Itepekimab

AstraZeneca’s anti-IL-33 monoclonal antibody failed a Phase 2a study in chronic obstructive pulmonary disease, though the company noted there were still “encouraging clinical efficacy signals.” In the 135-patient FRONTIER-4 trial, patients with COPD were enrolled in the small proof-of-concept study regardless of blood eosinophil counts and smoking status. They got 600 mg of AstraZeneca’s tozorakimab or placebo every four weeks for 12 weeks. The data were presented at the European Respiratory Society Congress in Vienna on Sept. 8. The study missed the primary endpoint of improvement in pre-bronchodilator forced expiratory volume, which is the amount of air an individual can exhale during a forced breath. But AstraZeneca said there was a greater pre-bronchodilator forced expiratory volume of 59 mL versus placebo in a subset of patients. The company also pointed out that tozorakimab numerically reduced the risk of COPDCompEx events by 36% in patients with two or more moderate or one or more severe previous exacerbations. About 41% of patients receiving tozorakimab and 64% of patients on placebo experienced a COPDCompEx event. According to AstraZeneca, COPDCompEx is a composite exacerbation endpoint “that is suited for use in smaller and shorter Phase 2 studies to predict treatment effect on COPD exacerbations in Phase 3 trials.” “Findings suggest that tozorakimab may improve lung function and reduces COPD worsening events, particularly in the population at high risk of future exacerbations being studied in the ongoing Phase 3 LUNA programme,” Dave Singh, the study’s lead investigator and professor of respiratory pharmacology at the University of Manchester, said in a release. AstraZeneca said tozorakimab is still being tested in several late-stage clinical trials to see if it can reduce excess inflammation and epithelial remodeling in COPD patients. It’s also being investigated in severe viral lower respiratory tract disease.

Tozorakimab performed better in patients who had experienced moderate or severe exacerbations in the past year. AstraZeneca executives say they are “not worried” that the failure of tozorakimab in a phase 2 chronic obstructive pulmonary disease (COPD) trial will throw their plans for the anti-IL-33 monoclonal antibody off track.The U.K.-based Big Pharma unveiled data from the phase 2 FRONTIER-4 study at the European Respiratory Society 2024 Congress in Vienna, Austria on Sunday. The study saw 135 COPD patients with chronic bronchitis receive either 600 mg of tozorakimab or placebo every four weeks for 12 weeks.The trial missed the primary endpoint of demonstrating an improvement in pre-bronchodilator forced expiratory volume (FEV), the amount of air that a person can exhale during a forced breath, according to the abstract.AstraZeneca is already running phase 3 trials of tozorakimab in patients who had experienced two or more moderate exacerbations or one or more severe exacerbations in the previous 12 months. When zooming into this sub-group in today’s phase 2 data, the company had better news—a 59 mL improvement in FEV.Among this subgroup, tozorakimab was also shown to reduce the risk of so-called COPDCompEx—a catch-all term for moderate and severe exacerbations as well as the study dropout rate—by 36%, the pharma noted. AstraZeneca's Caterina Brindicci, M.D., Ph.D., global head of respiratory and immunology late-stage development, BioPharmaceuticals R&D, told Fierce that today’s phase 2 fail would “not at all” impact the pharma’s late-stage strategy for tozorakimab.“In the phase 3 program we are targeting exactly the population where we saw a stronger signal in phase 2,” Brindicci said in an interview.Unlike other anti-IL-33 antibodies, tozorakimab has a dual mechanism of action that not only inhibits interleukin-33 signaling via the RAGE/EGFR pathway but also affects a separate ST2 receptor pathway involved in inflammation, Brindicci explained.“This dual pathway that we can target really gives us confidence that we will very likely have efficacy demonstrated in phase 3,” she added. “So we are not worried currently.”AstraZeneca is running a trio of phase 3 trials for tozorakimab in patients with a history of COPD exacerbations, with data set to read out “after 2025,” Brindicci said. There is also a late-stage trial ongoing in patients hospitalized for viral lung infection who require supplemental oxygen. Today’s readout isn’t the first time that tozorakimab has struggled in the clinic. Back in February, AstraZeneca dropped plans to develop the drug in diabetic kidney disease after it failed a phase 2 trial in that indication. A year earlier, the pharma stopped work on the molecule in atopic dermatitis.The company’s Big Pharma peers have also had some bad luck with IL-33. GSK dropped its candidate in 2019, and the following year Roche axed a candidate aimed at the IL-33 pathway after seeing asthma data.However, Sanofi and Regeneron overcame their own phase 2 setback and are now just weeks away from finding out if Dupixent will become the first biologic approved by the FDA for chronic COPD.