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Phase 3 MIRANDA found tozorakimab reduced COPD exacerbations in former smokers despite inhaled maintenance therapy.
AstraZeneca said its investigational anti–interleukin-33 monoclonal antibody tozorakimab met the primary end point in the phase 3 MIRANDA trial, reducing the annualized rate of moderate-to-severe exacerbations in former smokers with chronic obstructive pulmonary disease (COPD) who remained at risk despite inhaled maintenance therapy. The company also reported a meaningful benefit in the overall population including current and former smokers, a key secondary end point in MIRANDA.1
“These results add to the growing body of evidence that indicates tozorakimab delivered meaningful clinical benefits for COPD patients who urgently need new treatment options,” Frank Sciurba, MD, FCCP, professor of pulmonary and critical care medicine at the University of Pittsburgh and chief investigator of the LUNA program, said in the company statement.1 If confirmed in full data presentation and regulatory review, the findings could add to a limited biologic treatment landscape in COPD, where exacerbations remain common despite dual or triple inhaled therapy.2
MIRANDA is a randomized, double-blind, placebo-controlled phase 3 trial that enrolled 1454 adults with symptomatic COPD and a history of at least 2 moderate or 1 severe exacerbation in the prior 12 months.1 Participants included former and current smokers across blood eosinophil levels and lung function severity stages. Patients received tozorakimab 300 mg every 2 weeks or placebo for 52 weeks on top of inhaled standard of care.
“Tozarakimab is a monoclonal against the IL-33 ligand, and it's involved in a lot of the inflammatory pathways that are affected in COPD. It interestingly affects both Th2 pathways as well as Th1 pathways, and that is of great interest in COPD,” Sciurba said in a previous interview with HCPLive.
Only high-level results were disclosed. AstraZeneca did not report absolute exacerbation rates, rate ratios, confidence intervals, or detailed adverse-event frequencies.1 The company said the drug was “generally well tolerated” and that the safety profile was consistent with earlier studies, although a closer look at the data will have to wait for a medical meeting presentation or journal publication.
The MIRANDA announcement follows AstraZeneca’s March report that the replicate phase 3 OBERON and TITANIA trials, which evaluated tozorakimab 300 mg every 4 weeks, also met their primary end points.3 Together, these studies form the core of the LUNA development program, with the ongoing PROSPERO extension focusing on severe exacerbations, including hospitalization and death, over 104 weeks.
Drug: tozorakimab
Class: anti–IL-33 monoclonal antibody
Indication: COPD with exacerbation history
Trial: MIRANDA, phase 3
Design: DB, placebo-controlled
Dose: 300 mg every 2 weeks
Primary outcome: mod/severe exacerbations
Result: primary end point met
Safety: generally well tolerated
Status: investigational; filings planned
COPD remains a major source of morbidity and mortality globally and is the third leading cause of death worldwide excluding COVID-19, according to the World Health Organization.4 Current GOLD guidance emphasizes smoking cessation, vaccination, pulmonary rehabilitation, and inhaled bronchodilator-based therapy, with inhaled corticosteroids used selectively, often guided in part by eosinophil counts and exacerbation history.2 Despite these measures, many patients continue to exacerbate, and repeated events are associated with hospitalization, cardiovascular complications, accelerated disease progression, and death.
Tozorakimab targets IL-33, an upstream alarmin implicated in airway inflammation and epithelial dysfunction.5 Preclinical and translational work suggests the antibody may block signaling from both reduced and oxidized forms of IL-33, including pathways involving ST2 and RAGE/EGFR. In a phase 2a study in COPD, tozorakimab was previously investigated as a strategy to reduce exacerbations, but the precise place of IL-33 inhibition in COPD care remains unsettled pending phase 3 publication and regulatory review.6
Clinically, a positive program across former smokers, current smokers, and eosinophil strata would be notable because currently available biologic approaches in COPD have shown variable efficacy and often more selective target populations.2 Still, clinicians will likely want to see whether the effect size differs by smoking status, eosinophil count, concomitant inhaled triple therapy, and baseline exacerbation burden before judging where the drug might fit in practice.
Regulatory submissions are planned, according to the company.1 Key next steps are presentation of complete efficacy and safety data, peer-reviewed publication, and clarification of whether any eventual label would be limited to former smokers, a broader exacerbation-prone COPD population, or specific biomarker-defined groups.
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