ZEUS Phase 3 Trial Fails to Demonstrate Clinical Benefit

Novo Nordisk A/S (NVO)'s ziltivekimab (COR-001) is a once-monthly subcutaneous interleukin-6 ligand (IL-6 ligand) monoclonal antibody without a brand name. The Phase 3 ZEUS trial (NCT05021835), which randomized 6,376 patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and high-sensitivity C-reactive protein (hsCRP) levels of 2 mg/L or higher, evaluated a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, known as a 3-point major adverse cardiovascular event (MACE). While ziltivekimab reduced IL-6 and hsCRP, it failed to achieve the primary endpoint of reducing MACE, undermining the development rationale that biomarker improvement would translate into clinical event prevention.

Safety Signals and Challenges for Subsequent Trials

The overall incidence of adverse events and serious adverse events was similar between the ziltivekimab and placebo groups, but serious infections were more frequent in the ziltivekimab group, and there was no difference in the number of deaths. The failure to demonstrate cardiovascular benefit while carrying the risk of immunosuppression has raised the bar for regulatory agencies' benefit-risk assessment criteria. Ziltivekimab is a clinical development product without prior FDA, EMA, or PMDA approval or advisory committee (AdComm) review. Results from the HERMES and ATHENA trials targeting heart failure and the ARTEMIS Phase 3 trial targeting patients after acute myocardial infarction are expected in 2027.

Impact on Existing Treatments and Competing Pipelines

The standard of care for ASCVD includes high-intensity statins, ezetimibe, PCSK9 inhibitors, and antiplatelet agents. In terms of inflammation-targeting therapies, canakinumab (Ilaris) and colchicine (Lodoco) serve as clinical benchmarks. Direct competitors include Novartis AG (NVS)'s IL-6 antibody pacibekitug, which is in Phase 2, and CSL Limited (CSL.AX)'s IL-6 antibody clazakizumab, which is in Phase 2b/3. In the NLRP3 inhibitor class, BioAge Labs, Inc. (BIOA)'s BGE-102 is evaluating changes in hsCRP in a 160-patient Phase 2 QUELL-CV trial, and Neumora Therapeutics, Inc. (NMRA)'s NMRA-215 is expected to enter clinical trials in 2026, with the key being differentiation in mechanism of action.

Reassessment of Acquisition Value and Market Expectations

Novo Nordisk acquired Corvidia Therapeutics in 2020 for USD 725 million in upfront cash and up to USD 2.1 billion, including regulatory and sales milestones, to gain access to ziltivekimab. Following the ZEUS failure, the company will recognize a non-cash impairment charge in the third quarter of 2026, but it has not changed its annual operating profit outlook, and the stock price fell by as much as 10% during the day of the announcement. The major seven-country ASCVD treatment market was estimated at USD 24.0 billion in 2025, but the large-scale, event-driven Phase 3 failure is accelerating the shift from valuing the market based solely on inflammation biomarkers to prioritizing actual MACE reduction.