Q&A: Tozorakimab Reduces COPD Exacerbations in Phase 3 OBERON and TITANIA Trials

Chronic obstructive pulmonary disease (COPD) affects nearly 400 million people worldwide and remains the 3rd leading cause of death globally. Even with inhaled standard of care, more than 50% of patients continue to experience exacerbations, placing them at heightened risk of cardiopulmonary events, hospitalization, and death. Current approved biologics for COPD target the Th2 inflammatory pathway and provide meaningful benefit, but they are effective in only roughly 30% of patients, leaving the majority with significant unmet need.

Tozorakimab, a monoclonal antibody targeting interleukin-33 (IL-33), takes a mechanistically distinct approach. Unlike agents that target downstream Th2 mediators such as IL-4, IL-13, or IL-5, tozorakimab acts upstream in the inflammatory cascade, inhibiting both the reduced and oxidized forms of IL-33 to suppress inflammation and disrupt mucus dysfunction. Because IL-33 is proximal to both Th2 and Th1/Th17 pathways, the agent holds potential for patients across a broader range of eosinophil levels and smoking histories than existing biologics address.

Results from the phase 3 OBERON and TITANIA trials, part of AstraZeneca's LUNA development program, showed that tozorakimab 300mg administered once every 4 weeks reduced the annualized rate of moderate-to-severe COPD exacerbations compared with placebo. The trials enrolled 2306 patients regardless of blood eosinophil count, smoking status, or lung function severity stage. Efficacy was reported in both the primary population of former smokers and in the overall population, which included current smokers.

Frank Sciurba, MD, professor of pulmonary and critical care medicine at the University of Pittsburgh and chief investigator of the LUNA program, noted the breadth of the findings. "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," Sciurba said in a press release. "COPD has long been a difficult-to-treat disease with inherent heterogeneity and significant unmet need."

In the following interview, Frank Sciurba, MD, FCCP, discusses the mechanism of tozorakimab, the OBERON and TITANIA trial designs, the populations with the most pressing unmet need, and what clinicians can expect from the forthcoming PROSPERO and MIRANDA data readouts.

Q: To start, can you give some background on tozorakimab and how it works in COPD?

Sciurba: Tozorakimab is a monoclonal antibody directed against the IL‑33 ligand. IL‑33 is involved in multiple inflammatory pathways that are relevant in COPD. What makes it particularly interesting is that it influences both Th2 and Th1 pathways.

Right now in COPD, we have two approved monoclonal antibodies that are focused on the Th2 pathway and are often used in patients with high eosinophil counts. One targets the IL‑4α receptor (impacting IL‑4 and IL‑13 signaling), and another targets IL‑5—both are quite specific to Th2 biology.

IL‑33 sits upstream of those pathways. It’s released by the epithelium in response to a variety of stimuli—microbial, irritant, allergic—and then shapes both innate and adaptive immune responses, leading downstream into Th2 pathways but also influencing Th1 and Th17 inflammation. That means it may impact not only eosinophilic pathways but also neutrophilic and other non‑Th2 inflammatory processes, which are highly relevant in COPD.

The hope is that by targeting IL‑33, we can meaningfully reduce exacerbations. At the same time, we have to be cautious with Th1 suppression because those pathways are important for host defense against bacteria, viruses, and malignancy. So it’s a balance: dampening excessive inflammation in COPD without undermining essential immune functions.

Q: What can you tell us about the OBERON and TITANIA studies and the populations they enrolled?

Sciurba: OBERON and TITANIA are phase 3 registration trials, and like many biologic programs in COPD, they focus on frequent exacerbators.

A key design feature is that they include patients regardless of eosinophil level and include both current and former smokers. That’s important, because some prior IL‑33–pathway work raised the question of reduced efficacy in active smokers. These trials were specifically structured to allow us to examine:

• Former vs current smokers
• High vs low eosinophil levels

That gives us a broader, more representative COPD population than in some of the earlier biologic programs that were more narrowly focused on high‑eosinophil phenotypes.

Q: What is the unmet need you’re hoping to address with this mechanism?

Sciurba: The most obvious unmet need is in low‑eosinophil COPD, which generally reflects low Th2 and often higher Th1/Th17 activity.

These patients:

• Tend to be less responsive to inhaled corticosteroids
• Have weaker evidence supporting systemic steroids even during exacerbations when the inflammation is not Th2‑high

They actually represent the majority of COPD patients, whereas Th2‑high patients are probably closer to 30% of the population. The current Th2‑targeted monoclonals have been an important addition, but they don’t address the larger segment of COPD patients with non‑Th2‑dominant disease. IL‑33 targeting potentially gives us a way to address that gap.

Q: What was the primary endpoint in OBERON and TITANIA, and what can you say about the top‑line results?

Sciurba: Both trials were essentially identical registration studies. Each included:

• A q4‑week active dosing arm versus placebo
• A primary endpoint of the annualized rate of moderate or severe COPD exacerbations

These are classic frequent exacerbator trials by design.

In terms of results, I’m limited to what’s already been made public in the press release and can’t go into detailed numbers yet. What I can say is:

• The primary endpoint of annualized moderate/severe exacerbations was meaningfully improved in both trials.
• The magnitude of effect, as reported, appears to be at a level that most experts would consider clinically important, not just statistically significant.
• The reported benefit was seen across eosinophil strata and across smoking status (current and former smokers), suggesting broad applicability.

The detailed subgroup analyses and secondary endpoints haven’t been presented yet, so we can’t discuss those specifics. But from the top‑line data, there is real reason for optimism that this could be an add‑on option alongside existing approved biologics in COPD.

Q: You mentioned PROSPERO and MIRANDA. What are those studies evaluating, and what are you most interested to see from them?

Sciurba: The overall program is referred to as the Luna program. OBERON and TITANIA are the first two major components. Then we have:

1. PROSPERO – a long‑term extension study
   • Enrolls patients coming out of Oberon and Titania
   • Extends observation for up to an additional 52 weeks
   • A key interest is in more severe exacerbations, which are less frequent events. You need longer follow‑up and more patient‑years to really characterize those outcomes adequately.
2. MIRANDA – a separate study exploring more frequent dosing
   • Uses q2‑week dosing, compared with the q4‑week regimen used in Oberon and Titania
   • The question is whether increased dosing frequency changes the primary and secondary outcomes in a meaningful way.

Those readouts will add texture to how we think about dose, schedule, durability of effect, and impact on severe events. I don’t have those results yet—so even if I wanted to share them, I couldn’t—but they’ll be important in defining the full clinical profile.

Q: Looking beyond these specific trials, what remaining questions or future research priorities do you see for tozorakimab in COPD?

Sciurba: As the data are fully released, the first task for the community will be to understand where this agent fits among existing therapies. COPD, much like asthma, is becoming more complex as we gain therapeutic options, but that’s a good problem to have.

Key priorities include:

• Careful evaluation of secondary outcomes:
  • Symptoms
  • Lung function
  • Other patient‑centered measures
• Understanding which phenotypes or endotypes derive the greatest benefit
• Exploring how tozorakimab might be sequenced or combined with existing biologics and standard therapies
• Longer‑term assessment of safety, especially around host defense and infection risk, given IL‑33’s role in immune responses

Ultimately, I’d love to see head‑to‑head trials between different biologic strategies in COPD. That’s likely further down the road, but it’s the kind of work that will really clarify the optimal treatment algorithms.

For now, bringing a new, effective option into the armamentarium—especially one with broad applicability across eosinophil levels and smoking status—is a major step. Then it will be up to the clinical and research community to refine how and when to use it to best serve our patients.

Q: Any final thoughts for clinicians managing COPD patients today?

Sciurba: I’d say we’re entering a very exciting era in COPD care. We’re moving beyond a one‑size‑fits‑all approach toward biologically informed treatment choices. If the full data continue to support what we’re seeing at the top‑line level, tozorakimab has the potential to become an important addition to our existing options.

The challenge—and opportunity—for clinicians will be to stay engaged with the emerging data, think critically about patient selection, and work collaboratively to integrate new agents thoughtfully into practice. It’s a good challenge to have, especially for patients who have historically had limited options beyond inhaled therapies and systemic steroids.