Breakthrough Clinical Results
Zymeworks announced the presentation of preclinical data for ZW1528, a novel bispecific molecule targeting IL-4Rα and IL-33, at the American Thoracic Society (ATS) International Conference. ZW1528 demonstrates potent blockade of IL-4, IL-13, and IL-33 signaling pathways crucial in respiratory inflammation, showing promise in treating chronic obstructive pulmonary disease (COPD). The data highlight high-affinity binding, effective blockade of signaling pathways, efficacy in murine models, extended pharmacokinetics, and biophysical stability supporting subcutaneous administration. Regulatory filing for Phase 1 studies is expected in the second half of 2026.
Key Highlights
- Potent blockade of IL-4, IL-13, and IL-33 signaling pathways
- Efficacy in acute and chronic murine models of lung inflammation
- Extended pharmacokinetics and biophysical stability supporting subcutaneous administration
- Regulatory filing for Phase 1 studies expected in 2H-2026
Incidence and Prevalence
Global COPD Burden:
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A 2021 study using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 database estimated a total of 213.39 million prevalent cases of COPD globally in that year. The age-standardized prevalence of COPD increased with age and was more common in males.
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A 2019 meta-analysis estimated that 391.9 million people aged 30-79 years had COPD worldwide in 2019, with most (80.5%) living in low- and middle-income countries (LMICs). The overall prevalence of COPD among people aged 30-79 years was highest in the Western Pacific region (11.7%) and lowest in the Americas (6.8%).
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A 2021 study, using the GBD 2021 data, estimated 30,384,539 young COPD cases (aged 20-50) globally in 2021. Oceania had the highest age-standardized prevalence, death, and disability-adjusted life years (DALY) rates, while high-income North America had the highest age-standardized incidence rate.
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A 2022 study projected that the number of COPD cases globally among those aged 25 years and older will increase by 23% from 2020 to 2050, approaching 600 million patients with COPD globally by 2050. Growth in the burden of COPD was projected to be largest among women (47.1% increase) and in LMIC regions.
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A 2022 study using the GBD 2021 data found that in 2021, the global numbers of prevalent and incident COPD cases among adults aged 70 years and older were 99.7 million and 7.4 million, respectively, representing increases of 162.2% and 157.4% since 1990. The highest prevalence and largest increase in incidence rate occurred in high sociodemographic index regions.
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A 2019 study using the GBD 2019 data reported 212.3 million prevalent cases of COPD globally in 2019, with COPD accounting for 3.3 million deaths and 74.4 million DALYs. The global age-standardized prevalence, death, and DALY rates for COPD were lower in 2019 than in 1990.
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A 2019 study reported that the incidence of COPD increased by 85.89% from 8,722,966 cases in 1990 to 16,214,828 cases in 2019, while the age-standardized incidence rate decreased. Men had a higher age-standardized incidence rate than women over the past 30 years.
Trends and Risk Factors:
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Despite declines in age-standardized rates of prevalence, mortality, and DALYs, the absolute burden of COPD has increased due to population growth and aging.
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Smoking remains a significant risk factor for COPD, followed by ambient particulate matter pollution, household air pollution from solid fuels, and occupational exposures.
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COPD burden varies across regions and sociodemographic indices, with higher burdens often observed in low- and middle-income countries and regions with lower sociodemographic indices.
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COPD is more common in males and increases with age, although the burden among women is projected to grow significantly.
It is important to note that estimates can vary depending on the data source, methodology, and COPD definition used.
Emerging Mechanism of Action
COPD is a complex and heterogeneous disease, and research into its mechanisms of action (MoA) is ongoing and evolving. Based on PubMed publications within the past three years, several key MoAs and therapeutic targets are emerging:
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Inflammation and Immune Response:
- Abnormal Inflammatory Response: COPD involves a chronic, abnormal inflammatory response in the lungs, distinct from asthma. This response involves various immune cells (macrophages, neutrophils, lymphocytes) and inflammatory mediators (IL-8, TNF-α, CRP). Targeting specific inflammatory pathways with biologicals is a developing area of research. For example, monoclonal antibodies targeting IL-5 or its receptor have shown efficacy in reducing exacerbations in patients with eosinophilic COPD.
- Oxidative Stress: Exposure to cigarette smoke and other noxious particles leads to an imbalance between oxidants and antioxidants, resulting in oxidative stress. This contributes to inflammation, cell death, and tissue damage. Nrf2, an endogenous protective mechanism against oxidative stress, is being investigated as a potential therapeutic target.
- Mitochondrial Autophagy and Necroptosis: Cigarette smoke-induced mitochondrial autophagy can initiate programmed necrosis (necroptosis), a form of cell death that triggers exaggerated inflammation. This may contribute to the persistent airway inflammation seen in COPD.
- Cellular Senescence: Aging of the lungs leads to cellular senescence and the development of senescence-associated secretory phenotypes (SASPs). SASPs secrete inflammatory cytokines, chemokines, and matrix metalloproteinases, contributing to chronic low-grade inflammation.
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Airway Remodeling and Obstruction:
- Small Airway Disease (SAD): SAD, characterized by inflammation, damage, remodeling, and eventual loss of small airways, is a key feature of COPD and a major contributor to airflow limitation. Research is focused on developing better imaging techniques to measure SAD and exploring its role in early COPD.
- Mucus Hypersecretion: Chronic bronchitis, a common feature of COPD, involves excessive mucus production, which can obstruct airways and contribute to exacerbations. Targeting mucus hypersecretion is an area of ongoing research.
- Emphysema: Emphysema, characterized by destruction of the alveolar walls, leads to reduced gas exchange and airflow limitation. The relationship between SAD and emphysema is being investigated.
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Genetic and Epigenetic Factors:
- Genetic Susceptibility: Genetic factors play a role in COPD susceptibility. Genome-wide association studies have identified numerous genetic variants associated with lung function and COPD risk.
- Epigenetic Modifications: Epigenetic factors, such as DNA methylation and microRNA expression, are also implicated in COPD development and progression.
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Systemic Effects and Comorbidities:
- Systemic Inflammation: COPD is not just a lung disease; it has systemic effects driven by chronic inflammation. This contributes to comorbidities such as cardiovascular disease, muscle wasting, osteoporosis, and cognitive impairment.
- Gut Microbiome: Emerging research suggests a potential role for the gut microbiome in COPD pathogenesis and systemic inflammation.
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Exacerbations:
- Infections: Viral and bacterial infections are common triggers of COPD exacerbations. Research is focused on understanding the role of the lung microbiome and immune dysfunction in exacerbations.
- Eosinophilic Exacerbations: A subset of COPD exacerbations is characterized by increased eosinophils. Targeting eosinophilic inflammation with biologicals may be beneficial in these patients.
It is important to note that these MoAs are interconnected and contribute to the complex pathophysiology of COPD. Research continues to unravel the intricate interplay of these mechanisms, with the goal of developing more targeted and effective therapies.
Drug used in other indications
The provided text mentions that ensifentrine (also known as ZW1528) is being investigated for its potential use in asthma in addition to COPD. One source mentions that both tanimilast (CHF6001), an inhalational selective PDE4 inhibitor, and ensifentrine, a combined PDE3/4 inhibitor, show recent therapeutic success in asthma and warrant further large-scale clinical studies. However, the provided text does not describe the specific intervention models used in these trials. It only mentions that further large-scale clinical studies are warranted for ensifentrine in asthma.