Shots:
- Tozorakimab demonstrated a potential first-in-class advantage in COPD, becoming the first IL-33 biologic to achieve positive outcomes across three pivotal Phase III trials (OBERON, TITANIA, and MIRANDA), highlighting the clinical relevance of targeting both reduced and oxidized forms of IL-33 to reduce exacerbations in a broad patient population.
- The LUNA Phase III programme enrolled the most comprehensive COPD biologic population studied to date, including current and former smokers across all eosinophil levels and lung function severities, suggesting the potential for broader applicability beyond the patient subsets typically targeted by existing biologics.
- PharmaShots welcomes Caterina Brindicci, Senior Vice President & Global Head, Research and Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, and Frank C. Sciurba, MD, FCCP, Tenured Professor, University of Pittsburgh School of Medicine, for an insightful discussion on the evolving role of IL-33 inhibition in COPD, the scientific differentiation of tozorakimab, and its potential to redefine disease management across a heterogeneous patient population.
Saurabh: To begin, what key considerations supported the progression of Tozorakimab into pivotal Phase III trials for COPD?
Caterina: Everything that we do at AstraZeneca is driven by two things – patient need and following the science.
The impact of COPD is shocking – up to half of COPD patients still experience exacerbations even when taking standard-of-care inhaled therapies, putting them at risk of serious health consequences including hospitalization and death. By enhancing our understanding of disease biology we’re uncovering novel drivers of disease, and selecting the right target remains the most important decision we make.
Over a decade ago, scientists were beginning to uncover IL-33 as a key pathway involved in the biology of COPD. IL-33 is an alarmin cytokine that is released in response to tissue damage from both environmental and biological triggers. Our scientists made a major breakthrough in the understanding of IL-33, discovering two distinct forms – a reduced form (which activates immune cells through the ST2 pathway), and a newly discovered oxidized form (IL-33ox). Crucially, this discovery transformed our understanding of the biology of IL-33 in COPD and ultimately changed the direction of our scientific programme.
A further landmark discovery identified a novel signalling pathway for the newly discovered oxidised form, which drives COPD epithelial pathogenesis via an ST2-independent RAGE/EGFR signalling complex, disrupting the cycle of mucus production in COPD. Based on this evolving science, we made the bold decision to redesign tozorakimab to uniquely inhibit the signalling of both forms of IL-33.
Importantly this meant accepting that we would no longer be the first IL-33 biologic to read out a Phase III trial. But, by following the science, we strongly believed that this was the right scientific approach and had the potential to provide a meaningful clinical benefit for patients. This gave us the confidence to progress into Phase III before we had the full Phase II dataset in hand.
With the results from the Phase III LUNA Programme for tozorakimab in COPD, we are seeing that the scientific decisions made throughout development are translating into meaningful clinical benefit for patients.
Saurabh: With both trials achieving their primary endpoints, how should these outcomes be interpreted in terms of clinical relevance and patient impact?
Caterina: COPD is one of the most urgent public health threats of our time and a leading cause of death globally. Just 50% of patients live more than 3.5 years after their first severe COPD exacerbation.
Against this backdrop, the positive results from OBERON, TITANIA and MIRANDA represent a major scientific advance. Tozorakimab is the first IL-33 biologic to be successful in three pivotal Phase III COPD trials, supporting the potential of this novel mechanism in a disease where innovation has historically been challenging.
What is also particularly important to me is the breadth of the patient population we studied. Our trials for tozorakimab recruited the most comprehensive patient population studied for any COPD biologic to date, including current and former smokers, independent of blood eosinophil levels and across lung function severity.
This data suggests that tozorakimab has the potential to be a first-in-class monoclonal antibody with significant and broad implications in clinical practice.
Saurabh: Moving beyond the trials, how does Tozorakimab align with AstraZeneca’s long-term strategy in respiratory and immunology?
Caterina: Our ambition is to transform care for patients with respiratory and immune-mediated diseases. As an established leader in respiratory care, with a 50-year heritage and a growing portfolio of medicines, we are committed to addressing the vast unmet needs of chronic, and often debilitating, diseases with a pipeline and portfolio of inhaled medicines, biologics and new modalities aimed at previously unreachable biologic targets.
Our ambition is to eliminate COPD as a leading cause of death. With our transformative portfolio, we are working to address a broad range of patients across the disease journey. Tozorakimab is the cornerstone of our COPD biologics pipeline, and these positive Phase III results demonstrate its potential to be a first-in-class new treatment option for COPD patients who continue to face high unmet medical needs.
Beyond COPD, we’re continuing to explore the broader potential of tozorakimab in a Phase III clinical trial evaluating its use in severe viral lower respiratory disease (TILIA) and in a Phase II trial in asthma (UMBRIEL). Our programme reflects our belief in tozorakimab’s scientific differentiation and opportunity to help a broad range of patients across indications.
Saurabh: Targeting upstream drivers such as IL-33 represents a shift in approach, how significant could this be in redefining disease management?
Caterina: As a scientific community, our understanding of COPD and COPD biology have evolved most significantly over the last decade. We now recognise COPD as a highly heterogenous disease with multiple drivers and inflammatory pathways involved.
What makes IL-33 so interesting is that it is an upstream orchestrator of many downstream inflammatory pathways involved in COPD and disease progression. That creates an opportunity to address inflammation more broadly and provide for a better, and hopefully broader, impact on COPD.
Tozorakimab reflects this differentiated approach. By working in a fundamentally different way from other biologics, inhibiting signalling of the reduced and oxidised forms of IL-33, it is designed to both decrease inflammation and disrupt the cycle of mucus dysfunction that are key disease drivers in COPD.
The results for tozorakimab are a major advance in COPD. Now, for the first time, we have three positive Phase III trials for an IL-33 biologic in COPD which could represent a significant change in the way the disease is managed in the future.
Saurabh: Given the inherent heterogeneity of COPD highlighted in the LUNA programme, how should the consistency of Tozorakimab’s efficacy across diverse patient populations be interpreted?
Frank: We saw highly clinically meaningful results both in terms of the broad population studied and the efficacy observed, however at this stage the company is only disclosing the primary endpoints. The full results will be shared with the medical community at a future meeting.
Saurabh: The trials suggest benefits independent of smoking status and eosinophilic levels, how significant is this finding in addressing long-standing treatment gaps in COPD?
Frank: The population recruited for OBERON and TITANIA trials included former and current smokers, and patients across EOS levels and across all stages of lung function severity. We saw highly clinically meaningful results both in terms of this broad population studied and the efficacy observed.
There is a need for options that help address the high remaining unmet need in COPD: even one COPD exacerbation increases the risk of structural damage, hospitalisations, future cardiopulmonary events, and even death. Preventing these is a significant treatment priority in COPD, especially for the 50% of patients on inhaled standard of care who are still at risk for exacerbations.
Currently approved biologics for COPD were studied in populations with high eosinophilic inflammation levels (e.g. ≥300 or ≥150).
A biologic studied in the most comprehensive population of patients regardless of smoking status, across blood eosinophil counts, and across all stages of lung function severity that shows either equivalent or higher rates of exacerbation reduction would contribute to filling an unmet need and be highly clinically meaningful.
Saurabh: From an investigator’s standpoint, how does targeting the IL-33 pathway reshape current thinking around inflammation in COPD?
Frank: IL-33 functions as a key messenger released from cells that line the airways, and it plays a key role in both TH2 high eosinophilic, and non-TH2 neutrophilic associated immune processes involved in COPD and other respiratory diseases. Tozorakimab uniquely inhibits signaling of the reduced and oxidized forms of IL-33, offering the potential to both reduce inflammation and disrupt the cycle of mucus dysfunction that contribute to COPD worsening.
Saurabh: Considering the high global burden of exacerbations and hospitalizations, how do these results translate into potential real-world clinical impact?
Frank: COPD remains one of the greatest respiratory health challenges of our time: COPD exacerbations have a profound impact on the lives of those with the disease, accelerating disease progression, increasing hospitalisations, increasing the risk of future cardiopulmonary events, and increasing the risk of death.
A biologic studied in the most comprehensive population of patients regardless of smoking status, across blood eosinophil counts, and across all stages of lung function severity that shows either equivalent or higher rates of exacerbation reduction would be highly clinically meaningful.
The positive OBERON and TITANIA trials suggest that tozorakimab, a potential first-in-class monoclonal antibody targeting interleukin-33 (IL-33) that uniquely inhibits signaling of the reduced and oxidized forms of IL-33, may have positive benefits for these patients who continue to exacerbate while on standard of care inhaled therapy, offering hope for more patients living with this heterogenous disease.
Saurabh: What aspects of the trial data provide the strongest confidence in the robustness and reproducibility of the outcomes?
Frank: The positive high-level results from these two Phase III trials in COPD have demonstrated tozorakimab’ s efficacy and safety in COPD, meeting their primary endpoints as part of the largest COPD biologic programme to date.
We look forward to sharing the full data from the TITANIA and OBERON trials with the scientific community at a future medical meeting.
About Caterina Brindicci
As Senior Vice President & Global Head Research and Development, Respiratory & Immunology, Caterina Brindicci works end-to-end from pre-clinical discovery research through to Phase III, regulatory submission, approval, and subsequently into life cycle management. Caterina leads a global team of +900 inspirational scientists, clinicians, biometrics experts, and regulatory affairs specialists.
Caterina is a Respiratory Physician, holding a PhD in clinical pharmacology and molecular biology from Imperial College London and an MBA from Bocconi University. Health
Caterina plays a pivotal role in AstraZeneca’s BioPharmaceuticals R&D Leadership Team and holds +15 years of experience in senior roles across the pharmaceutical industry. Prior to joining industry, Caterina worked as a Pulmonologist at the National Heart & Lung Institute and Royal Brompton Hospital.
About Frank Sciurba
Frank C. Sciurba, M.D., FCCP is a Tenured Professor at the University of Pittsburgh School of Medicine. He is the director of the Emphysema COPD Research Center and the Director of the Clinical Pulmonary physiology laboratories and pulmonary rehabilitation program. He earned his B.S. degree in Biochemistry from the University of Illinois and attended medical school at the University of Chicago Pritzker School of Medicine. Dr. Sciurba completed his residency and fellowship in Pulmonary and Critical Care Medicine at the University of Pittsburgh Medical Center.
Dr. Sciurba’s research has been inspired by real clinical problems facing his patients. He has authored over 400 peer reviewed publications with a particular emphasis on lung physiology and COPD. Dr. Sciurba is fully supported on grants from the National Institutes of Health, foundations, and industry. He is also a member of the Western PA Regional American Lung Association Board.
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