IL-6 inhibition with ziltivekimab fails to reduce MACE in patients with ASCVD, CKD and inflammation
In the phase 3 ZEUS trial, ziltivekimab did not reduce the risk of MACE compared with placebo in patients with ASCVD, CKD, and inflammation, despite reducing IL-6 and hsCRP.
The phase 3 ZEUS trial did not meet its primary endpoint. The investigational anti-IL-6 monoclonal antibody ziltivekimab failed to reduce the risk of MACE compared with placebo in patients with ASCVD, CKD, and inflammation.
ZEUS was a double-blind, placebo-controlled cardiovascular outcomes trial that enrolled more than 6,300 patients with established ASCVD, CKD, and elevated hsCRP (≥2 mg/L). Participants received once-monthly subcutaneous ziltivekimab 15 mg or placebo in addition to standard of care. The primary endpoint was time to first occurrence of cardiovascular death, non-fatal MI, or non-fatal stroke (3-point MACE).
Although ziltivekimab inhibited the IL-6 pathway, as reflected by the expected reductions in free IL-6 and hsCRP, this did not translate into improved cardiovascular outcomes (HR for 3-point MACE: 0.99; 95%CI: 0.88–1.11).
Overall rates of adverse events and serious adverse events were similar between treatment groups. However, serious infections occurred more frequently in patients treated with ziltivekimab, consistent with IL-6 inhibition, whereas all-cause mortality did not differ between groups.
The ongoing phase 3 HERMES and ARTEMIS cardiovascular outcomes trials evaluating ziltivekimab in patients with HF and following acute MI, respectively, will continue as planned, with results expected in the first half of 2027. Full results of ZEUS will be presented at a scientific meeting later in 2026.