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

Abstract

BackgroundIncreased 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).MethodsACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg+standard of care [SoC] or SoC alone. The primary endpoint 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 endpoints included death or respiratory failure, mortality, intensive care unit (ICU) admissions by day 29 and safety. Serum IL-33/soluble ST2 (sST2) complex was measured by high sensitivity immunoassay.ResultsEfficacy 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 [hazard ratio 0.96 (80% confidence interval [CI] 0.70–1.31), one-sided p=0.33]). Tozorakimab was well tolerated, and the odds ratio for risk of death or respiratory failure with treatmentversusSoC was 0.55 ([80% CI 0.27–1.120], p=0.26), whilst the odds ratio was 0.31 (80% CI 0.09–1.06) in patents with high baseline serum IL-33/sST2.ConclusionsOverall, 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.

ATP/IL-33-Co-Sensing by Mast Cells (MCs) Requires Activated c-Kit to Ensure Effective Cytokine Responses

“…Therefore, ATP/IL-33 co-sensing in infected lung tissues might be a potential mechanism explaining the hyperactivated MC phenotype in SARS-CoV2-infected individuals [14]. Confirming this, the role of activated MCs and of IL-33 in COVID-19 pathogenesis has been shown recently [21,25], demonstrating that released alarmins and MCs are indeed important for hyperinflammatory reactions in peripheral tissues. In this work, we show that in addition to ATP/IL-33 co-sensing, SCF is a further stimulus which enhances the hyperinflammatory MC phenotype.…”

Therapeutic Targets and Precision Medicine in COPD: Inflammation, Ion Channels, Both, or Neither?

“…Finally, tozorakimab, which can block signaling mediated by both reduced IL-33 and oxidized IL-33 (see Ref. [71]), has been tested in patients hospitalized for COVID-19 pneumonia [72]; two phase 3 trials in COPD are ongoing. Successful completion of any of these clinical trials would provide essential verification of IL-33 and/or its receptor as key therapeutic targets in COPD.…”