Biologics Across the Airway: Selection, Remission Goals, and Real-World Barriers

The management of severe asthma and chronic obstructive pulmonary disease (COPD) has been transformed over the past several years by the recognition that type 2 (T2) inflammation — characterized by eosinophilic infiltration, elevated fractional exhaled nitric oxide (FeNO), and IgE-mediated signaling — represents a distinct, therapeutically targetable biological axis across both conditions. In severe asthma, biologics targeting the interleukin (IL)-4/13, IL-5, IL-5 receptor alpha (IL-5Rα), and thymic stromal lymphopoietin (TSLP) pathways have accumulated robust, long-term efficacy and safety data. Dupilumab demonstrated sustained reductions in exacerbation rates and FEV1 improvements through 148 weeks in the TRAVERSE open-label extension,¹ while benralizumab showed a stable safety profile with no new signals over 5 years in the MELTEMI extension.² The most recent addition to the asthma biologic armamentarium, depemokimab — an ultra–long-acting anti-IL-5 monoclonal antibody — received FDA approval in December 2025 under the brand name Exdensur, supported by data from the phase 3 SWIFT-1 and SWIFT-2 trials demonstrating 58% and 48% reductions in annualized exacerbation rates vs placebo, respectively.³ In COPD, where the prevailing inflammatory paradigm historically centered on neutrophilic pathways, the landscape has shifted considerably: an estimated 20%–40% of patients with COPD harbor an eosinophilic phenotype associated with increased exacerbation risk,⁴ and both dupilumab and mepolizumab now carry regulatory approval as add-on therapies for this subset, based on the BOREAS/NOTUS and MATINEE trial programs, respectively.⁵˒⁶˒⁷

Against this backdrop, HCPLive convened a virtual clinical forum in March 2026 moderated by Joe Khabbaza, MD, a pulmonary and critical care physician at Cleveland Clinic, that featured 12 additional panelists — including pulmonologists, a critical care specialist, and a physician assistant — drawn from academic medical centers and community practices across the Midwest and Southeast United States. Participants included clinicians from Cleveland Clinic, practices in Altoona, Pennsylvania, Mishawaka, Indiana, Morehead, Kentucky, and Oakland, Illinois, and a pulmonologist practicing in Atlanta, Georgia — representing a range of clinical contexts from large academic systems to independent community practice.

The forum convened at a moment of particular relevance to the pulmonology community: clinicians now face a biologic landscape encompassing more approved agents than can be navigated by phenotype alone, alongside mounting pressure from payers, evolving questions about optimal sequencing, and an urgent need to define where emerging agents fit in day-to-day practice. The group's stated objectives — to examine biomarker-driven escalation criteria, identify real-world barriers to biologic initiation, and apply emerging trial data to patient selection in both asthma and COPD — addressed precisely the decision points that practitioners encounter across care settings. The GOLD 2026 report, which now formally includes dupilumab and mepolizumab as escalation options for patients with ongoing exacerbations, provided additional urgency to the COPD portion of the discussion.⁸

The most clinically substantive discussion in the asthma segment centered on biologic selection and the field's shift from a treatment goal of symptom control toward clinical remission. Panelists broadly agreed that phenotyping — primarily via blood eosinophil count, with FeNO as a secondary tool — underpins escalation decisions, with thresholds of 150 and 300 cells/µL anchoring most clinical reasoning. Dupilumab emerged as a common first-line choice for patients with elevated eosinophils and FeNO or allergic features, while tezepelumab was preferred for T2-low patients and those lacking clear phenotypic markers. Benralizumab showed a slight practical advantage over mepolizumab in at least 1 panelist's experience based on patient-perceived benefit.

“Even if they are controlled, I think having an obsession of always knowing what somebody's EOS are, that's kind of been my biggest thing. And when I trained… I never thought about this stuff… Now it's just always what are their EOS and FeNO, most people have that biomarker already, which is kind of unique for a biomarker as well,” Khabbaza said.

Regarding depemokimab, the group identified the twice-yearly dosing schedule as most relevant for patients who require in-office biologic administration or who struggle with treatment adherence, while acknowledging that clinical experience is limited given the agent's recent approval. Mucus plugging data from VESTIGE⁹ and CASCADE¹⁰ were acknowledged as scientifically interesting — both trials demonstrated CT-assessed reductions in mucus plug scores with dupilumab and tezepelumab, respectively — but multiple panelists stated these findings have not changed their prescribing approach, as clinicians are not routinely obtaining CT scans to identify mucus plugging in the absence of other indications. A recurring theme across the asthma discussion was frustration with payer restrictions: prior authorization requirements, insurer unfamiliarity with T2 inflammation as a treatment rationale, and mandates to maintain inhaled corticosteroid therapy even when patients have achieved durable biologic-mediated control.

Turning to COPD, panelists reflected a field gaining practical confidence in biologic use but still working through significant uncertainties in patient selection and agent positioning. The eosinophilic COPD phenotype — driven by T2 inflammation independent of or concurrent with asthma overlap — was recognized as clinically meaningful, with panelists noting they now routinely check eosinophil counts in COPD patients and use them to guide both ICS use and biologic eligibility. When choosing between dupilumab and mepolizumab in COPD, the group relied heavily on study inclusion criteria: dupilumab was preferred for patients with eosinophils ≥300 cells/µL and chronic bronchitis predominance, while mepolizumab was favored for eosinophils in the 150–300 cells/µL range, severe airflow limitation (FEV1 <30%), and pure emphysema phenotypes. Clinical responses in COPD were described as slower to manifest and less dramatic than in asthma, reflecting the coexistence of irreversible obstruction and parenchymal disease alongside the treatable T2 component.

“I think generally going to the biologics earlier in these patients just to avoid any amount of steroid if you can is a valuable goal. I was also going to mention the problem that I think probably many of us have had. The patients feel so well that they don't take their maintenance medications like they're supposed to. Then they get a ding from the insurance company, we're going to stop this stuff because you're not filling your maintenance. So just that subtle reminder that you feel so well, you don't need these other medications, you have to take them because otherwise we're going to get behind the evolved insurance people,” one panelist said.

Polling conducted during the forum revealed that approximately half of panelists identified payer support and reimbursement guidance as the factor that would most improve their ability to integrate biologics into COPD care — a finding that distilled much of the session's underlying tension. Unmet needs flagged by the group included an absence of approved targeted therapies for T2-low, neutrophilic-predominant COPD, with tezepelumab and anti-IL-33 agents under investigation; brensocatib was noted as an agent being explored off-label in patients with overlapping bronchiectasis.

References

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