Two large Phase III trials of ziltivekimab, Novo Nordisk's investigational IL-6 inhibitor, have been stopped early on the recommendation of an independent data monitoring committee, as reported by ClinicalTrialsArena. The HERMES (NCT05636176) and ATHENA (NCT06200207) trials, both evaluating ziltivekimab against placebo in patients with heart failure and systemic inflammation, were terminated after the committee concluded that neither study was likely to reach a different outcome than the Phase III ZEUS trial, which missed its primary endpoint in July 2026. Novo Nordisk told ClinicalTrialsArena it notified investigators on 4 September.
HERMES was designed to measure the time to first occurrence of cardiovascular death, heart failure hospitalization, or urgent heart failure visit, and had had enrolled about 4,900 patients against a planned 5,600 participants since May 2023. ATHENA, the smaller of the two studies with a planned enrolment of approximately 680 participants across roughly 150 sites in 18 countries, focused on heart failure symptoms and physical function in patients with preserved ejection fraction and elevated high-sensitivity C-reactive protein. Both trials used once-monthly subcutaneous ziltivekimab. Novo Nordisk said all enrolled patients will continue through their planned three-month follow-up visits. The terminations were not attributed to safety concerns.
The ZEUS study, which enrolled 6,376 patients with atherosclerotic cardiovascular disease, chronic kidney disease, and elevated inflammation markers, failed to reduce three-point major adverse cardiovascular events compared with placebo despite confirmed pharmacodynamic target engagement. Ziltivekimab robustly suppressed IL-6 pathway activity, reducing circulating IL-6 and C-reactive protein, but this did not translate into clinical benefit in this population.
Ziltivekimab is a fully human IgG1 monoclonal antibody that binds the free IL-6 ligand directly, blocking both classic and trans-signalling and preventing downstream JAK/STAT3 pathway activation. Unlike tocilizumab and sarilumab, which target the IL-6 receptor, ligand-directed blockade does not cause a paradoxical rise in circulating IL-6 or the lipid perturbations associated with receptor inhibition.