Shots:
- Tozorakimab reinforced its potential as a first-in-class COPD biologic with a third positive Phase III trial (MIRANDA), complementing OBERON and TITANIA and strengthening AstraZeneca’s regulatory package while validating IL-33 as a critical therapeutic pathway in COPD.
- The MIRANDA trial demonstrated efficacy across one of the broadest COPD populations studied for a biologic, including former and current smokers, patients across all eosinophil levels, and varying degrees of lung function severity, highlighting the potential for broader real-world clinical applicability.
- 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 conversation on tozorakimab’s strategic importance within AstraZeneca’s respiratory portfolio, the significance of three positive Phase III trials, and how dual inhibition of reduced and oxidized IL-33 could redefine treatment for a broad spectrum of COPD patients.
Saurabh: With three positive Phase III trials (MIRANDA, OBERON, TITANIA), how does AstraZeneca position tozorakimab within its respiratory portfolio?
Caterina: Our ambition at AstraZeneca is to eliminate COPD as a leading cause of death and truly transform care for patients through our broad portfolio. A key part of our commitment is our long-standing investment in respiratory diseases – and as a result, we have the broadest and most robust pipeline in the industry.
Tozorakimab is big piece of our COPD biologics pipeline.
With an estimated 50% of people on triple inhaled therapy still experiencing COPD exacerbations and requiring further treatment escalation, significant unmet needs for new treatment options remain.
The positive high-level results from OBERON, TITANIA and MIRANDA demonstrate tozorakimab’s potential to be a first-in-class new treatment option for COPD patients who continue to face high unmet medical needs.
Saurabh: How significant is this third positive Phase III readout in terms of regulatory strategy and upcoming submissions?
Caterina: Following the high-level results for MIRANDA in addition to OBERON and TITANIA, we now have three confirmatory Phase III trials to support our discussion with regulators. This marks the first time an IL-33 biologic has seen three positive Phase III trial readouts. We look forward to sharing the full results with regulators in due course and bringing this medicine to patients as quickly as possible.
Saurabh: COPD remains a highly heterogeneous disease. How does tozorakimab address this complexity compared to existing biologics?
Caterina: COPD is a highly heterogeneous disease with multiple underlying inflammatory drivers, which is one reason it has historically been so difficult to treat effectively.
We need treatments that can address the different underlying mechanisms of COPD. Tozorakimab was studied in one of the broadest patient populations of former and current smokers, independent of blood eosinophil count, and across lung function severity.
What makes tozorakimab different is that it targets the top of the inflammatory cascade, uniquely inhibiting IL-33 signalling in two ways – through both the reduced and oxidised forms of IL-33 via the ST2 and RAGE/EGFR pathways. With this truly differentiated mechanism of action, tozorakimab offers the potential to decrease inflammation and reduce mucus production that contributes to COPD worsening. Tozorakimab has also been investigated in the most comprehensive patient population studied for any COPD biologic.
Saurabh: Can you comment on the commercial potential of tozorakimab and its role in AstraZeneca’s long-term growth strategy?
Caterina: Tozorakimab is expected to be one of AstraZeneca’s 20 new medicines and a key contributor to our $80 billion total revenue ambition by 2030.
Saurabh: How does this program align with AstraZeneca’s broader focus on respiratory and immunology innovation?
Caterina: We are committed to transforming care for some of the most debilitating and chronic respiratory and immune-mediated diseases, with COPD remaining one of the greatest respiratory health challenges of our time.
Our scientists have helped shape the science of IL-33 in COPD, playing a central role in driving understanding of the IL-33 pathway’s involvement in COPD and tozorakimab was purpose-built to address key drivers of COPD disease activity.
With tozorakimab, we have a potential first-in-class monoclonal antibody targeting IL-33, that uniquely inhibits signalling of the reduced and oxidised forms of IL-33 via the ST2 and RAGE/EGFR pathways. This mechanism offers the potential to decrease inflammation and disrupt the cycle of mucus dysfunction that contributes to COPD worsening.
We are proud to be driving such innovation which represents a potential major shift in the way COPD can be treated in the future.
Saurabh: Are there plans to expand tozorakimab into other indications beyond COPD, such as asthma or viral respiratory diseases?
Caterina: I am very excited about tozorakimab’s potential in other diseases. Currently, we are studying tozorakimab in LRTD (viral lung infections) with our Phase III TILIA trial that is ongoing, and also in asthma, with Phase II data expected in 2027. We look forward to sharing the results with the medical community in due course.
Saurabh: How do you envision the competitive landscape evolving, particularly with other biologics targeting inflammatory pathways in COPD?
Caterina: COPD isn’t a single, uniform disease. It is an incredibly complex, heterogeneous disease, requiring multiple approaches to treatment.
We see multiple drivers of inflammation that span across many biological pathways and show up differently from patient to patient. That’s why optimising therapy and care, especially for those who remain symptomatic or continue to exacerbate, is so critical.
COPD’s complex pathophysiology and varied clinical manifestations add another layer of challenge. Examples include: emphysema, dyspnea, chronic cough, mucus overproduction, persistent inflammation, airway remodelling and tissue destruction, and epithelial injury—varying widely between patients.
Altogether, this reinforces the need for tailored, multifaceted treatment strategies that address the many mechanisms driving disease activity.
With tozorakimab, we have established IL-33 as a critical pathway for COPD. Our R&D team followed the science, strengthened the understanding of IL-33 and purpose-built tozorakimab as the first biologic for COPD to specifically address the 2 key disease drivers within the IL-33 pathway.
Beyond this, we have a transformative portfolio in COPD to address this and establish leadership across inhaled, biologics and novel oral and inhaled medicines for patients who don’t respond to inhaled standard of care but won’t be prescribed a biologic.
Saurabh: Could you briefly describe the design and objectives of the Phase III MIRANDA trial evaluating tozorakimab in COPD?
Frank: MIRANDA is a Phase III double-blind, placebo-controlled trial investigating the efficacy and safety of tozorakimab in adults with symptomatic COPD and a history of a history of moderate or severe COPD exacerbations in the 12 months prior to enrolment. Patients received tozorakimab 300mg or placebo on top of standard of care once every two weeks.
Our objective was to assess tozorakimab’s ability to reduce the annualized rate of moderate-to-severe COPD exacerbations in the primary population of former smokers with COPD, as well as in the overall population, which included former and current smokers, and patients across all blood eosinophil counts and all stages of lung function severity.
Saurabh: The study met its primary endpoint of reducing moderate-to-severe exacerbations – how clinically meaningful are these findings for patients who remain symptomatic despite standard of care?
Frank: Up to half of patients today still experience exacerbations even when taking standard-of-care inhaled therapies, which puts them at risk of serious health consequences including hospitalization and death.
The positive high-level results from the MIRANDA trial, in addition to OBERON and TITANIA, suggest that tozorakimab may have positive benefits for patients who continue to exacerbate while on standard-of-care therapy.
Saurabh: Tozorakimab demonstrated efficacy across both former and current smokers. How important is this broad applicability in the COPD treatment landscape?
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 hospitalizations, increasing the risk of future cardiopulmonary events, and increasing the risk of death.
A biologic studied in the most comprehensive, real-world–representative population – encompassing patients irrespective of smoking status, spanning the full range of blood eosinophil levels, and including all degrees of lung function severity – provides evidence that is directly applicable to everyday clinical practice. Demonstrating reductions in exacerbations across these diverse subgroups underscores its clinical relevance and highlights its potential to address unmet needs across the treatment landscape.
Saurabh: The trial included patients across varying eosinophil levels and disease severity. What does this suggest about the mechanism of action targeting IL-33?
Frank: Based on research spearheaded by AstraZeneca scientists, we know that there are two forms of IL-33: the reduced form activates immune cells through the ST2 pathway, whereas the oxidized form activates the RAGE/EGFR pathways to disrupt the cycle of mucus production in COPD.
Tozorakimab provides a unique mechanism of action, inhibiting the signaling of both the reduced and oxidized forms of IL-33 via the ST2 and RAGE/EGFR pathways, offering the potential to decrease inflammation and disrupt the cycle of mucus dysfunction that contribute to COPD worsening.
Saurabh: How does the efficacy observed in MIRANDA compare with earlier Phase III trials such as OBERON and TITANIA?
Frank: Following MIRANDA, we now have three confirmatory statistically significant Phase III trials for tozorakimab in COPD. These additional positive results further strengthen our confidence in tozorakimab’s potential as a first-in-class COPD biologic treatment.
Saurabh: Could you elaborate on the safety and tolerability profile observed in this study, and how it aligns with previous data?
Frank: In the MIRANDA Phase III trial, tozorakimab was generally well tolerated, with a favorable safety profile consistent with previous trials.
Saurabh: Given that patients were already on inhaled standard therapies, how do you see tozorakimab fitting into the current treatment paradigm?
Frank: Even with inhaled standard of care, more than 50% of patients continue to experience exacerbations, putting them at risk of cardiopulmonary events, hospitalization, and even death. Current approved biologics for COPD target the Th2 inflammatory pathway and whilst they provide meaningful benefit, they are effective in only roughly 30% of patients, leaving the majority with significant unmet need.
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, tozorakimab holds potential for patients across a broader range of eosinophil levels and smoking histories than existing biologics address.
Saurabh: What are the key unmet needs in COPD that this therapy could potentially address?
Frank: Even when on inhaled standard-of-care, approximately 50% of patients living with COPD still experience exacerbations, which can increase a patient’s risk of heart attack, stroke, even death.
Results from the Phase III trials OBERON, TITANIA and now MIRANDA suggest that tozorakimab may have positive benefits for these patients who continue to exacerbate while on standard-of-care inhaled therapy, as tozorakimab provides a new mechanism of action in COPD – uniquely inhibiting both the reduced and oxidized forms of IL-33 via the ST2 and RAGE/EGFR pathways.
Saurabh: Are there any specific patient subgroups that appeared to benefit more prominently from treatment?
Frank: For now, we are just focusing on the high-level results which demonstrated tozorakimab’s efficacy across the broadest patient population studied for a COPD biologic. We look forward to sharing the full data and any further analyses 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.
Related Post: IL-33 Breakthrough in COPD: Caterina Brindicci and Frank Sciurba on Tozorakimab’s Phase III Success