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OBERON and TITANIA Showcase Tozorakimab's Emerging Benefit for COPD, With Frank Sciurba, MD
The phase 3 trials enrolled frequent exacerbators regardless of eosinophil count or smoking status.
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.
HCPLive 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.
