Few areas of respiratory medicine have faced as much challenge as chronic obstructive pulmonary disease (COPD) drug development. Despite decades of work, COPD remains a leading global cause of death. Over the past ten years, a procession of biologics and novel anti-inflammatory agents advanced to phase 3 only to miss their primary endpoints. Those disappointments have reshaped how we think about COPD and re-centered attention on what reliably improves outcomes: optimized, guideline-directed care.
In 2025 the picture is more nuanced. The first reproducibly positive biologic trials have emerged, and a novel small molecule has been approved. The improvements are impressive but limited to carefully selected patient populations.
For two decades, progress was steady but incremental. Widespread uptake of long-acting bronchodilators and, later, single-inhaler triple therapy (ICS/LABA/LAMA) reduced moderate–severe exacerbations and likely improved survival in high-risk patients, as shown in IMPACT and ETHOS (Lipson et al., N Engl J Med 2018; Rabe et al., N Engl J Med 2020). Beyond inhaled combinations, only a few anti-inflammatory add-ons achieved durable clinical impact. Roflumilast benefited patients with chronic bronchitis and severe obstruction but was limited by gastrointestinal side effects (Calverley et al., Lancet 2009). Chronic azithromycin reduced exacerbations in frequent exacerbators, tempered by antimicrobial-resistance and QT concerns (Albert et al., N Engl J Med 2011).
As biologics transformed asthma, COPD trials shifted toward “treatable traits.” The hope was that neutralizing cytokines such as IL-5, IL-33, or TSLP would reproduce asthma’s success. The last few years showed how different COPD biology is.
The twin phase-3 trials GALATHEA and TERRANOVA evaluated benralizumab in >2,500 patients with moderate–very severe COPD and frequent exacerbations on optimized inhaled therapy. Neither reduced annualized exacerbation rate versus placebo; near-complete eosinophil depletion did not translate into fewer events (Criner et al., N Engl J Med 2019). Exploratory analyses suggested a delayed effect after an index exacerbation, but AstraZeneca’s 2025 update on the follow-on program reported another primary-endpoint miss. The lesson is population-biology mismatch: eosinophil depletion does not address the dominant drivers of most COPD exacerbations and may not fully do so among those patients with high eosinophils (who may have concomitant drivers of disease beyond eosinophilia alone).
Despite strong efficacy in severe asthma (Menzies-Gow et al., N Engl J Med 2021), tezepelumab failed to significantly reduce moderate/severe COPD exacerbations overall in a phase-2a COPD program when added to background inhaled therapy (COURSE/UPSTREAM; ATS 2024 reporting). Neutral secondary outcomes (lung function, symptoms) reinforced that epithelial alarmin signaling in COPD-especially among current smokers-may not mirror T2-high asthma.
Phase-2 work suggested greater benefit among former smokers, consistent with reduced ongoing epithelial injury (Rabe et al., ERJ Open Res 2024). The paired phase-3 studies AERIFY-1 and AERIFY-2 in 2025 delivered mixed topline results, one positive, one negative, illustrating how event-rate variability can sway outcomes in large global COPD trials.
Repurposed classes also disappointed. Simvastatin did not prevent exacerbations in patients without cardiovascular indications (STATCOPE; Criner et al., N Engl J Med 2014). Metoprolol failed to delay time to first exacerbation and increased severe respiratory events (BLOCK-COPD; Dransfield et al., N Engl J Med 2019). Vitamin D supplementation showed no consistent benefit outside profound deficiency (Martineau et al., Lancet Respir Med 2015). Modifying comorbidity pathways rarely changes COPD’s structural and infectious drivers.
Collectively, these misses do not indict the targets outright; they indict how COPD trials were designed: broad “frequent exacerbator” entry criteria, heterogeneous inflammatory drivers, progressively lower background event rates, and endpoints dominated by infectious and neutrophilic triggers that the tested cytokine axis cannot meaningfully modify.
Amid the disappointments, several successes have reshaped the narrative.
By targeting IL-4/IL-13 signaling, dupilumab modulates T2 inflammation. BOREAS and NOTUS showed ~30–34% reductions in annualized moderate–severe exacerbations and clinically meaningful FEV₁ gains in patients with blood eosinophils ≥300 cells/µL on top of optimized triple therapy (Bhatt et al., N Engl J Med 2023). In 2024, the FDA approved dupilumab as the first biologic for COPD, specifically for eosinophilic COPD inadequately controlled on standard care.
Earlier mixed results gave way to the positive phase-3 MATINEE trial in 2025, which reported a 21% reduction in exacerbations versus placebo among eosinophilic COPD patients already on triple therapy (Sciurba et al., N Engl J Med 2025). Along with dupilumab, this establishes eosinophilic COPD as a treatable minority phenotype.
The inhaled dual PDE3/4 inhibitor ensifentrine (Ohtuvayre™) gained FDA approval in 2024 based on ENHANCE-1/-2, which demonstrated consistent FEV₁ improvements (~90–94 mL over placebo) and symptom relief as maintenance add-on therapy, with modest exacerbation signals (Anzueto et al AJRCC). It is the first novel non-steroidal mechanism for COPD in nearly two decades.
Five themes recur across empirical discussion.
COPD is not one disease. Molecular and histopathologic profiling reveal overlapping endotypes-neutrophilic, eosinophilic, infection-driven, mucus-dominant, small-airway collapse.
Background care keeps improving. Placebo-arm exacerbation rates have fallen as inhaled therapy, vaccination, and smoking abstinence improve, narrowing the absolute margin for add-on benefit. A meta-regression suggests ~50% decline per decade (Andreas et al., Respir Res 2019).
Exacerbations are multifactorial. Many events are infectious and neutrophilic, driven by bacterial/viral dynamics or mucus plugging rather than T2 cytokines; pathway-specific biologics may affect only a subset.
Smoking status matters. Ongoing tobacco exposure sustains epithelial injury and colonization, which can overwhelm cytokine blockade. Signals with anti-IL-33 (and perhaps Ensifentrine) were stronger in former smokers.
Endpoints and design. Annualized exacerbation rate is variable and seasonally sensitive. Structural imaging, severe-exacerbation-weighted endpoints, and trajectories of lung function and health status may better capture pathway effects.
The new precision therapies do not replace fundamentals. In dupilumab and mepolizumab trials, every participant received optimized triple therapy, careful adherence support, and non-pharmacologic measures when available. GOLD guidance continues to emphasize that foundational management yields the largest absolute gains for most patients: correct inhaler selection and technique, single-inhaler triple therapy in high-risk patients, pulmonary rehabilitation, vaccination, smoking cessation, long-term oxygen therapy for chronic hypoxemia, and nocturnal non-invasive ventilation in selected patients with chronic hypercapnic failure.
Device-based therapies can work adjunctively to address physiology directly. Airway-clearance devices reduce mucus burden and V/Q mismatch in secretion-prone phenotypes; home ventilatory support augments alveolar ventilation and lowers PaCO₂ in chronic hypercapnic failure; long-term oxygen improves survival in persistent severe hypoxemia. Durable medical equipment partners-including Apria-deliver these elements reliably in the home, close the hospital-to-home gap, and sustain adherence.
After years of disappointment, 2025 finally brings reproducible progress-but only when biology, design, and clinical reality align. The failures of benralizumab, tezepelumab, and others were not wasted; they mapped what COPD is not in the context of clinical trials. The successes of dupilumab, mepolizumab, and ensifentrine reveal what COPD is: heterogeneous disease in which targeted therapy works when anchored to the right biology and layered on top of standard care.
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