Effects of interleukin-6 inhibition with ziltivekimab in patients at high risk of atherosclerotic events in Japan: results from the phase 2 RESCUE-2 trial

Abstract

Abstract Introduction In the US phase 2 RESCUE trial, ziltivekimab, a fully human monoclonal antibody against the ligand of the pro-inflammatory cytokine interleukin-6, was shown to reduce biomarkers of inflammation in patients with chronic kidney disease (CKD) and elevated levels of high-sensitivity C-reactive protein (hsCRP), a marker of inflammation and cardiac risk.1 Here, we present outcomes from the phase 2 RESCUE-2 trial of ziltivekimab in a patient population from Japan. Purpose To evaluate the efficacy and safety of ziltivekimab 15 mg and 30 mg compared with placebo in Japanese patients with non-dialysis-dependent CKD (NDD-CKD). Methods We conducted a randomized, double-blind, placebo-controlled trial in 36 patients aged ≥20 years with stage 3–5 NDD-CKD and hsCRP ≥2 mg/L. Patients were randomly assigned to receive subcutaneous ziltivekimab 15 mg (n=11) or 30 mg (n=12), or placebo (n=13) at weeks 0, 4 and 8. The primary endpoint was percentage change in hsCRP levels from baseline to end of treatment (EOT) (average of week 10 and week 12 values); secondary endpoints included percentage change from baseline to EOT in levels of fibrinogen, serum amyloid A (SAA), N-terminal pro B-type natriuretic peptide (NT-proBNP) and lipids. Analysis of endpoints was performed using Wilcoxon two-sample test; differences between treatment groups were calculated using the Hodges–Lehmann estimator. Results Baseline characteristics are shown in the Table. At EOT, median hsCRP levels were reduced by 96% and 93% in the ziltivekimab 15 mg and 30 mg groups, respectively, compared with 27% for placebo (both p<0.001 vs placebo). At both doses, ziltivekimab provided rapid and sustained suppression of hsCRP over the 12-week treatment period (Figure). Statistically significant reductions in levels of the inflammatory markers SAA (15 mg: 71%; 30 mg: 58%; placebo: 30%; both p<0.01 vs placebo) and fibrinogen (38%; 34%; 2%; both p<0.0001 vs placebo) were also observed. Ziltivekimab was well tolerated, did not result in persistent neutropenia or thrombocytopenia, and had minimal effect on liver enzyme levels. There was a non-significant increase in low-density lipoprotein levels and a neutral effect on high-density lipoprotein levels. There was a limited, but statistically significant (p<0.05 vs placebo) increase in triglycerides, whereby levels increased in some patients and decreased in others. Conclusion Ziltivekimab effectively reduced inflammatory biomarkers associated with atherosclerosis in patients from Japan with CKD and residual inflammatory risk as measured by hsCRP. A significant reduction of more than 90% in hsCRP levels for both doses of ziltivekimab was demonstrated, with a safety profile similar to placebo. Overall, the results of the RESCUE-2 trial in Japan are consistent with the efficacy and safety results of the US-based RESCUE trial. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was funded by Novo Nordisk A/S. Medical writing support was provided by Johanna Scheinost PhD, PharmaGenesis Oxford Central, Oxford, UK, with funding from Novo Nordisk A/S.