HERMES and ATHENA have been stopped after the earlier cardiovascular outcomes failure, leaving the post-heart attack ARTEMIS trial as the key remaining test of IL-6 inhibition for ziltivekimab.
Key Takeaways
- Novo Nordisk has discontinued HERMES and ATHENA, two Phase 3 trials testing ziltivekimab in heart failure with mildly reduced or preserved ejection fraction.
- The decision followed a data monitoring committee review that found a low likelihood that the studies would produce an outcome meaningfully different from ZEUS, which failed to reduce major cardiovascular events despite clear IL-6 pathway suppression.
- ARTEMIS will continue as planned in patients following acute myocardial infarction, with a readout expected in the first half of 2027. (Fierce Biotech program update)
Data Snapshot
| Trial | Population | Size | Main question | Status |
|---|---|---|---|---|
| ZEUS | ASCVD + CKD + hsCRP ≥2 mg/L | 6,376 | 3-point MACE | Primary endpoint missed |
| HERMES | HFmrEF/HFpEF + inflammation | ~4,900 | CV death / HF hospitalization / urgent HF visit | Discontinued |
| ATHENA | HFmrEF/HFpEF + inflammation | 673 | Change in KCCQ-CSS at 12 months | Discontinued |
| ARTEMIS | Recent acute MI | Phase 3 | Cardiovascular outcomes after acute MI | Ongoing |
HERMES and ATHENA both evaluated ziltivekimab 15 mg subcutaneously once monthly in patients with LVEF above 40% and hsCRP ≥2 mg/L, but they were designed to answer different clinical questions: HERMES focused on morbidity and mortality, while ATHENA focused on health status and symptoms. (HERMES and ATHENA trial design)
What Happened
Novo Nordisk has ended HERMES and ATHENA, further narrowing the late-stage development program for its investigational anti-IL-6 antibody ziltivekimab.
The decision was not announced as the result of a new safety signal or a separate efficacy failure from either trial. Instead, the studies’ data monitoring committee reviewed the available evidence and judged that there was a low likelihood of a different outcome from ZEUS.
That distinction matters. Novo is effectively stopping two expensive Phase 3 programs before waiting for independent readouts because the earlier ZEUS result materially changed the probability that IL-6 inhibition would deliver the cardiovascular benefit those studies were designed to test.
HERMES had enrolled roughly 4,900 patients with HFmrEF or HFpEF and cardiovascular inflammation. Its primary endpoint measured time to cardiovascular death, heart-failure hospitalization or an urgent heart-failure visit.
ATHENA enrolled 673 patients in a similar heart-failure population but asked a different question: whether ziltivekimab could improve patients’ health status, measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 12 months.
The latest discontinuations leave ARTEMIS as the principal remaining Phase 3 test of ziltivekimab in cardiovascular disease. Unlike ZEUS, HERMES and ATHENA, ARTEMIS evaluates patients after an acute myocardial infarction, where the inflammatory environment may be substantially different.
Why ZEUS Changed the Program
ZEUS was the pivotal test of whether strong suppression of IL-6-driven inflammation could reduce cardiovascular events.
The Phase 3 trial randomized 6,376 patients with established atherosclerotic cardiovascular disease, chronic kidney disease and elevated inflammation to ziltivekimab 15 mg subcutaneously once monthly or placebo on top of standard care.
Ziltivekimab produced the expected biological response. Free IL-6 and hsCRP declined, confirming target engagement and downstream pathway inhibition.
But the clinical endpoint was essentially unchanged:
3-point MACE: HR 0.99; 95% CI, 0.88–1.11
The trial therefore failed to show a significant reduction in cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. (Novo Nordisk ZEUS results)
BioPharma Dive noted at the time that ZEUS raised broader questions for companies developing cardiovascular drugs around inflammation and hsCRP reduction, because the study demonstrated a clear biological effect without a corresponding cardiovascular benefit. (BioPharma Dive ZEUS analysis)
Why It Matters
The HERMES and ATHENA cancellations do not mean that cardiovascular inflammation is no longer a viable therapeutic field.
They do, however, make the bar substantially higher for drugs that use IL-6 or hsCRP reduction as the biological rationale for preventing cardiovascular events.
| Candidate / Therapy | Company | Target / approach | Current cardiovascular position |
|---|---|---|---|
| Ziltivekimab | Novo Nordisk | IL-6 ligand | ZEUS failed; HERMES/ATHENA stopped; ARTEMIS ongoing |
| Pacibekitug | Novartis | IL-6 ligand | Phase 2 TRANQUILITY completed; Phase 3-ready |
| Clazakizumab | CSL | IL-6 ligand | Phase 3 CV outcomes development in ESKD |
| Low-dose colchicine | Multiple | Broad anti-inflammatory | Established CV outcomes evidence; approved in the U.S. |
Novartis’s pacibekitug produced large and sustained reductions in hsCRP in the Phase 2 TRANQUILITY program and is positioned as a Phase 3-ready cardiovascular asset. However, it has not yet established that those biomarker changes translate into fewer cardiovascular events—the exact question highlighted by ZEUS. (Novartis pacibekitug update)
CSL is taking clazakizumab, another anti-IL-6 monoclonal antibody, into cardiovascular outcomes testing in patients with end-stage kidney disease on dialysis. CSL retained the cardiovascular rights in this population when it licensed other clazakizumab indications to Eli Lilly earlier this year. (CSL clazakizumab development)
The contrast with low-dose colchicine is also important. Colchicine has already demonstrated hard cardiovascular outcomes benefit and is FDA-approved to reduce the risk of myocardial infarction, stroke, coronary revascularization and cardiovascular death in selected adults with atherosclerotic disease or cardiovascular risk factors. (FDA colchicine cardiovascular indication)
The emerging competitive question is therefore no longer simply which therapy lowers inflammation most strongly. It is which intervention can convert that anti-inflammatory effect into a measurable reduction in cardiovascular events.
The Science Behind Ziltivekimab
Ziltivekimab successfully inhibits the IL-6 pathway.
The harder question is why:
IL-6 ↓ → hsCRP ↓
did not become:
MACE ↓
Read the BP Science explainer:
Why Lowering IL-6 Wasn’t Enough: What Ziltivekimab’s Cardiovascular Setback Means
BP View
Stopping HERMES and ATHENA materially changes the outlook for ziltivekimab. Rather than waiting for two additional Phase 3 readouts after ZEUS produced virtually no MACE signal, Novo has chosen to concentrate what remains of the cardiovascular program around a biologically different setting.
That makes ARTEMIS considerably more important. Acute myocardial infarction triggers an intense inflammatory response that differs from the chronic inflammatory state seen in established ASCVD, CKD or HFpEF. A positive result would not erase the ZEUS failure, but it could support a narrower role for IL-6 inhibition in patients whose cardiovascular inflammation is more acute and time-dependent.
The implications also extend to competing IL-6 programs. Pacibekitug and clazakizumab can still succeed in different patient populations, but biomarker reductions alone will now carry less weight. Their development programs will ultimately need to show that suppressing IL-6 changes outcomes rather than simply changing laboratory values.
For Novo Nordisk, the realistic opportunity has therefore become narrower. If ARTEMIS succeeds, ziltivekimab could retain a focused development path in post-MI cardiovascular care. If it does not, further expansion of the asset across cardiovascular indications would become increasingly difficult to justify.
Related Post
For another recent case in which strong target engagement failed to deliver the expected cardiovascular outcome, read my previous analysis of Novartis and Ionis’ pelacarsen Phase 3 Lp(a)HORIZON result.
About BP
Biopharma Perspective (BP) explains global biopharma news through strategic, clinical and market perspectives.
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