Treatment with tozorakimab as an add-on to inhaled maintenance therapy helps lessen the frequency of moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations, and this benefit is observed in both former and current smokers.
In two replicate phase III trials, OBERON and TITANIA, the primary endpoint of annualized rate of moderate or severe exacerbations that occurred over a 52-week period in the cohort of former smokers was 1.34 events with tozorakimab vs 1.90 events with placebo (rate ratio, 0.71, 95 percent confidence interval [CI], 0.57–0.88; p=0.002) in OBERON and 1.37 vs 2.07 events, respectively (rate ratio, 0.66, 95 percent CI, 0.55–0.80; p<0.001), in TITANIA. [N Engl J Med 2026;doi:10.1056/NEJMoa2606998]
Results in the overall population of current and former smokers also favoured tozorakimab. The annualized rate of moderate or severe exacerbations was 1.41 events with tozorakimab vs 2.0 events with placebo (rate ratio, 0.70, 95 percent CI, 0.58–0.85; p<0.001) in OBERON and 1.44 vs 2.03 events, respectively (rate ratio, 0.71, 95 percent CI, 0.59–0.84; p<0.001), in TITANIA.
“The trial populations included patients with a broad range of blood eosinophil counts and severity of airflow obstruction, which reflects real-world presentation among patients,” said first author Frank Sciurba from the University of Pittsburgh, Pittsburgh, US, and colleagues.
“In the prespecified pooled analysis, the efficacy of tozorakimab appeared to be similar across most subgroups,” Sciurba and colleagues added.
The role of IL-33 in COPD
COPD patients, including current and former smokers, have elevated interleukin (IL)-33 levels, which have been associated with an increased risk of exacerbations, as the authors noted. [Eur Respir J 2024;64:2400347; Am J Respir Crit Care Med 2023;208:1075-1087; Am J Respir Crit Care Med 2023;208:395-405]
Tozorakimab, a high-affinity human anti–IL-33 monoclonal antibody, helps prevent exacerbations by inhibiting the activity of both the reduced form and the oxidized form of IL-33, they added.
“Consistent findings across the replicate OBERON and TITANIA trials confirm the efficacy of tozorakimab in COPD,” Sciurba and colleagues said.
There are other drugs targeting the IL-33–ST2 pathway, including itepekimab and astegolimab. However, their efficacy in terms of reducing the frequency of moderate or severe COPD exacerbations have not been consistently demonstrated, particularly in replicate phase III trials AERIFY-1 and AERIFY-2 for itepekimab and in the phase IIb ALIENTO and phase III ARNASA for astegolimab. [Am J Respir Crit Care Med 2026;212:Suppl 2:599; Lancet 2026;407:2027-2039]
Nevertheless, “the efficacy signals support the clinical value of IL-33 as a therapeutic target in COPD,” the authors said.
OBERON and TITANIA
The replicate phase III trials enrolled adults with COPD who were current or former smokers and had a history of exacerbations in the previous year despite receiving stable standard-of-care inhaled maintenance therapy. There was no eligibility requirement related to blood eosinophil count.
Patients were randomly assigned to receive tozorakimab 300 mg or placebo. Treatment was administered subcutaneously every 4 weeks for 52 weeks. OBERON included 446 patients in the tozorakimab group and 431 in the placebo group, while TITANIA included 438 in the tozorakimab group and 435 in the placebo group.
The demographic and clinical characteristics of the patients at baseline were balanced between the groups in the cohort of former smokers and in the overall population in the two trials. The mean age of the patients was 67.1 years in OBERON and 68 years in TITANIA, and the majority of the patients were male (65.8 percent in OBERON and 68.1 percent in TITANIA). Most patients received triple inhaled maintenance therapy (91 percent and 90 percent in the respective trials).
The severity of airflow obstruction among patients ranged from mild to very severe (grades 1 through 4 according to Global Initiative for Chronic Obstructive Lung Disease criteria), and the blood eosinophil counts at screening covered a broad range.
Moderate exacerbations were defined as worsening COPD symptoms resulting in treatment with systemic glucocorticoids for at least 3 days or antibiotics or both, or an emergency department visit lasting less than 24 h with intensive treatment. Severe exacerbations were defined as worsening COPD symptoms resulting in hospitalization for at least 24 h or death.
Safety
Adverse events (AEs) occurred in 70.4 percent of patients in the tozorakimab group and in 77.2 percent of those in the placebo group in OBERON and in 80.1 percent and 79.8 percent, respectively, in TITANIA. The incidence of serious AEs was also similar in the two groups in OBERON (23.3 percent and 27 percent, respectively) and TITANIA (31.1 percent and 32.4 percent, respectively).
AEs of special interest were balanced between the two groups in all categories, with the exception of injection-site reactions, which occurred in 6.5 percent of patients in the tozorakimab group and in 3.3 percent of those in the placebo group in OBERON and in 9.8 percent and 4.6 percent, respectively, in TITANIA. Serious AEs that resulted in death occurred in 1.3 percent and 1.2 percent patients in the respective groups in OBERON and in 2.5 percent and 0.9 percent, respectively, in TITANIA.
The prevalence and incidence of antidrug antibodies were between 2 percent and 4 percent across treatment groups.