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Clinical Trial
. 2025 Jul 14;66(1):2402231.
doi: 10.1183/13993003.02231-2024. Print 2025 Jul.

A phase 2a trial of the IL-33 monoclonal antibody tozorakimab in patients with COPD: FRONTIER-4

Dave Singh  1 , Patricia Guller  2 , Fred Reid  3 , Sarah Doffman  3 , Ulla Seppälä  2 , Ioannis Psallidas  4 , Rachel Moate  5 , Rebecca Smith  5 , Joanna Kiraga  6 , Eulalia Jimenez  7 , Dennis Brooks  8 , Aoife Kelly  9 , Lars H Nordenmark  10 , Muhammad Waqas Sadiq  11 , Luis Mateos Caballero  12 , Chris Kell  13 , Maria G Belvisi  14   15 , Hitesh Pandya  16
Affiliations
Clinical Trial

A phase 2a trial of the IL-33 monoclonal antibody tozorakimab in patients with COPD: FRONTIER-4

Dave Singh et al. Eur Respir J. .

Abstract

Background: Interleukin-33 may have a role in COPD pathobiology. FRONTIER-4 (NCT04631016) investigated tozorakimab (an anti-interleukin-33 monoclonal antibody) in patients with moderate-to-severe COPD with chronic bronchitis receiving dual or triple inhaled therapy.

Methods: FRONTIER-4 was a phase 2a, randomised, double-blind, placebo-controlled study. Patients received tozorakimab 600 mg or placebo subcutaneously every 4 weeks for 24 weeks. The primary end‑point was change in pre-bronchodilator forced expiratory volume in 1 s (FEV1) from baseline to week 12. Secondary outcomes included post-bronchodilator FEV1, time-to-first COPD composite exacerbation event and safety.

Results: The intent-to-treat population included 135 patients (tozorakimab, n=67; placebo, n=68). At week 12 in the intent-to-treat population, tozorakimab showed a greater increase, although nonsignificant, from baseline in pre-bronchodilator FEV1 (least-squares mean difference (LSMD) 24 mL, 80% confidence interval (CI) -15-63 mL, p=0.216) and a significantly greater increase in post-bronchodilator FEV1 (LSMD 67 mL, 80% CI 17-116 mL, p=0.044) when compared with placebo. At week 12 in a prespecified subgroup of patients with at least two prior exacerbations, tozorakimab also showed improvements versus placebo in change from baseline in pre-bronchodilator FEV1 (LSMD 69 mL, 80% CI 9-130 mL, p=0.072) and post-bronchodilator FEV1 (LSMD 124 mL, 80% CI 47-201 mL, p=0.020). Tozorakimab did not significantly reduce the risk of COPD composite exacerbation events (hazard ratio 0.79, 80% CI 0.57-1.11, p=0.186) in the intent-to-treat population, although there were greater effects in patients with at least two prior exacerbations (hazard ratio 0.61, 80% CI 0.37-1.00). Results were similar in former and current smokers. Tozorakimab was well tolerated.

Conclusion: Although the primary end-point was not met in the intent-to-treat population, tozorakimab showed positive efficacy signals versus placebo in a subgroup of patients with COPD with a high risk of exacerbations.

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Conflict of interest statement

Conflicts of interest: D. Singh has received personal fees from Adovate, Aerogen, Almirall, Apogee, Arrowhead, AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, Cipla, CONNECT Biopharma, Covis Pharma, CSL Behring, DevPro Biopharma, Elpen, Empirico, EpiEndo Pharmaceuticals, Genentech, Generate Biomedicines, GSK, Glenmark, Kamada, Kinaset Therapeutics, Kymera Therapeutics, Menarini, MicroA, OM Pharma, Orion Pharma, Pieris Pharmaceuticals, Pulmatrix, Revolo Biotherapeutics, Roivant Sciences, Sanofi, Synairgen, Tetherex, Teva Pharmaceuticals, Theravance Biopharma, Upstream Bio and Verona Pharma. P. Guller, F. Reid, S. Doffman, U. Seppälä, I. Psallidas, R. Moate, J. Kiraga, E. Jimenez, D. Brooks, A. Kelly, L.H. Nordenmark, M.W. Sadiq, C. Kell, M.G. Belvisi and H. Pandya are employees of AstraZeneca and may hold stock or stock options in AstraZeneca. R. Smith was an employee of AstraZeneca at the time the study was conducted and may hold stock or stock options in AstraZeneca. L.M. Caballero has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Sanofi.

Figures

None
Trial overview. BD: bronchodilator; CI: confidence interval; COPDCompEx: COPD composite exacerbation; FEV1: forced expiratory volume in 1 s; HR: hazard ratio; IL: interleukin; ITT: intent-to-treat; LS: least-squares; SC: subcutaneously.
FIGURE 1
FIGURE 1
Patient disposition. % based on those who were randomised (n=137: tozorakimab, n=69; placebo, n=68). AE: adverse event.
FIGURE 2
FIGURE 2
Change in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1) in the intent-to-treat population. CI: confidence interval; EOT: end of treatment; LS: least-squares.
FIGURE 3
FIGURE 3
Kaplan–Meier plots of time-to-first COPD composite exacerbation (COPDCompEx) event in the intent-to-treat population. CI: confidence interval; EOT: end of treatment; HR: hazard ratio.
FIGURE 4
FIGURE 4
Kaplan–Meier plots of time-to-first COPD composite exacerbation (COPDCompEx) event by a) prespecified exacerbation history, b) post hoc exacerbation history, c) baseline blood eosinophil count (BEC) and d) current and former smoker subgroups. CI: confidence interval; EOT: end of treatment; HR: hazard ratio.
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