IL-33 Inhibitor Delivers in COPD Trials

A broad population of people with chronic obstructive pulmonary disease (COPD), current and former smokers alike, experienced fewer exacerbations taking a first-in-class biologic targeting interleukin (IL)-33, a pair of double-blind trials showed.

In OBERON and TITANIA, the addition of once-monthly tozorakimab injections to standard inhaled maintenance therapy resulted in fewer moderate or severe COPD exacerbations. Among former smokers, the annualized rate of these exacerbations occurring over a 52-week period was significantly lower with tozorakimab than placebo in both studies:

• OBERON: 1.34 vs 1.90 events (RR 0.71, 95% CI 0.57-0.88)
• TITANIA: 1.37 vs 2.07 events (RR 0.66, 95% CI 0.55-0.80)

This result was replicated in an overall population of former and current smokers in the two trials:

• OBERON: 1.41 vs 2.00 events (RR 0.70, 95% CI 0.58-0.85)
• TITANIA: 1.44 vs 2.03 events (RR 0.71, 95% CI 0.59-0.84)

“Tozorakimab, a first-in-class biologic, demonstrates a valuable potential therapeutic agent for our patients with COPD who continue to exacerbate despite guideline-based therapy,” said Frank Sciurba, MD, of the University of Pittsburgh, presenting the two trials at the European Respiratory Society (ERS) Congress, held this year in Barcelona, Spain.

OBERON and TITANIA were simultaneously published in the New England Journal of Medicine.

These phase III trials now position tozorakimab as another option for biologic treatment in COPD. With its unique targeting of IL-33 — setting it apart from IL-4/IL-13 blocker dupilumab (Dupixent) and IL-5-targeting mepolizumab (Nucala) — tozorakimab potentially adds another way for clinicians to tailor therapies to patients based on biologic parameters.

Of note, OBERON and TITANIA did not restrict enrollment by blood eosinophil count, unlike the trials for dupilumab and mepolizumab.

“With tozorakimab, we really move more upstream towards the airway epithelium, and kind of having more response towards these innate immune challenges, such as everything that we inhale, but also particulate damage,” commented Lena Uller, PhD, MSc, of Lund University in Sweden.

“If we can block this response, we could have an effect on inflammation, not just T2 inflammation, but bronchial hyperactivity and exacerbation. So I think it’s really, really, really interesting with the data you presented with tozorakimab today,” Uller said as the ERS session discussant.

Tozorakimab is a monoclonal antibody that inhibits the activity of IL-33, which can act on multiple inflammatory pathways and is implicated in the pathogenesis of COPD. Multiple studies have shown the large role that IL-33 plays in allergic inflammation by driving persistent type 2 immune responses; IL-33 is also associated with increased mucus production and vascular endothelial permeability, contributing to inflammation.

Sciurba addressed an audience question on why tozorakimab succeeded in the present trials whereas other IL-33 agents have failed in COPD.

“It could be due to multiple different things,” he said during the Q&A portion of the ERS session. “IL-33 is a very complex molecule. It has multiple conformational states and where the antibody binds on that molecule plausibly makes a difference, and that very well may have been the case with this molecule.”

Studies are ongoing to clarify tozorakimab’s mechanism of action in preventing COPD exacerbations, the trialists noted.

OBERON and TITANIA were replicate phase III trials, conducted at separate sites, with nearly 900 participants each (mean age 67-68 years across study arms, around 65% men).

Eligible patients were adults with COPD who were current or former smokers and had a history of exacerbations in the previous year despite being on stable inhaled maintenance therapy. Patients had to have had at least two moderate or one severe recent COPD exacerbation. Patients with clinically significant or radiologically evident pulmonary disease other than COPD were ineligible, including those with asthma.

Sciurba and colleagues had trial participants randomized to add-on subcutaneous tozorakimab (300 mg) or placebo every 4 weeks for 52 weeks.

In both trials, the primary endpoint counted moderate exacerbations (resulting in treatment with systemic glucocorticoids for at least 3 days or antibiotics or both, or an emergency department visit) and severe ones as well (those leading to hospitalization or death).

Tozorakimab’s efficacy was supported by 1-year improvements in prebronchodilator forced expiratory volume in 1 second and total scores on the Evaluating Respiratory Symptoms in COPD assessment. Another key secondary endpoint, change in the St. George’s Respiratory Questionnaire total score, trended in favor of the tozorakimab group without reaching statistical significance.

As for safety, adverse events occurred in a similar 70.4% with tozorakimab versus 77.2% with placebo in OBERON and 80.1% versus 79.8%, respectively, in TITANIA.

Though rare, major adverse cardiovascular events were numerically more frequent with tozorakimab than with placebo (0.4% vs 0), as were serious adverse events that resulted in death (1.3% vs 1.2%).

Monitoring of rare safety events requires longer follow-up and a larger sample than was available in OBERON and TITANIA, the investigators acknowledged. They also cautioned that adherence to inhaled maintenance therapy was not monitored systematically in these trials, nor were they able to assess efficacy among patients who had never smoked.