What Is Tozorakimab: a New Hope for COPD?

If you or someone you love has been living with chronic obstructive pulmonary disease (COPD), you’ll know all too well the exhaustion of breathless days, persistent coughs, and the fear that comes with every flare-up.

For too long, the treatment landscape has offered limited options beyond inhalers. And even the best inhaled therapies leave more than half of patients still suffering regular exacerbations. Today, courtesy of AstraZeneca, that picture may be about to change.

Introduction to Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) is a long-term, progressive lung condition that makes it increasingly difficult to breathe. Characterized by persistent airway inflammation, COPD leads to symptoms such as breathlessness, chronic cough, and the production of excess mucus. According to the World Health Organization, COPD is a major global health challenge, affecting nearly 400 million people and ranking as the third leading cause of death worldwide. While smoking is the most common risk factor, exposure to air pollutants and genetic factors can also contribute to the development of COPD. One of the most serious aspects of COPD is the occurrence of exacerbations which are sudden episodes where symptoms worsen significantly. These exacerbations not only accelerate the progression of the disease but also place a heavy burden on healthcare systems, with thousands of emergency department visits each day in the US alone. Managing airway inflammation and preventing exacerbations are therefore central goals in the treatment of COPD.

The Role of IL-33 in COPD Pathogenesis

IL-33, or interleukin-33, is a crucial molecule involved in the inflammatory processes that drive COPD, especially in patients with chronic bronchitis. When lung tissue is damaged or stressed, IL-33 is released in a reduced form (IL-33red), which activates the ST2 receptor and triggers a cascade of pro-inflammatory signals. This leads to the release of cytokines and chemokines, fueling ongoing inflammation in the airways. Over time, IL-33red can be converted into an oxidation-resistant form (IL-33ox) through oxidation and disulfide bond formation. This oxidized form signals through a different pathway involving the RAGE/EGFR complex, which is linked to airway epithelial remodeling and increased mucus production—two hallmarks of COPD. Because IL-33 plays such a central role in both inflammation and mucus dysfunction, it has emerged as a promising target for new therapies aimed at improving outcomes for COPD patients.

Groundbreaking Results From Two Major Clinical Trials

Positive high-level results from the Phase III OBERON and TITANIA trials showed that tozorakimab significantly reduced the rate of moderate-to-severe COPD exacerbations compared with placebo, in former smokers and in the overall population, which included both former and current smokers, across all blood eosinophil counts and all stages of lung function severity. These were large, randomized, placebo-controlled clinical trials representing a broad COPD population, designed to assess the safety and efficacy of IL-33 targeting biologics like tozorakimab.

This is a landmark moment. Not because it is simply another treatment showing modest benefit in a narrowly selected group, but because it worked broadly, across the full spectrum of COPD patients. These trials included patients irrespective of smoking status or eosinophil levels, making the results representative of the wider COPD community. The Phase III OBERON and TITANIA trials showed that tozorakimab reduced the annualised rate of moderate-to-severe COPD exacerbations compared with placebo.

That matters enormously to the millions of people currently told there is nothing more that can be done for them on top of their inhalers. Exacerbations often lead to patients hospitalised, increasing healthcare burden and highlighting the importance of reducing hospital admissions to improve patient outcomes.

What Is Tozorakimab and How Does It Work?

Tozorakimab is a new type of medicine called a biologic, specifically an anti IL 33 antibody developed with dual-pharmacology to inhibit both ST2 and RAGE/EGFR signalling pathways. It is a targeted antibody treatment delivered by injection that works very differently from the inhalers you may already be using.

Tozorakimab is a potential first-in-class monoclonal antibody targeting interleukin-33 (IL-33), that uniquely inhibits the signalling of the reduced and oxidised forms of IL-33, offering the potential to both reduce inflammation and disrupt the cycle of mucus dysfunction that contribute to COPD worsening. Tozorakimab is the first anti-IL-33 antibody reported to inhibit signaling through both the IL-33red–ST2 and IL-33ox–RAGE/EGFR pathways.

In simple language, IL-33 is a chemical messenger in the body that acts as an alarm signal when the lungs are stressed, damaged, or under attack. IL-33 is released in a reduced form (IL-33red), which signals via ST2, and in an oxidized form (IL-33ox), which signals via the RAGE/EGFR complex. The oxidation of IL-33 limits its ST2-dependent activities, but IL-33ox can signal via RAGE/EGFR on airway epithelial cells. IL-33 has emerged as a chief orchestrator of immunity, with roles in the pathogenesis of respiratory and inflammatory diseases, and is involved in immune responses and tissue injury. Mast cells are key immune cells that respond to IL-33 signaling, contributing to airway inflammation. The soluble form of ST2 acts as a decoy receptor for IL-33, regulating its activity. The functional activities of IL-33 include cytokine release and inflammation modulation, and tozorakimab targets these activities to help control disease processes.

Tozorakimab essentially silences that faulty alarm thus tackling the disease at its root rather than simply managing the symptoms.

What makes it particularly special is that it blocks both forms of IL-33, the reduced form and the oxidised form. Other approaches only target one. By blocking both, tozorakimab can address both the inflammatory damage and the mucus dysfunction simultaneously.

Tozorakimab as a Lead MAB

Tozorakimab (MEDI3506) stands out as a leading IL-33 monoclonal antibody, designed with high affinity for the reduced form of IL-33 (IL-33red). Its binding strength is approximately three times greater than that of the body’s natural IL-33 receptor, sST2, allowing it to effectively neutralize IL-33red and block its inflammatory effects. Tozorakimab’s rapid association rate means it can quickly bind to IL-33red in the body, preventing it from activating pro-inflammatory pathways in primary human cells and in experimental models of airway inflammation. Uniquely, while Tozorakimab does not bind directly to the oxidation-resistant form (IL-33ox), it prevents the conversion of IL-33red to IL-33ox, thereby also inhibiting the downstream effects mediated by the RAGE/EGFR signalling pathways. This dual mechanism—targeting both inflammation and epithelial dysfunction—positions Tozorakimab as a promising therapy for COPD and other IL-33-driven diseases.

Anti-IL-33 Therapy

Anti-IL-33 therapies like Tozorakimab are opening new possibilities for COPD patients by targeting the underlying inflammation that drives exacerbations and disease progression. In the OBERON and TITANIA clinical trials, the primary endpoint was the annualised rate of moderate-to-severe COPD exacerbations—a key measure of efficacy and safety in this patient population. The trial results suggest that Tozorakimab can deliver statistically significant and clinically meaningful reductions in exacerbations, offering hope for patients who continue to struggle despite standard treatments. Beyond COPD, anti-IL-33 therapies are also being explored in other inflammatory diseases, such as moderate to severe asthma and diabetic kidney disease, highlighting their broad potential. Ongoing clinical investigation will further clarify the role of Tozorakimab and similar agents in improving outcomes for patients with moderate to severe COPD and related conditions.

Why Does This Matter for COPD Patients?

To understand the significance, you need to appreciate the scale of the problem that COPD presents.

Nearly 400 million people are diagnosed with COPD globally, making it the third leading cause of death worldwide. Even when on inhaled standard of care, more than 50% of patients still experience exacerbations, putting them at increased risk of cardiopulmonary events and mortality. Notably, even patients with mild COPD or symptomatic COPD can experience exacerbations and disease progression, highlighting the need for early and targeted interventions.

Exacerbations, which are those episodes where symptoms suddenly worsen, are not just unpleasant. They are genuinely dangerous. Only 50% of COPD patients live more than 3.5 years after their first severe exacerbation. Each one accelerates disease progression, strains the heart, and raises the risk of hospitalisation or death. In advanced cases, exacerbations can increase the need for supplemental oxygen to support patients with severe airflow limitation and hypoxemia.

In the US alone, exacerbations cause more than 2,500 emergency department visits per day. The human and economic toll is immense and until now, biologics had failed to deliver a convincing answer for COPD in the way they have transformed conditions like asthma and rheumatoid arthritis. White blood cells, particularly eosinophils, play a key role in COPD-related inflammation and exacerbations, and their levels can impact both disease mechanisms and treatment responses.

What Makes These Trial Results So Significant?

The OBERON and TITANIA trials enrolled 2,306 patients in total, randomised irrespective of blood eosinophil count or smoking status and across all stages of lung function severity. These were double-blind, placebo-controlled studies conducted as part of the clinical development of tozorakimab. Patients received tozorakimab 300mg once every four weeks on top of their existing inhaled therapy for 52 weeks.

These trials represent a significant step in the early development and experimental medicine phases for anti-IL-33 therapies. This broad eligibility is crucial. Many previous biologic trials in COPD only showed benefit in patients with high levels of a specific immune marker called eosinophils, meaning most COPD patients were simply left out. Tozorakimab appears to work regardless of eosinophil levels, smoking history, or how severe the airflow limitation is.

Pharmacokinetic and pharmacodynamic modeling supported the trial design and dosing strategies for tozorakimab, optimizing its clinical application. The scientific background for these studies builds on the contributions of researchers such as Reid F and Scott IC, who have advanced understanding of the IL-33 pathway and its role in COPD inflammation and disease progression.

Professor Frank Sciurba of the University of Pittsburgh, who led the trial programme, noted that these results suggest that targeting the IL-33 pathway delivers meaningful clinical benefit in a broad COPD population, independent of smoking status and eosinophilic levels.

A Completely New Mechanism

Sharon Barr, Executive Vice President of BioPharmaceuticals R&D at AstraZeneca, described the significance from a scientific standpoint: tozorakimab works in a fundamentally different way from other biologics, inhibiting the signalling of both forms of IL-33 to decrease inflammation and disrupt the cycle of mucus dysfunction that are key disease drivers in COPD. To achieve this, researchers used advanced methods to isolate antibodies with high affinity for IL-33, such as phage display and screening with stabilized IL-33 variants. Kinetic exclusion assays were employed to precisely measure the binding kinetics and affinity of tozorakimab for IL-33red, confirming its fast association rate (8.5 × 10^7 M−1 s−1) and high affinity (KD ~30 fM), which is significantly higher than the affinity of sST2 for IL-33red. Clinical pharmacology studies have played a crucial role in understanding the pharmacokinetics and safety profile of tozorakimab, showing that it has a mean half-life of 11.7 to 17.3 days and demonstrates linear, time-independent pharmacokinetics. Importantly, tozorakimab prevents the oxidation of IL-33red, thereby inhibiting downstream IL-33ox signaling via the RAGE/EGFR pathway. In preclinical studies, tozorakimab also increased epithelial cell migration and repair, unlike other anti-IL-33/ST2 antibodies that only stop inflammation.

This dual action of fighting inflammation and mucus dysfunction at the same time is something no existing COPD treatment achieves. Current inhalers open the airways and reduce local inflammation, but they don’t get to the root cause of exacerbations in the way that IL-33 inhibition appears to.

What Happens Next?

Tozorakimab is not yet approved or available as a prescription medicine, however, based on the strength of these Phase III results, combined with existing regulatory fast-tracking, suggests it could move through the approval process at pace. Full results from the ongoing Phase III clinical trials (OBERON and TITANIA) will be presented at an upcoming medical meeting.

Two further Phase III trials called PROSPERO and MIRANDA are ongoing.

• PROSPERO is a long-term extension study tracking patients over 104 weeks, with results expected in the first half of 2026.
• MIRANDA is testing a different dosing frequency (once every two weeks) in 1,454 patients, with results also expected imminently.

Tozorakimab has already been granted Fast Track Designation by the US FDA for the treatment of COPD, as well as for severe viral lower respiratory tract disease. Fast Track designations are generally reserved for medicines that address serious unmet medical needs and which accelerates the path to approval.

Tozorakimab is also being investigated in Phase III trials for treating severe viral lung infections that could lead to Acute Respiratory Distress Syndrome (ARDS). In addition, tozorakimab is currently being investigated in multiple clinical trials for COPD and other inflammatory diseases, including atopic dermatitis and diabetic kidney disease.

What This Could Mean for You

If you have COPD and continue to experience flare-ups despite using your inhalers correctly, you may eventually be eligible for a biologic add-on therapy like tozorakimab. While it won’t replace your existing inhalers (which remain the backbone of COPD management), it could be added on top of them to provide an extra layer of protection against exacerbations.

Tozorakimab was well tolerated in clinical trials, with a favourable safety profile and no meaningful differences in adverse events compared to placebo. The safety of tozorakimab was further supported by low rates of injection site reactions and low immunogenicity in early clinical trials. In addition, tozorakimab significantly reduced serum IL-5 and IL-13 levels in patients with COPD compared with placebo. In the FRONTIER-4 and Phase 2a studies, tozorakimab achieved a statistically significant improvement in post-bronchodilator FEV1 compared with placebo.

The prospect of a once-monthly injection that tackles the underlying biology of COPD flare-ups is genuinely exciting, and these Phase III results represent the most convincing evidence yet that this approach works.

At NowPatient, we will keep you updated as tozorakimab moves through the regulatory process and gets closer to clinical availability. If you have COPD and would like to understand your current treatment options, our clinical team is here to help.