On 18 May at the 2025 American Thoracic Society (ATS) International Conference, AstraZeneca presented results on its interleukin-33 (IL-33) inhibitor, tozorakimab, from its FRONTIER programmes, which are a series of four Phase II clinical trials. The focus of the research was on adverse events of special interest (AESIs), which included progression of heart failure (HF), injection-site reactions, and Covid-19. Across all four FRONTIER studies, tozorakimab’s safety profile was favourable and well tolerated. The latest set of safety results could bolster the asset’s profile in the respiratory space while development is being halted for the remaining inflammatory conditions.
The four trials were completed at different points in time, with each one focusing on a specific dose range that was dependent on which indications were being studied, including diabetic kidney disease (DKD) (FRONTIER-1, 30-300mg), moderate-to-severe atopic dermatitis (FRONTIER-2, 60-600mg), moderate-to-severe asthma (FRONTIER-3, 300-600mg), and moderate-to-severe chronic obstructive pulmonary disease (COPD) with chronic bronchitis (FRONTIER-4, 600mg).
Researchers compared the cumulative data from all four FRONTIER studies with a focus on AESIs. With regards to progression to HF, patients treated with tozorakimab within the DKD study population were observed to have a slightly higher rate compared to participants in the placebo arm. Overall, there were no meaningful differences between the groups. Across all four studies, the frequency of injection-site reactions was consistently higher in the tozorakimab arms compared to placebo, with the highest rate observed in the FRONTIER-4 study (20.9% versus 0% placebo). Additionally, the formation of antidrug antibodies was observed to be low across all four studies, drawing a cautiously optimistic outlook about the potential of this asset in COPD. While still in clinical development, tozorakimab’s safety data helps to address a key unmet need within the respiratory space, which is the need for long-term safety data for biologics, as highlighted by key opinion leaders (KOLs) interviewed by leading data and analytics company GlobalData.
The latest set of safety results is expected to strengthen the asset’s profile in COPD, following publication of data at the European Respiratory Society Congress 2024 demonstrating that the asset was not meeting the primary endpoint of improvement in forced expiratory volume in one second (FEV1) in FRONTIER-4. However, within that same set of results, a numerical improvement in FEV1 was seen in patients with a higher risk of exacerbation. The asset is currently being evaluated in multiple Phase III clinical trials in COPD patients who have experienced two or more moderate exacerbations or one or more severe exacerbations within 12 months prior to enrollment.
IL-33 inhibitors such as tozorakimab target the IL-33 pathway that can trigger broader inflammation, compared to Regeneron and Sanofi’s Dupixent, which targets IL-4 and IL-13 pathways that are primary drivers of type 2 inflammation; the latter is currently a key biologic in asthma and dominates the biologics space within COPD. A KOL previously interviewed by GlobalData stated: “A drug related to IL-33 could be promising. As it acts to block the activities of IL-33 in the upper area of the route, which is far different from blood eosinophils, I believe it can be used for a wider range of patients.” While clinical data suggests that IL-33 inhibitors can potentially reduce exacerbations in COPD patients and results from tozorakimab’s Phase II trials look promising in treating COPD, there are concerns that IL-33 inhibitors’ broader set of action could result in off-target effects and have potential for immune dysregulation. The latest set of safety results attempts to allay any concerns on this front; however, there is a sense of anticipation to see how favourable the safety outcomes in ongoing Phase III trials for tozorakimab within COPD will be, and if and how the broad mechanism of action could affect the risk of causing respiratory infections by dampening the immune response. That set of questions will also be applicable for other assets within this drug class that are currently in late-stage development for COPD, including Sanofi’s itepekimab and Roche’s astegolimab, all attempting to break into the biologics space that is currently dominated by Dupixent.
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By GlobalData