Abstract 4137311: Inhibition of IL-33 by tozorakimab in patients with diabetic kidney disease: Cardiovascular insights from FRONTIER-1

Introduction: Interleukin-33 (IL-33) is a potent mediator of injury-induced local inflammation. Soluble ST2 (sST2), a decoy receptor of IL-33, is a prognostic serum biomarker for heart failure (HF). Here, we evaluated the impact of tozorakimab, an IL-33-neutralizing monoclonal antibody, on sST2-related secondary cardiac endpoints. Methods: FRONTIER-1 was a 24-week phase 2B study (NCT04170543) in patients with diabetic kidney disease (DKD). Key cardiac exclusion criteria were: 1) NYHA Class 3/4; 2) Left ventricular ejection fraction (LVEF) < 40%; 3) B-type natriuretic peptide (BNP) > 200 pg/mL. Local echocardiography (LVEF) was performed at Screening and Week 24. For exploratory analysis, echocardiography recordings were evaluated by a core laboratory. Throughout the study, BNP and sST2 were assessed and adverse events (AE) recorded. Safety and tolerability were evaluated for all dosed participants (Safety Analysis Population, SAP). Results: 573 participants were included in the SAP (139 = placebo / 434 = tozorakimab). Baseline characteristics were balanced across treatment groups. Tozorakimab was generally well tolerated and the incidences of AE, serious AE (SAEs), discontinuations, and death were similar to placebo. In the placebo group, cardiac disorder AE were reported in 6.5%, and SAE in 2.2%. Decline in LVEF of > 10% was seen in 5 participants (4.3%). None developed BNP > 200 pg/mL or clinical signs of HF. 1 participant (0.7%) presented with clinical symptoms of HF (SAE) without significant changes in LVEF or BNP. On tozorakimab, cardiac disorder AE/SAE were less frequent (3.7%/1.8%). Decline in LVEF of > 10% was observed in 31 participants (8.3%), with 3 showing BNP elevation to 200–308 pg/mL. Two of these participants (0.5%) developed clinical signs of HF with LVEF 55%/30% and BNP < 200 pg/mL. No further AE related to HF were reported for tozorakimab. Central analysis of LVEF revealed a substantial variability of site-based measurements indicating LVEF reductions > 10 % in 2 (3.7%) participants on placebo and 6 (2.9%) on tozorakimab. Furthermore, central exploratory analysis demonstrated a slight increase in LVEF from baseline (1.62%, 95% CI: 0.22, 3.03) and a reduction in average E/e' (-0.47, 95% CI: -0.93, -0.01) for tozorakimab, but not placebo. Trends in BNP and sST2 over time were comparable. Conclusion: This study suggests a favorable cardiac safety profile for tozorakimab in patients with DKD. IL-33 inhibition did not elevate serum sST2 significantly.