IL-33 Inhibitor Tozorakimab Cuts COPD Exacerbations in Phase 3 Trials

An investigational interleukin-33 (IL-33)–targeting monoclonal antibody, tozorakimab, met its primary endpoint in both the OBERON and TITANIA phase 3 trials, reducing the annualized rate of moderate-to-severe chronic obstructive pulmonary disease (COPD) exacerbations compared with placebo in a broad patient population, according to high-level results announced by AstraZeneca on March 27, 2026.

According to AstraZeneca, the findings, which have not yet been published in full in a peer-reviewed journal, position tozorakimab as the first IL-33–targeting biologic to demonstrate statistically significant reductions in COPD exacerbations across 2 replicate confirmatory trials.

“These trial results suggest that targeting the IL-33 pathway with tozorakimab delivers meaningful clinical benefit in a trial representing a broad COPD population, independent of smoking status and eosinophilic levels,” said chief investigator of the LUNA program Frank Sciurba, MD, professor of Pulmonary and Critical Care Medicine at the University of Pittsburgh.1

Trial Design and Topline Findings

OBERON (NCT05166889) and TITANIA (NCT05158387) are replicate Phase III, double-blind, placebo-controlled trials enrolling adults with symptomatic COPD who had a history of at least 2 moderate or at least 1 severe exacerbation in the 12 months prior to enrollment.2,3

A combined total of 2306 patients were randomized across both trials, irrespective of blood eosinophil count or smoking status, and across all stages of lung function severity.2,3

Participants were required to have received inhaled standard-of-care maintenance therapy for a minimum of 3 months before enrollment. They were subsequently randomized to receive tozorakimab 300 mg administered subcutaneously once every 4 weeks, or placebo, added to their background inhaled therapy over 52 weeks.2,3

The primary endpoint in both trials was the annualized rate of moderate-to-severe COPD exacerbations in the primary population of former smokers. A key secondary endpoint assessed the annualized rate of moderate-to-severe exacerbations in the overall population, which included both former and current smokers.2,3

According to the press release, tozorakimab met the primary endpoint in both OBERON and TITANIA and also demonstrated a reduction in exacerbation rates in the overall population.¹

Specific magnitude-of-effect data, including rate ratios, confidence intervals, and P-values, were not disclosed in the high-level announcement. Tozorakimab was described as generally well-tolerated with a favorable safety profile; detailed safety data were not reported.1

Full results are expected to be presented at an upcoming medical meeting, according to AstraZeneca.1

Tozorakimab’s Mechanism of Action and Drug Background

Tozorakimab (also designated MEDI3506) is a fully human immunoglobulin G monoclonal antibody binds IL-33, an alarmin cytokine released in response to cellular damage, infection, and environmental stressors.1,2,3

According to published preclinical and clinical pharmacology data, tozorakimab uniquely inhibits IL-33 signaling through two distinct pathways: the canonical ST2 receptor pathway and the RAGE/EGFR signaling complex, the latter of which is activated by oxidized IL-33.

This dual inhibitory mechanism is proposed to both attenuate downstream type 2 and non–type 2 inflammation and disrupt the cycle of mucus hypersecretion and epithelial dysfunction implicated in COPD progression.1,2,3

The phase 2a FRONTIER-4 trial evaluated tozorakimab in patients with COPD and provided earlier-phase evidence supporting the biological rationale and tolerability profile of this approach. Results from the trial were published in the European Respiratory Journal in 2025.4

Tozorakimab has received Fast Track Designation from the US Food and Drug Administration for the treatment of severe viral lower respiratory tract disease in November 2023 and for COPD in December 2024. The agent is also under investigation in a phase 3 trial for severe viral lower respiratory tract infection (TILIA; NCT05624450) and a phase 2 dose-ranging trial in uncontrolled asthma (UMBRIEL; NCT06932263).1

What’s Next for Tozorakimab

Two additional phase 3 trials within the LUNA program remain ongoing. PROSPERO (NCT05742802) is a long-term extension trial enrolling completers of OBERON and TITANIA, with a primary endpoint of annualized severe exacerbation rate over 104 weeks in former smokers. According to AstraZeneca, results are expected in the first half of 2026. 1

MIRANDA (NCT06040086) is investigating a more frequent dosing regimen of tozorakimab 300 mg every 2 weeks in a similar population (n=1454), with results also anticipated in the first half of 2026.1

Regulatory submission timelines have not been announced. 1

References

1. AstraZeneca. Tozorakimab met primary endpoint in both OBERON and TITANIA Phase III trials in patients with COPD [press release]. Wilmington, DE: AstraZeneca; March 27, 2026. Available at: https://www.businesswire.com/news/home/20260327464200/en/Tozorakimab-met-primary-endpoint-in-both-OBERON-and-TITANIA-Phase-III-trials-in-patients-with-COPD
2. ClinicalTrials.gov. Efficacy and Safety of Tozorakimab in Symptomatic Chronic Obstructive Pulmonary Disease With a History of Exacerbations (OBERON). NCT05166889. Available at: https://clinicaltrials.gov/study/NCT05166889. Accessed March 2026.
3. ClinicalTrials.gov. Efficacy and Safety of Tozorakimab in Symptomatic Chronic Obstructive Pulmonary Disease With a History of Exacerbations (TITANIA). NCT05158387. Available at: https://clinicaltrials.gov/study/NCT05158387. Accessed March 2026.
4. Singh D, Guller P, Reid F, et al. A phase 2a trial of the IL-33 monoclonal antibody tozorakimab in patients with COPD: FRONTIER-4. Eur Respir J. 2025;66(1):2402231. Published 2025 Jul 14. doi:10.1183/13993003.02231-2024