George Washko, MD

Mucus plugging is increasingly recognized as a pathophysiological feature of 

chronic obstructive pulmonary disease (COPD)

, associated in prior literature with worse symptoms, poorer quality of life, higher exacerbation risk, and increased mortality. A late-breaking integrated analysis of the replicate phase 3 OBERON and TITANIA trials introduced a segmental mucus plug score, a standardized metric scoring 18 lung segments for the presence or absence of a plug using a centralized double-read CT paradigm.

Nearly 79% of the imaging cohort had at least 1 mucus-plugged segment at baseline, and these patients had worse lung function, higher symptom burden, and more prior exacerbations than those without plugging. Tozorakimab produced a dose-dependent reduction in segmental mucus plug score at week 52, with both current and former smokers contributing to the overall effect. The finding is consistent with the earlier FRONTIER-4 CT substudy, making tozorakimab the first biologic shown to significantly reduce mucus plugging in a broad COPD population.

Tozorakimab is a monoclonal antibody inhibiting both the reduced and oxidized forms of interleukin-33, a dual mechanism the investigators say offers a biologically coherent explanation for effects on mucus dysfunction alongside inflammation. The mucus-plug finding is exploratory and was not adjusted for multiplicity, but it sits alongside the primary result from OBERON and TITANIA, where tozorakimab reduced moderate or severe exacerbations, including those requiring hospitalization or emergency care, by approximately 30% compared with placebo across 2 replicate phase 3 trials.

George Washko, MD, associate professor of medicine at Harvard Medical School and a co-author on the integrated mucus-plug analysis, spoke with 

ERS Congress 2026 held in Barcelona in September

 . In the following interview, Washko discusses what the segmental mucus plug score adds to the clinical picture of tozorakimab in COPD.

HCPLive: Why is the new segmental mucus plug score an important measure, and how does it compare with prior COPD imaging assessments?

The segmental mucus plug score gives us a standardized, quantitative way to assess mucus plugging across the lung. Each of 18 lung segments is assessed for the presence or absence of a mucus plug, producing a score from 0 to 18. This allows us to measure not only how much of the lung is affected by mucus plugging, but importantly, whether that burden changes with treatment over time. This is clinically relevant because mucus plugging is increasingly recognized as an important pathophysiological feature of COPD and has been associated with worse symptoms, poorer quality of life, increased exacerbation risk, and higher mortality. Prior CT studies helped establish those associations. What this analysis adds is a longitudinal assessment within a randomized phase 3 program, the first to show a biologic treatment, tozorakimab, can significantly reduce mucus plugging in a broad COPD population, measured at week 52. The finding is also consistent with the earlier FRONTIER-4 CT substudy, which showed a reduction in segmental mucus plug score with tozorakimab versus placebo.

HCPLive: Does mucus plugging mark a distinct, more severe COPD phenotype, or simply general disease severity?

The most important finding is that mucus plugging identified a group of patients with greater clinical disease burden. Nearly 80% of evaluable patients had at least one mucus plug at baseline, and those with mucus plugging had worse lung function, poorer quality of life, and a greater exacerbation burden than patients without mucus plugs. So mucus plugging appears to be an important imaging feature of clinically more burdensome COPD. Whether it represents a completely distinct biological phenotype independent of other measures of disease severity is a separate question, but these results reinforce that mucus plugging is not simply an incidental CT finding.

HCPLive: The mucus-plugging reduction appeared numerically larger in current smokers than former smokers. How should this be interpreted given the smaller sample?

The most robust finding is the significant reduction in mucus plug burden in the overall population, together with a dose-dependent reduction in segmental mucus plug score. The numerical finding in current smokers is interesting, however the current smoker group was a small subgroup of the overall population and therefore difficult to interpret in isolation. It is important to note that a reduction in mucus plugs was noted in both the smoker and former smoker population, with both populations contributing to the overall effect seen with tozorakimab.

HCPLive: As an exploratory endpoint without multiplicity adjustment, what weight should this finding carry alongside the primary exacerbation results?

Reducing exacerbations is a key aim for COPD treatment, as they are the most clinically meaningful events that drive disease trajectory, patient survival, and economic burden in COPD. For that reason, the most important finding is that these trials represent the first phase 3 evidence of a biologic demonstrating clinically meaningful reductions in COPD exacerbations across this broad COPD population. The mucus-plug analysis is exploratory, but it adds important biological context to the clinical efficacy results. Tozorakimab significantly reduced a CT-defined airway abnormality associated with worse COPD outcomes, and the finding is consistent with the earlier FRONTIER-4 CT substudy. The mucus data can be interpreted as complementary evidence: they strengthen the overall picture that tozorakimab is affecting both clinically meaningful exacerbations and an airway process relevant to COPD pathophysiology.

HCPLive: Is tozorakimab the first biologic to reduce mucus plugging due to a data gap, or does IL-33 blockade act on mucus specifically?

What we can say is that tozorakimab is the first biologic shown to significantly reduce mucus plugging in a broad COPD population, and there is a strong biological rationale for that effect. IL-33 sits upstream of several processes relevant to COPD. More specifically, tozorakimab uniquely inhibits IL-33 signaling in two ways: suppressing inflammation and disrupting the cycle of mucus dysfunction. This provides a biologically coherent explanation for why we would see an effect on mucus dysfunction as well as exacerbations.

HCPLive: If this mucus-plug reduction holds up, what needs to be shown next to confirm it translates into harder clinical outcomes?

What is encouraging is that the mucus-plug finding is not occurring in isolation. Higher mucus plug scores have been associated with increased exacerbation risk, accelerated lung function decline, and increased all-cause mortality. At the same time, the OBERON and TITANIA program showed that tozorakimab significantly reduced mucus plugging and also reduced moderate or severe COPD exacerbations by approximately 30% in two replicate phase 3 trials. We also saw reductions in more consequential events, including exacerbations requiring hospitalization or emergency department care. That convergence is important: the imaging effect is occurring alongside demonstrated clinical efficacy, rather than as an isolated radiographic finding.

Editor's Note: This Q&A has been lightly edited for clarity. Washko’s disclosures include Sanofi and Regeneron.

Washko G, Sciurba F, Watz H, et al. Tozorakimab reduces the number of lung segments with mucus plugs in patients with COPD at high risk of exacerbations: integrated analysis of the replicate OBERON and TITANIA phase 3 studies [late-breaking abstract]. Presented at: ERS Congress 2026; September 5-9, 2026; Barcelona, Spain.

Singh D, Guller P, Reid F, et al. A phase 2a trial of the IL-33 mAb tozorakimab in patients with COPD: FRONTIER-4. Eur Respir J. 2025;66(1):2402231.

Sciurba FC, Watz H, Bourdin A, et al. Tozorakimab to prevent COPD exacerbations. N Engl J Med. 2026. doi:10.1056/NEJMoa2606998

Articles

George Washko, MD, discusses a late-breaking OBERON/TITANIA analysis showing tozorakimab reduces segmental mucus plug scores in COPD.