Itepekimab

AstraZeneca has unveiled detailed results from two Phase III trials of tozorakimab in chronic obstructive pulmonary disease (COPD) showing that the IL-33 antibody reduced moderate-to-severe exacerbations by about 30% in both."Today's…results, from two replicate trials, set a new standard for COPD treatment outcomes in a broad population of patients," stated Sharon Barr, the company's EVP of BioPharmaceuticals R&D.Toplined in March, results from the OBERON and TITANIA trials, published Tuesday in NEJM and presented at the European Respiratory Society (ERS) meeting, showed the antibody worked across current and former smokers and a range of blood eosinophil counts, as well as all stages of lung function severity.The studies, which included over 1700 participants combined, tested tozorakimab in patients with persistent COPD exacerbations despite inhaled standard of care. They were randomised to tozorakimab 300 mg or placebo once every four weeks, on top of background therapy.IL-33's mixed recordIn OBERON, the primary endpoint was met with a 29% reduction in annualised rate of moderate-to-severe exacerbations among former smokers, while the reduction was 34% in TITANIA. In the overall population involving both current and former smokers, the corresponding reductions were 30% and 29% in the two studies, respectively.The detailed readouts stand out against a backdrop of previous mixed findings with other drugs targeting the IL-33 pathway (see – KOL Views Q&A: AstraZeneca's IL-33 could expand the reach of biologics in COPD).Sanofi and Regeneron's IL-33 antibody itepekimab yielded split results in the Phase III AERIFY-1 and AERIFY-2 trials last year, as did Roche's astegolimab — which targets ST2, a receptor for IL-33 — succeeding in the Phase IIb ALIENTO study, but falling short in the Phase III ARNASA trial (see – KOL Views Q&A: Itepekimab setback more instructive than destructive for IL-33 therapies in COPD and Spotlight On: Roche further muddies water with more "mixed" messages about IL-33 in COPD).Meanwhile, eosinophil counts appeared to influence the magnitude of tozorakimab's benefit. In a pooled analysis of OBERON and TITANIA, exacerbations fell by 43% among patients with baseline blood eosinophils of at least 300 cells/µL, compared to 23% among those below 150 cells/µL. Patients at or above 150 achieved a 34% reduction.Additionally, AstraZeneca said a separate integrated analysis of the two studies presented at ERS found that tozorakimab also reduced mucus plugging, an emerging COPD measure associated with worse disease outcomes.'Rare' fatal eventsThe drug was generally well tolerated, with the only adverse drug reaction being injection-site reactions. The safety analysis did show that while fatal serious adverse events were similar in OBERON between the tozorakimab and placebo arms (1.3% vs 1.2%), they were more frequent with tozorakimab in TITANIA (2.5% vs 0.9%, respectively)."Although these events were rare, the incidence was similar among patients who received tozorakimab every 4 weeks and those who received tozorakimab every 8 weeks," the study authors wrote. "No patterns in adjudicated components of major adverse cardiovascular events, adjudicated causes of death, or in preferred terms for serious adverse events with the outcome of death were apparent."In April, AstraZeneca reported that tozorakimab had succeeded in the Phase III MIRANDA trial in COPD as well.The FDA has accepted AstraZeneca's filing of tozorakimab for priority review as an add-on maintenance treatment for adults with COPD. A decision is expected in the first quarter of 2027, while regulatory reviews are also underway in Europe and China.Tozorakimab is also being tested in a Phase II trial for severe asthma and in a Phase III trial in severe viral lower respiratory tract disease.