A randomised phase 2a study to investigate the effects of blocking interleukin-33 with tozorakimab in patients hospitalised with COVID-19: ACCORD-2.

Background: Increased serum interleukin (IL)-33 predicts poor outcomes in patients hospitalised with coronavirus disease 2019 (COVID-19). We examined the efficacy and safety of tozorakimab, a monoclonal antibody that neutralises IL-33, in improving outcomes in ACCORD-2 (EudraCT: 2020-001736-95).
Methods: ACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg plus standard of care (SoC) or SoC alone. The primary end-point was time to clinical response (sustained clinical improvement of ≥2 points on the World Health Organization ordinal scale, discharge from hospital or fit for discharge) by day 29. Other end-points included death or respiratory failure, mortality and intensive care unit admission by day 29, and safety. Serum IL-33/soluble stimulated-2 (sST2) complex levels were measured by high-sensitivity immunoassay.
Results: Efficacy analyses included 97 patients (tozorakimab+SoC, n=53; SoC, n=44). Median time to clinical response did not differ between the tozorakimab and SoC arms (8.0 and 9.5 days, respectively; HR 0.96, 80% CI 0.70-1.31; one-sided p=0.33). Tozorakimab was well tolerated and the OR for risk of death or respiratory failure with treatment versus SoC was 0.55 (80% CI 0.27-1.12; p=0.26), while the OR was 0.31 (80% CI 0.09-1.06) in patents with high baseline serum IL-33/sST2 complex levels.
Conclusions: Overall, ACCORD-2 results suggest that tozorakimab could be a novel therapy for patients hospitalised with COVID-19, warranting further investigation in confirmatory phase 3 studies.
Competing Interests: Conflict of interest: T. Wilkinson has received grants and fees from AstraZeneca, Bergenbio, Boehringer Ingelheim, Chiesi, GSK, Janssen, Olam, MMH, Synairgen, Union Chimique Belge and Valneva. M. Carroll has received consulting fees from OxDx Ltd and VacciTech Ltd. C. Page has received personal fees from EpiEndo, Eurodrug, Glycosynnovation, Helperby, PrEP Biopharma and Recipharm, and owns stock in Verona Pharma. J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GSK, Gilead Sciences, Insmed and Novartis, has received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, Janssen, Novartis and Zambon, and is a member of the Editorial Board of ERJ Open Research. A. De Soyza has received grants and fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Gilead Sciences, GSK and Insmed. S. Siddiqui has received speaker/consultancy fees or research grants from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Novartis and Owlstone Medical. A. Ustianowski has received speaker and/or advisory board fees from AstraZeneca, Gilead Sciences, GSK and Merck/MSD. M.G. Crooks has received grants, fees and non-financial support from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Pfizer and Philips. A. Horsley has received personal fees from Roche-Genentech and Vertex Pharmaceuticals, and is supported by the NIHR Manchester Biomedical Research Centre. H. Pandya, R. Moate, N. van Zuydam, C. Kell, F. Reid and I.C. Scott are employees of AstraZeneca and may hold stock or stock options in AstraZeneca. G. Griffiths has received funding from Astex, AstraZeneca, BionTech, Bristol Myers Squibb, British Lung Foundation, Cancer Research UK, Celldex, GSK, Heartflow, Janssen-Cilag, NIHR, Novartis, Roche and Unitaid for unrelated academic clinical trials and programme funding, and personal fees from AstraZeneca to deliver continuing professional development training courses. M. Shankar-Hari has received funding from the NIHR, has received a grant from the Chief Scientists Office, Scotland, and reports industry interactions for the TRAITS research programme (www.ed.ac.uk/inflammation-research/clinical-trials/traits-ci-trial). D. Singh has received personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo, Genentech, Glenmark, Gossamer Bio, GSK, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva Pharmaceuticals, Theravance Biopharma and Verona. L-P. Ho, D. Saralaya, B. Lara, J. Raw, A. Woodcock and B. Mishra have no conflicts of interest to disclose.
(Copyright ©The authors 2023.)