Anti-IL-33 biologics represent a promising new frontier for refractory COPD, especially for patients with low type 2 inflammation who do not respond to existing treatments. Phase III data from the OBERON and TITANIA trials show tozorakimab can reduce exacerbation rates. This article unpacks the mechanism, trial results, and what pulmonologists need to know for clinical application.
For pulmonologists, the hardest conversations often happen in the exam room with a patient who has tried everything. Triple therapy, pulmonary rehab, smoking cessation programs. Still, they return every few months with another exacerbation. That familiar feeling of hitting a wall is why the respiratory community paid close attention when AstraZeneca announced positive Phase III results for tozorakimab, an anti-IL-33 monoclonal antibody, in the OBERON and TITANIA trials. The question at the APSR 2024 meeting in Hong Kong was direct: is there a role for anti-IL-33 biologics in refractory COPD? The answer, based on the data presented, appears to be yes, especially for patients who have not benefited from other biologic approaches.
Understanding the IL-33 Pathway in COPD
Interleukin-33 is an alarmin cytokine. It sits inside epithelial cells and gets released when those cells sense damage from cigarette smoke, pollution, or infection. Once outside the cell, IL-33 binds to its receptor ST2 on immune cells. This interaction triggers downstream inflammatory cascades that include both type 1 and type 2 pathways.
This dual activation is what makes IL-33 unique. Many existing biologics target a single pathway. For example, anti-IL-5 and anti-IL-4R therapies work well for eosinophilic or type 2 high inflammation. But a large subset of COPD patients, particularly those with refractory disease, show low eosinophil counts and do not respond to those drugs. IL-33 sits upstream of that fork in the road. By blocking it, you may be able to dampen inflammation across multiple pathways at once.
What the Phase III Data Tell Us
The OBERON and TITANIA trials enrolled patients with moderate to very severe COPD who had a history of exacerbations. Participants continued their usual maintenance therapy and received tozorakimab or placebo subcutaneously every four weeks.
Key results include:
- A statistically significant reduction in the annualized rate of moderate to severe exacerbations.
- Benefit was observed regardless of baseline blood eosinophil count.
- The safety profile appeared consistent with other monoclonal antibodies in this class.
For clinicians, the most striking finding was the efficacy in the low eosinophil subgroup. This group has historically been difficult to treat. Standard inhaled corticosteroids often provide limited benefit, and existing biologics have not shown consistent results. The fact that tozorakimab worked across eosinophil levels suggests that anti-IL-33 therapy could fill a genuine gap in care.
Who Should Be Considered for Anti-IL-33 Therapy?
Not every COPD patient needs a biologic. The decision to use tozorakimab or any anti-IL-33 agent should be based on clear criteria. Here is a practical framework for evaluation:
- Confirm a history of recurrent exacerbations despite optimal bronchodilator and inhaled corticosteroid use.
- Check blood eosinophil count. If it is below 150 cells per microliter, existing type 2 targeted biologics are less likely to help.
- Assess for ongoing airway inflammation through sputum or bronchial biopsy if available, but recognize that IL-33 blockade may work even without these advanced diagnostics.
The table below compares anti-IL-33 therapy with other biologic options currently available or in development for COPD.
| Biologic Target | Example Drug | Eosinophil Requirement | Primary Benefit | Refractory COPD Fit |
|---|---|---|---|---|
| IL-33 | Tozorakimab | None | Exacerbation reduction across phenotypes | Strong |
| IL-5 | Mepolizumab | High | Eosinophil reduction | Limited |
| IL-4R alpha | Dupilumab | Medium to high | Improved lung function and exacerbations | Moderate |
| TSLP | Tezepelumab | None | Exacerbation reduction | Moderate to strong |
Practical Considerations for Implementation
Starting a patient on an anti-IL-33 biologic requires more than writing a prescription. You need a structured approach to ensure success. Here are the steps I recommend discussing with your team:
- Review the patient’s exacerbation history over the past 12 months. Aim for at least two moderate to severe exacerbations.
- Perform a baseline blood eosinophil count, but do not use it as a gatekeeper. The data suggest benefit even at low counts.
- Discuss adherence. These are injectable therapies administered every four weeks. Set up a reminder system.
- Plan for a 6 to 12 month trial period. Evaluate exacerbation rates and symptom control at regular intervals.
- Coordinate with the patient’s primary care physician and any specialists involved in their care.
Expert advice from a respiratory researcher at APSR 2024: “Do not wait for perfect biomarkers. The field has been paralyzed by the search for the ideal predictor. Anti-IL-33 biologics work across a broad population. Start with patients who have failed other options and track their response carefully. That real world data will be invaluable.”
Common Pitfalls to Avoid
Even with a promising new therapy, mistakes can happen. Here are some pitfalls I have seen in early adoption of biologics for COPD:
- Expecting immediate results. Biologics reduce exacerbations over time. They are not rescue medications for acute symptoms.
- Discontinuing maintenance therapy prematurely. Tozorakimab is an add on treatment, not a replacement for bronchodilators or inhaled steroids.
- Ignoring the patient’s vaccination status. Pneumococcal and influenza vaccines remain critical for infection prevention.
- Overlooking injection site reactions. Educate patients about mild redness or swelling and when to seek medical attention.
The Future of Anti-IL-33 Therapy
The success of tozorakimab opens the door for other anti-IL-33 compounds currently in development. Researchers are also investigating combination approaches. For instance, blocking IL-33 alongside TSLP could provide even broader upstream suppression of airway inflammation. Early preclinical models suggest synergy, but clinical trials are needed.
Another area of interest is the use of anti-IL-33 biologics in patients with mucus hypersecretion. IL-33 is known to stimulate goblet cell hyperplasia. Early data from the TITANIA trial showed improvements in airway mucus plugging on CT scans. This could represent a new way to measure treatment response beyond traditional spirometry.
If you are interested in how these therapies compare with other advanced interventions, check out our piece on emerging therapies in pulmonary fibrosis. For a broader look at the biologic landscape, read about advances in respiratory biologics for severe asthma management.
Building a Personalized Treatment Plan
Every patient is different. A one size fits all approach does not work for refractory COPD. Use the following checklist when building a plan that includes an anti-IL-33 biologic:
- Confirm the patient has tried and failed on standard therapy.
- Rule out alternative causes of symptoms, such as undiagnosed heart failure or interstitial lung disease.
- Discuss the treatment goals with the patient. Is the focus on reducing exacerbations, improving daily symptoms, or both?
- Establish a baseline with a symptom diary and spirometry.
- Schedule follow up visits at 3, 6, and 12 months to review progress.
A New Chapter for Refractory COPD
For years, pulmonologists had few options for patients with low type 2 inflammation. We watched them cycle through exacerbations, each one causing more lung function decline. The arrival of anti-IL-33 biologics changes that story. The data from the OBERON and TITANIA trials are robust enough to warrant serious consideration in clinical practice.
Start by identifying one or two patients in your panel who fit the profile. Have the conversation. Explain that this is not a cure, but a tool to reduce the frequency of those dangerous exacerbations. Track the outcomes. Share your experience with colleagues. That is how we move from clinical trial data to real world impact.
If you are curious about how home monitoring tools can support your patients on biologics, take a look at our guide on how to integrate home spirometry into routine COPD management in 2026. And for a summary of the year’s biggest changes, read 5 key updates in COPD management for 2026.
The evidence is clear. Anti-IL-33 biologics have a place in the treatment of refractory COPD. The next step is for you to decide how they fit into your practice.