Frank C. Sciurba, MD

OBERON and TITANIA Showcase Tozorakimab's Emerging Benefit for COPD, With Frank Sciurba, MD

The investigational IL-33 inhibitor tozorakimab (AstraZeneca) produced statistically significant and clinically meaningful reductions in annualized moderate-to-severe exacerbation rates in people with chronic obstructive pulmonary disease (COPD) in both phase 3 OBERON and TITANIA trials, with efficacy extending across all blood eosinophil levels and both former and current smokers.

spoke with Frank C. Sciurba, MD, chief investigator of the LUNA program, about the news as announced by AstraZeneca. Sciurba, tenured professor of medicine and director of the Emphysema COPD Research Center at the University of Pittsburgh School of Medicine, described the findings as indicative of broad potential applicability in a disease where current biologics serve a narrow patient subset.

OBERON and TITANIA were identically designed, randomized, double-blind, placebo-controlled phase 3 trials enrolling a combined 2,306 adults with COPD, randomized to tozorakimab 300 mg subcutaneously every 4 weeks or placebo for 52 weeks on a background of standard-of-care inhaled maintenance therapy. Both trials targeted a frequent exacerbator population — the same enrichment strategy applied across most contemporary COPD biologic development programs — and enrolled patients without restriction on blood eosinophil count, including both former and current smokers. The primary endpoint in both studies was the annualized rate of moderate-to-severe COPD exacerbations in the primary population of former smokers, with the overall population of former and current smokers together assessed as a key secondary population.

Sciurba explained that the decision to enroll current smokers alongside former smokers was deliberate and clinically meaningful. Prior signals from agents targeting the IL-33 pathway had raised questions about whether active smoking might attenuate efficacy — a consideration given that cigarette smoke can modulate epithelial IL-33 release and downstream signaling. By prospectively enrolling both populations, OBERON and TITANIA were positioned to assess this question directly. The results, as reported in the press release, showed benefit in both the primary former-smoker population and the combined population including current smokers, suggesting that smoking status did not substantially limit treatment effect. Similarly, the inclusion of patients across all blood eosinophil categories — a deliberate departure from the enrichment strategies used in the COPD approval programs for dupilumab and IL-5 inhibitors — was intended to characterize tozorakimab's utility in the low-eosinophil majority, which represents approximately 70% of COPD patients and currently has no approved biologic option. The press release confirmed efficacy across all eosinophil levels, consistent with the mechanistic rationale that IL-33 sits upstream of both Th2 and Th1/Th17 inflammatory pathways.

Sciurba was careful to note that the full results — including subgroup analyses, secondary endpoint data covering symptoms, lung function, and quality of life, and complete safety characterization — remain to be presented at a forthcoming scientific meeting and have not yet been disclosed. He expressed confidence that the magnitude of benefit reported would be viewed as clinically, not just statistically, meaningful by COPD specialists, and that the breadth of the effect across subgroups positions tozorakimab as potentially complementary to rather than simply competitive with existing agents.

Two additional studies under the broader LUNA program will provide further data in the near term. PROSPERO, a long-term extension enrolling completers from OBERON and TITANIA, will assess outcomes including severe exacerbations — events that are less frequent than moderate exacerbations and require extended follow-up to accrue adequate numbers — over an additional year of observation. MIRANDA is evaluating a more frequent dosing regimen of tozorakimab every 2 weeks, compared with the every-4-week schedule used in OBERON and TITANIA, to determine whether dosing intensity affects primary and secondary outcomes. Sciurba also noted that, should tozorakimab reach approval, the field will face the productive challenge of positioning multiple mechanistically distinct COPD biologics relative to one another. He expressed hope for head-to-head comparative trials in the longer term, while acknowledging that near-term priority lies in presenting and debating the full dataset with the specialist community.

“I'm super excited to be in the box seats on this and and then to you know, work with our community to decide [tozorakimab’s] position in the treatment regimen of COPD,” Sciurba said.

Sciurba has reported disclosures including AstraZeneca, COPD Foundation, Gala Therapeutics, GlaxoSmithKline, National Institute of Health, Nuvaira, Patient-Centered Outcomes Research Institute, Pulmonx Corporation, Sano, U.S. Department of Defense, University of Pittsburgh, and Verona Pharma.

AstraZeneca. Tozorakimab met primary endpoint in both OBERON and TITANIA phase III trials in patients with COPD. Press release. March 27, 2026. Accessed March 27, 2026. 

https://www.businesswire.com/news/home/20260327464200/en/Tozorakimab-met-primary-endpoint-in-both-OBERON-and-TITANIA-Phase-III-trials-in-patients-with-COPD

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The phase 3 trials enrolled frequent exacerbators regardless of eosinophil count or smoking status.

Reducing COPD Exacerbations With Tozorakimab, With Frank Sciurba, MD

Tozorakimab, an investigational monoclonal antibody targeting the IL-33 pathway has demonstrated statistically significant and clinically meaningful reductions in 

 (COPD) exacerbations in 2 phase 3 trials, with benefit extending across all blood eosinophil counts and all stages of lung function severity, according to an announcement by AstraZeneca on the phase 3 OBERON and TITANIA trials.

spoke with investigator Frank C. Sciurba, MD, about the new findings, who argued that tozorakimab could open a new therapeutic avenue for the majority of COPD patients who remain inadequately served by current biologic options.

Sciurba, tenured professor of medicine and director of the Emphysema COPD Research Center at the University of Pittsburgh School of Medicine, serves as chief investigator of the LUNA program evaluating tozorakimab (AstraZeneca) in COPD.

Both TITANIA and OBERON were randomized, double-blind, placebo-controlled trials with a combined enrollment of 2,306 patients, recruited irrespective of blood eosinophil count, smoking status, or lung function severity stage, all of whom received tozorakimab 300 mg subcutaneously once every 4 weeks or placebo for 52 weeks on top of standard-of-care inhaled maintenance therapy. The primary endpoint in both trials was the annualized rate of moderate-to-severe COPD exacerbations in the primary population of former smokers; key secondary endpoints assessed the overall population of former and current smokers combined. Both studies met their primary and key secondary endpoints, with tozorakimab demonstrating a statistically significant reduction in moderate-to-severe exacerbations versus placebo in the primary population and in the broader overall population. The safety profile was described as generally favorable and consistent with prior tozorakimab experience. Full results will be presented at a forthcoming scientific meeting; no specific effect-size data have yet been disclosed.

Sciurba described tozorakimab's mechanism as mechanistically upstream of every currently approved biologic in COPD. IL-33 is released by the airway epithelium in response to a variety of stimuli — microbial, irritant, and allergic — and upon release, it engages both innate and adaptive immune responses, feeding into the Th2-mediated pathway that drives eosinophilic inflammation as well as the Th1 and Th17 pathways associated with neutrophilic inflammation. Tozorakimab uniquely inhibits both the reduced and oxidised forms of IL-33, potentially disrupting not only the inflammatory cascade but also the cycle of mucus dysfunction that contributes to disease progression in COPD. This positioning upstream of existing therapeutic targets means the drug theoretically modulates pathways that IL-4 receptor antagonists such as dupilumab and IL-5 inhibitors do not reach — in particular the Th1-dominant inflammatory environment that characterizes most COPD patients.

That distinction has direct clinical implications. The currently approved biologics for COPD — dupilumab, which targets the IL-4 receptor α chain and thus blocks IL-4 and IL-13 signaling, and IL-5 inhibitors — are mechanistically specific to the Th2 pathway and are most effective in patients with elevated blood eosinophil counts. Sciurba estimated that Th2-predominant patients represent approximately 30% of the overall COPD population, leaving the majority — those with low eosinophil counts and a Th1- or Th17-dominant inflammatory phenotype — without a targeted biologic option. This group tends to respond poorly to inhaled corticosteroids and, data suggest, may also derive less benefit from systemic steroids during exacerbations. The OBERON and TITANIA finding that tozorakimab reduced exacerbations across all blood eosinophil counts therefore carries particular significance: it raises the possibility that IL-33 blockade may provide benefit regardless of the dominant inflammatory subtype, addressing a population for which no comparable agent currently exists.

Sciurba noted a pharmacological nuance in this context: the Th1 pathway, while contributing to pathological inflammation in COPD when excessively activated, also serves important homeostatic functions in antimicrobial defense, antiviral immunity, and cancer surveillance. Therapeutic strategies that broadly suppress Th1 responses therefore carry theoretical risks that pathway-specific targeting approaches must carefully calibrate. The OBERON and TITANIA safety data, described as favorable, will be scrutinized in this context when full results are disclosed. Additional trials under the LUNA program — including PROSPERO, a long-term extension study enrolling completers from OBERON and TITANIA, and MIRANDA, assessing an alternative dosing regimen — are ongoing, with data expected in the first half of 2026.

“Tozarakimab is a monoclonal against the IL-33 ligand, and it's involved in a lot of the inflammatory pathways that are affected in COPD. It interestingly affects both Th2 pathways as well as Th1 pathways, and that is of great interest in COPD,” Sciurba said.

Tozorakimab significantly reduced moderate-to-severe exacerbations in COPD regardless of blood eosinophil count.

Expanding Precision Medicine in COPD With Mepolizumab, with Frank Sciurba, MD

The recent approval of mepolizumab for chronic obstructive pulmonary disease (COPD) marks another step forward for the treatment landscape, offering clinicians a biologic therapy that targets a distinct inflammatory pathway.

 Unlike traditional COPD regimens, which rely heavily on long-acting bronchodilators and inhaled corticosteroids, mepolizumab acts through IL-5 modulation to address TH2-driven inflammation, particularly in patients with elevated eosinophil counts.

Following the 2023 approval of dupilumab, which targets the IL-4/IL-13 axis, mepolizumab becomes the second biologic option for TH2-high COPD and expands the toolkit for precision medicine in a historically underserved population.

 While approximately 20–30% of patients may qualify based on eosinophil levels, the drug’s safety profile has been favorable across trials, showing no increased adverse events over placebo.

 spoke with principal investigator Frank Sciurba, MD, Associate Professor of Medicine at the University of Pittsburgh School of Medicine, and Medical Director of the Pulmonary Physiology Laboratory in the Division of Pulmonary, Allergy and Critical Care Medicine, to learn more about his reaction to mepolizumab’s approval and what it means for the COPD population.

“Just within the last couple years now, we've really now started to achieve that promise of new products for COPD with new mechanisms and indications. The first TH2 modulating drug, dupilumab, was approved last year, and it's a different mechanism of action. This is IL-5 modulation versus the IL-4a receptor, which modulates IL-13 and IL-4, and it's very likely that those differences will result in some difference in responses in individual patients," Sciurba said.

Nucala (mepolizumab) approved by US FDA for use in adults with chronic obstructive pulmonary disease (COPD). News release. GSK. May 22, 2025. https://www.gsk.com/en-gb/media/press-releases/nucala-mepolizumab-approved-by-us-fda/

Dupixent® (dupilumab) Approved in the U.S. as the First-ever Biologic Medicine for Patients with COPD. Regeneron Pharmaceuticals, Inc. September 27, 2024. https://www.globenewswire.com/news-release/2024/09/27/2954552/0/en/Dupixent-dupilumab-Approved-in-the-U-S-as-the-First-ever-Biologic-Medicine-for-Patients-with-COPD.html. Date accessed: September 27, 2024.

Sciurba shared his excitement for the recent approval of mepolizumab for people with COPD and an eosinophilic phenotype.

Frank C. Sciurba, MD

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