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Reducing COPD Exacerbations With Tozorakimab, With Frank Sciurba, MD
Tozorakimab significantly reduced moderate-to-severe exacerbations in COPD regardless of blood eosinophil count.
Tozorakimab, an investigational monoclonal antibody targeting the IL-33 pathway has demonstrated statistically significant and clinically meaningful reductions in chronic obstructive pulmonary disease (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.
HCPLive 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.
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.
