Positioning New Agents and Overcoming Real-World Barriers for Asthma and COPD

The therapeutic landscape for severe asthma has been reshaped over the past decade by biologic agents targeting type 2 inflammatory pathways, with approved options now spanning 4 mechanistic classes: anti-IgE (omalizumab), anti-IL-4/IL-13 (dupilumab), anti-IL-5 and anti-IL-5 receptor (mepolizumab, benralizumab, reslizumab, and depemokimab), and anti-thymic stromal lymphopoietin (tezepelumab).¹

Long-term extension studies across these drug classes have demonstrated sustained reductions in annualized exacerbation rates over 3 to 4 years of follow-up, with the ANANKE study of benralizumab additionally demonstrating a median improvement in pre-bronchodilator FEV1 of approximately 400 mL at 96 weeks — a magnitude that has focused attention on mucus plug resolution as a meaningful and potentially underappreciated mechanism of spirometric benefit.²

Depemokimab (Exdensur; GSK), a long-acting anti-IL-5 monoclonal antibody dosed every 6 months, received FDA approval on December 16, 2025, based on SWIFT-1 and SWIFT-2, which demonstrated 58% and 48% reductions in annualized exacerbation rates, respectively — establishing twice-yearly dosing as a first for the anti-IL-5 class.³ Despite this expanding armamentarium, prescribing rates remain far below the scale of the eligible patient population, with data from Florida indicating that only approximately 1 in 10 patients with eosinophilic asthma on inhaled corticosteroids are currently receiving biologic therapy.

Against this backdrop, HCPLive convened a panel of pulmonologists from across South Florida for an in-depth roundtable discussion on advancing biologic therapy for asthma and chronic obstructive pulmonary disease (COPD) in a complex real-world prescribing environment. The forum was moderated by Trishul Siddharthan, MD, an associate professor at the University of Miami and director of clinical trials for severe asthma and COPD, and included clinicians representing Cleveland Clinic Treasure Coast and Orlando-area medical centers to discuss bridging clinical trial data with the insurance, administrative, and patient-engagement realities of South Florida practice, including a payer environment dominated by Medicaid Advantage plans for which many high-cost biologics remain subject to active prior authorization management.

The timing of the forum reflected a field at an inflection point in COPD management. Dupilumab received FDA approval for COPD in September 2024 based on BOREAS and NOTUS, which demonstrated approximately 30% and 34% reductions in moderate-to-severe exacerbation rates, respectively, in patients with blood eosinophil counts of 300 cells/µL or greater on maximal triple inhaled therapy — alongside early FEV1 improvements that were sustained through 52 weeks.⁴ Mepolizumab's GOLD-endorsed indication in COPD, supported by the METREX and METREO programs, expanded the biologic-eligible population to patients with eosinophil counts as low as 150 cells/µL when combined with a prior-year count above 300 cells/µL.⁵

Simultaneously, phase 3 data announced in March 2026 from AstraZeneca's OBERON and TITANIA trials showed that tozorakimab, an investigational IL-33 inhibitor, met its primary endpoint of reducing annualized moderate-to-severe exacerbations in a broad COPD population independent of eosinophil count or smoking status — a finding not yet published in full but representing the first IL-33–targeting biologic to achieve this endpoint in replicate confirmatory trials.⁶

The panel reached broad consensus that biologic selection in asthma is driven in practice by a combination of comorbidity profile, patient preference for injection frequency, and insurance coverage rather than by granular pharmacologic differentiation. Dupilumab was identified as the preferred first choice for patients with concurrent atopic dermatitis or eosinophilic esophagitis given its shared indication, while mepolizumab's once-monthly dosing was frequently cited as a patient preference advantage over dupilumab's biweekly regimen. Depemokimab was positioned as a niche agent appropriate for non-adherent patients and those with needle phobia, with panel reservations expressed regarding its use in women of reproductive age and the potential for symptom recurrence in the weeks preceding a repeat dose.

The discussion of mucus plugging represented a notable clinical focal point: Siddharthan outlined VESTIGE and CASCADE data demonstrating that dupilumab and tezepelumab, respectively, reduce CT-quantified mucus plug burden within weeks of initiation — with corresponding early FEV1 improvement in patients with high baseline plug scores — an observation that may explain the disproportionate spirometric gains observed with benralizumab in ANANKE.²,⁷,⁸ Several panelists acknowledged manually reviewing CT scans for mucus plugs but noted the absence of standardized clinical scoring tools as a practical barrier, with AI-augmented fractional mucus volume platforms identified as a promising near-term solution. As one panelist noted: "There is software that's currently on the market that's AI augmented and that is actually not doing a segment by segment, but they give you a fractional mucus volume so you get a better idea of improvement."

The COPD biologic discussion surfaced both clinical enthusiasm and significant unresolved questions around prescribing access and evidence adequacy. The panel endorsed dupilumab and mepolizumab as meaningful tools for eosinophilic COPD, with panelists citing a 30% to 34% reduction in exacerbations as clinically significant given that post-hospitalization COPD mortality reaches approximately 31% within 2 years of a severe exacerbation.⁹ The distinction between emphysematous and bronchitic disease subtypes was identified as the primary driver of agent selection, with eosinophil counts between 150 and 300 cells/µL favoring mepolizumab and counts above 300 cells/µL supporting either agent. Inpatient biologic initiation programs at point of discharge — modeled on heart failure readmission-reduction protocols — were described as actively being implemented at one participating institution, with depemokimab cited as uniquely suited for this model given that a single administration confers 6 months of protection.

The greatest unmet need identified was cost-effectiveness data: several panelists noted that dupilumab's rejection by England's National Institute for Health and Care Excellence (NICE) for COPD based on cost-effectiveness modeling stands as a cautionary example of how the absence of this evidence type translates directly into restricted access. Tozorakimab was identified with near-universal enthusiasm as the most anticipated next development, with OBERON and TITANIA data suggesting exacerbation reductions in a broad population that includes patients below the 150-cells/µL eosinophil threshold that currently limits available COPD biologics.⁶ Unmet needs highlighted for future research included early-intervention studies examining whether biologic treatment of asthma can prevent COPD, formal age-extension trials for depemokimab and tezepelumab in patients under 6 years, and cost-effectiveness analyses that would most likely shift payer behavior toward broader access.

References

1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Updated 2024. Accessed June 2026. https://ginasthma.org/2024-gina-report-global-strategy-for-asthma-management-and-prevention

2. Vultaggio A, Aliani M, Altieri E, et al. Long-term effectiveness of benralizumab in severe eosinophilic asthma patients treated for 96 weeks: data from the ANANKE study. Respir Res. 2023;24(1):135. doi:10.1186/s12931-023-02439-w

3. Jackson DJ, Wechsler ME, Jackson DJ, et al; SWIFT-1 and SWIFT-2 Investigators. Twice-yearly depemokimab in severe asthma with an eosinophilic phenotype. N Engl J Med. 2024;391(24):2337–2349. doi:10.1056/NEJMoa2406673

4. Bhatt SP, Rabe KF, Hanania NA, et al; BOREAS Investigators. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023;389(3):205–214. doi:10.1056/NEJMoa2303951

5. Pavord ID, Chanez P, Criner GJ, et al; METREX and METREO Investigators. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N Engl J Med. 2017;377(17):1613–1629. doi:10.1056/NEJMoa1708208

6. AstraZeneca. Tozorakimab met primary endpoint in both OBERON and TITANIA phase III trials in patients with COPD. Press release. March 27, 2026. Accessed June 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/tozorakimab-met-primary-endpoint-in-oberon-titania-phase-iii-trials-in-patients-with-copd.html

7. Maspero J, Laidlaw TM, Onoue M, et al. Effect of dupilumab on exhaled nitric oxide, mucus plugs, and functional respiratory imaging in patients with type 2 asthma (VESTIGE): a randomised, double-blind, placebo-controlled, phase 4 trial. Lancet Respir Med. 2025. doi:10.1016/S2213-2600(24)00362-X

8. Nordenmark LH, Hellqvist Å, Emson C, et al. Tezepelumab and mucus plugs in patients with moderate-to-severe asthma. NEJM Evid. 2023;2(10):EVIDoa2300135. doi:10.1056/EVIDoa2300135

9. Sethi S, Yin J, Anderson PK. Hospitalization for acute exacerbations of COPD and 2-year mortality: a systematic review and meta-analysis. Respir Med. 2017;122:1–8. doi:10.1016/j.rmed.2016.11.004