COPD has been refractory to disease modification for so long that the September 2024 approval of dupilumab felt like a category shift. For the first time in the disease's history, a biological agent targeting the underlying type 2 inflammatory pathway was approved — not just a better bronchodilator, not just an improved inhaler combination, but something that modifies the biological process driving exacerbations in a specific patient subgroup. The critical qualifier is "specific": dupilumab's benefit is concentrated in patients with eosinophilic inflammation (blood eosinophils ≥300 cells/μL), roughly 20–30% of the COPD population. The rest of the pipeline is working on two problems simultaneously: extending biologic benefit to non-eosinophilic phenotypes, and finding approaches that slow structural lung progression rather than just reducing exacerbation rates.
This article is for informational purposes only and does not constitute medical advice. Clinical trial eligibility and availability vary. Always consult a qualified healthcare professional before making any medical decisions or considering participation in a clinical trial.
Summary
COPD affects over 300 million people globally and is the third leading cause of death worldwide. Until September 2024, no biologic had been approved for COPD; dupilumab's approval for patients with eosinophils ≥300 cells/μL marks the first disease-modifying therapeutic in the condition's history. In 2026, the pipeline includes two additional anti-IL-33 biologics (itepekimab and astegolimab) in Phase 3, tezepelumab (anti-TSLP) with Phase 3 results pending, the first new bronchodilator class in 20 years (ensifentrine, approved June 2024), and early-stage lung regeneration research that remains a decade or more from clinical application.
Dupilumab for COPD: The Data Behind the Breakthrough
Dupilumab (Dupixent) targets the shared IL-4Rα receptor of IL-4 and IL-13 — the canonical type 2 inflammatory cytokines. Already approved for atopic dermatitis, asthma, nasal polyps, and eosinophilic esophagitis, the COPD program added a major indication in 2024.
The pivotal evidence came from two Phase 3 trials. BOREAS (NCT03930732, N=939) enrolled COPD patients with eosinophils ≥300 cells/μL on triple inhaler therapy and showed a 30% reduction in moderate-to-severe exacerbation rate vs. placebo (annual rate 0.78 vs. 1.10, p<0.001), with FEV1 improvement of 160 mL at 52 weeks. NOTUS (NCT04456673, N=935) confirmed these findings in a replicate design: 34% exacerbation reduction (rate 0.86 vs. 1.30) and FEV1 improvement of 139 mL. Post-hoc analyses at lower eosinophil counts (200–299 cells/μL) showed attenuated benefit, supporting the biomarker-selected label FDA approved. The approval was specifically for adults with inadequately controlled COPD and ≥300 cells/μL blood eosinophils.
Active 2026 trials are testing dupilumab at the 200–299 cells/μL threshold and in patients not on triple therapy — attempting to determine whether the eosinophil boundary is a hard biological threshold or an artifact of Phase 3 enrollment design.
Anti-IL-33 Biologics: Itepekimab and Astegolimab
Itepekimab (Sanofi/Regeneron)
Itepekimab targets IL-33 directly — an epithelial alarmin that initiates type 2 airway inflammation upstream of IL-4 and IL-13. Phase 2b results showed a clinically interesting bifurcation: ex-smokers experienced 42% exacerbation reduction vs. placebo, while current smokers showed no benefit. The proposed mechanism is that nicotine attenuates ST2 (the IL-33 receptor) expression, making the drug pharmacologically less active in active smokers.
Sanofi's AERIFY-1 (NCT04751487) and AERIFY-2 (NCT04760015) Phase 3 trials are enrolling former smokers with COPD and documented exacerbation history. Results anticipated 2026. If confirmed, this would be the first COPD biologic with a smoking status-specific label — a genuinely useful clinical differentiator from dupilumab.
Astegolimab (Roche/Genentech)
Astegolimab targets IL-33 at a distinct epitope from itepekimab. The SKYLARK Phase 3 trial (NCT04615949) in COPD with eosinophilic inflammation is enrolling, with Phase 2 asthma data suggesting a potentially steeper eosinophil response gradient — a profile that could mean meaningfully better efficacy at high eosinophil counts than dupilumab or lesser agents at lower counts.
Tezepelumab (AstraZeneca/Amgen)
Tezepelumab targets TSLP, an epithelial cytokine upstream of IL-33, IL-4, and IL-13. It's approved for severe asthma (NAVIGATOR: 70% exacerbation reduction vs. placebo across all eosinophil strata, including low-eosinophil patients). The COURSE Phase 3 trial in COPD (NCT04039113) explicitly does not restrict by eosinophil count — the hypothesis being that blocking TSLP upstream covers a broader inflammatory population than downstream targets. Phase 3 results anticipated 2026. If positive across eosinophil strata, this would be the first biologic with a plausible label for the non-eosinophilic majority.
Ensifentrine: A New Bronchodilator Mechanism After 20 Years
Ensifentrine (Ohtuvayre, Verona Pharma) received FDA approval in June 2024 — the first new bronchodilator mechanism class since the long-acting muscarinic antagonists in the early 2000s. As a dual PDE3/PDE4 inhibitor delivered via nebulization, ensifentrine simultaneously provides bronchodilation (PDE3 inhibition increases cAMP in airway smooth muscle, causing relaxation) and anti-inflammatory effects (PDE4 inhibition reduces inflammatory mediator release from eosinophils, neutrophils, and macrophages).
ENHANCE-1 and ENHANCE-2 Phase 3 trials demonstrated trough FEV1 improvements of 48–59 mL vs. placebo and significant reductions in moderate-to-severe exacerbation rates. The positioning question is where ensifentrine fits relative to LABA/LAMA combinations, which produce FEV1 improvements in the 200–300 mL range. Likely answer: as add-on therapy in patients who remain symptomatic on LABA/LAMA ± ICS. Post-marketing trials (NCT06237088) are evaluating exactly that — add-on to LABA/LAMA and triple therapy.
Lung Regeneration: Where the Research Actually Stands
Emphysema involves permanent destruction of alveolar walls — irreversible loss of elastin, collagen, and type I pneumocyte populations. The question is whether adult lung tissue retains any regenerative capacity that can be reactivated.
All-trans retinoic acid (ATRA) demonstrated alveolar regeneration in elastase-induced rat emphysema models through retinoic acid receptor activation in type II pneumocytes. Human Phase 2 trials (including NCT00000556) showed modest and inconsistent signal. HGF and FGF pathway activators are in early-phase investigation. Mesenchymal stem cell approaches are in Phase 1/2 trials in China, Brazil, and Europe — safety established, functional benefit inconsistent. The REGENAIR trial in the UK is testing a novel acellular extracellular matrix scaffold delivered bronchoscopically to emphysematous regions.
The honest clinical projection: lung regeneration is a 10–15 year horizon for any approach with real utility. For emphysema-predominant patients, the 2026 trial options are biologic and bronchodilator approaches targeting exacerbation frequency and symptom burden — not structural restoration.
What to Bring to a COPD Trial Screening Call
Most COPD biologic trials require: confirmed COPD with post-bronchodilator FEV1/FVC <0.70; FEV1 % predicted in a specified range (typically 25–70%); smoking history ≥10 pack-years; ≥2 moderate or ≥1 severe exacerbation in the past 12 months; stable disease at screening (no exacerbation within 4–6 weeks); and blood eosinophil count for any biologic trial. The eosinophil count is the gating criterion for dupilumab access and is a key stratification variable for itepekimab and astegolimab eligibility.
Information to have ready: most recent spirometry results (FEV1/FVC and FEV1 % predicted), blood eosinophil count from within the past 6 months, documented exacerbation history for the past 12 months, current inhaler names and doses, and pack-year smoking history. Academic pulmonology centers and university respiratory programs run the highest concentration of COPD biologic trials.
Key Takeaways
- Dupilumab approval for COPD (September 2024) is the first biologic in the disease's history. BOREAS and NOTUS Phase 3 trials showed 30–34% exacerbation reduction in patients with eosinophils ≥300 cells/μL. Get your blood eosinophil count before pursuing biologic trial eligibility.
- Ensifentrine (Ohtuvayre, June 2024) is the first new bronchodilator mechanism in over 20 years. Post-marketing trials are evaluating it as add-on therapy in patients on LABA/LAMA or triple therapy who remain symptomatic.
- Itepekimab AERIFY Phase 3 trials enroll former smokers specifically — smoking status affects both eligibility and anticipated treatment effect for this anti-IL-33 biologic.
- Tezepelumab (COURSE trial) is the key 2026 test of whether blocking the TSLP alarmin can benefit non-eosinophilic COPD patients — a subgroup for whom no biologic currently exists.
- Lung regeneration research is Phase 1/2 with a 10–15 year clinical horizon. The 2026 trial landscape offers meaningful options for exacerbation reduction and symptom management — not structural lung repair.