itepekimab and Dupixent for COPD indications could exceed 5 billion euros (approximately 5.507 billion US dollars).

In addition, AstraZeneca's IL-33-targeted monoclonal antibody tozorakimab and Roche's ST-targeted monoclonal antibody astegolimab are both undergoing Phase III clinical trials for the treatment of moderate to severe COPD patients.

TSLP: The Latecomer Takes the Lead

TSLP is an epithelial cell-derived cytokine produced by airway epithelial cells and stromal cells during the inflammatory process. Multiple studies have shown increased expression in airway diseases. Furthermore, evidence suggests that excessive production of TSLP during viral infections can lead to AECOPD.

Tezspire (tezepelumab), a TSLP-targeted monoclonal antibody co-developed by Amgen and AstraZeneca, was first approved by the FDA in 2021 for the treatment of severe asthma. Tezspire is also the only biologic for asthma without phenotypic or biomarker restrictions.

In April this year, the results of the Phase IIa COURSE proof-of-concept trial for Tezspire in the treatment of COPD were announced. Compared with placebo, Tezspire reduced the average annual rate of moderate to severe AECOPD exacerbations by 17%, which was not statistically significant. However, the study covered patients with various eosinophil levels, regardless of inflammatory drivers, emphysema, chronic bronchitis, and smoking status.

Notably, a significant reduction (37%) was observed in the pre-specified subgroup of patients with BEC≥150/μL. In the subgroup analysis, a smaller number of subjects with BEC≥300/μL showed an even greater reduction, reaching 46%.

AstraZeneca/Amgen is actively conducting Phase III studies on Tezspire for the treatment of COPD based on Phase IIa data. If Tezspire can maintain the same results in late-stage trials, it will surpass Dupixent in terms of the target population. Moreover, Tezspire is more convenient than Dupixent in terms of dosing frequency, as Tezspire requires administration only once every 4 weeks, while Dupixent needs to be administered once every 2 weeks.

Interestingly, apart from the deployment of IL-4Ra/IL-13 monoclonal antibody Dupixent and IL-33 monoclonal antibody itepekimab in the COPD field, the IL-13/TSLP nanobody developed by Sanofi is currently undergoing a Phase II clinical trial for asthma treatment. The possibility of further developing it for COPD indications in the future cannot be ruled out.

New Explorations Will Continue

The exploration of COPD biologics development mainly involves conducting COPD indication expansion studies on products that are already marketed or in late-stage clinical trials (such as those approved for treating diseases like eosinophilic phenotype asthma).

Traditionally, asthma is considered a disease characterized by eosinophils. Although there has been ongoing discussion within the industry about a COPD subtype characterized by eosinophils, traditionally, COPD is not characterized by high levels of eosinophils. Therefore, treating COPD patients based on eosinophil levels is an approach for the expansion of indications for many drugs. For newly developed projects, there are often more uncertainties.

Although the pharmaceutical industry has accumulated extensive experience in COPD trials and established endpoints for COPD exacerbations across multiple clinical development programs, there is no industry or regulatory experience in targeted treatments for COPD based on eosinophil counts. The current lack of clinical consensus on defining the COPD eosinophilic phenotype presents challenges in identifying which patients may benefit from biologics.

Not only that, but early developers of COPD biologics often neither conducted proof-of-concept studies in COPD patients nor performed formal dose-selection studies; the mechanism of action (MoA) and dose selection were solely based on information derived from severe asthma development programs, increasing the risks in late-stage clinical trials.

From the perspective of immune/inflammatory pathways, early research targets for COPD biologics were mainly downstream in cellular signaling pathways, but are now extending upstream. If successful, this will greatly increase the opportunities for biologics in this field.

Recent results from several randomized controlled clinical trials (RCTs) indicate that blocking a single cytokine (e.g., IL-5) or its primary target (i.e., IL-5Rα on eosinophils) can moderately reduce acute exacerbations of COPD. In contrast, targeting IL-4 and IL-13 significantly improves lung function and decreases the exacerbation rate of COPD.

TSLP and IL-33 are upstream epithelial-derived cytokines that target not only type 2 inflammation-high expression patterns but also type 2 inflammation-low expression patterns of airway immune responses. However, several RCTs are currently underway to evaluate the effects of targeting TSLP, IL-33, or its ST2 receptor in COPD patients, and the final results are still pending.

In summary, targeting type 2 inflammation and epithelial-derived alarmins (TSLP, IL-33, ST2 receptor) may represent an important step forward for monoclonal antibody precision medicine in treating COPD subgroups.

The success represented by Dupixent, at the very least, signifies that the exploration of biologics for COPD is achieving new milestone-level progress.

Although several companies in China have laid out plans for IL-4Ra, IL-33, and TSLP monoclonal antibodies, in the research of COPD indications, Conmen's IL-4Ra monoclonal antibody, Spesolimab, has entered the mid-to-late stage of clinical trials (Phase II/III), while other competitors are still in the early stages. The future development of the COPD track is worth looking forward to.