Tozorakimab Benefits Current and Former Smokers: Frank Sciurba, MD

Tozorakimab reduced moderate or severe exacerbations by up to 34% in former smokers with chronic obstructive pulmonary disease (COPD) and by up to 30% in a broader population of current and former smokers by targeting IL-33 upstream of the pathways addressed by existing biologics, according to Frank Sciurba, MD, professor of pulmonary and critical care medicine at the University of Pittsburgh and chief investigator of the trial program.

Sciurba presented data on the phase 3 OBERON (NCT05166889) and TITANIA (NCT05158387) trials at the European Respiratory Society Congress 2026.

Why IL-33 Reaches Beyond Th2-High COPD Patients

Approved biologics targeting T-helper type 2 (Th2)–high inflammation address an estimated 20% to 40% of patients with COPD, according to Sciurba, leaving a substantial unmet need for those driven by neutrophilic, Th1, and Th17 inflammation instead. IL-33 sits upstream of these pathways, so blocking it affects a broader immunologic profile than eosinophil-focused drugs. The molecule also has a distinct epithelial role: an oxidized conformational state of IL-33 binds the receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) on airway epithelium, driving scarring, remodeling, and mucus production.

"There are different conformational states of the IL-33 molecule, and one of them, which involves the oxidation of the molecule, changes its receptor binding affinity to bind to the RAGE [and] EGFR receptors on the epithelium that drives airway scarring and remodeling and mucus production," said Sciurba.

Tozorakimab appears to block conversion to that oxidized state, adding a direct epithelial benefit on top of its anti-inflammatory effect.

How Trial Design Balanced Risk and Broader Applicability

The trials set annualized exacerbation rate in former smokers as the primary end point, with current and former smokers together as a key secondary end point, a design shaped by precedent. A separate antibody targeting the ST2 receptor had shown benefit only in former smokers during phase 2 testing, prompting the tozorakimab program to de-risk around the same possibility. Investigators also had biological reason to expect the oxidized-pathway effect could extend benefit to current smokers, so they preserved that population as a key secondary analysis rather than excluding it.

“The primary outcome parameter was annualized rate of moderate or severe exacerbations in former smokers...in that population, they had a 29 to 34% reduction in exacerbation rate in the 2 clinical trials in the primary population. In the secondary population of overall current and former smokers...they had a 29 to 30% reduction," said Sciurba.

The consistency between the primary and secondary populations suggests the drug's benefit is not limited to former smokers alone, a distinction that could matter for how broadly it is eventually used in practice.