Novo's Ziltivekimab Fails in ZEUS, Invalidating the hs-CRP Biomarker Strategy for MACE Reduction

Novo Nordisk's Ziltivekimab Fails Phase 3 ZEUS Trial

Novo Nordisk's investigational IL-6 inhibitor, ziltivekimab, failed to reduce the risk of cardiovascular complications in its Phase 3 ZEUS trial, sending significant negative repercussions across the inflammatory drug development sector. This failure particularly impacted companies like BioAge Labs and Monte Rosa Therapeutics, whose stock prices plummeted by 63.6% and 27% respectively, due to concerns that a reduction in the inflammation biomarker hs-CRP may not correlate with improved major adverse cardiovascular events (MACE) protection. The trial's outcome challenges the development strategies of other drugmakers targeting similar pathways.

• Novo Nordisk's IL-6 inhibitor, ziltivekimab, did not meet its primary endpoint of lowering the risk of cardiovascular complications in the Phase 3 ZEUS trial. This outcome dashes hopes for the drug's potential in the cardiometabolic space and raises questions about the efficacy of IL-6 inhibition for cardiovascular benefits.
• The ZEUS trial's failure significantly impacted BioAge Labs, whose stock dropped 63.6%. Analysts noted a 'negative readthrough' challenging the correlation between significant hs-CRP reduction and MACE protection, a key premise for BioAge's lead asset, BGE-102, which showed an 85% hs-CRP reduction in Phase 1.
• Monte Rosa Therapeutics also experienced a substantial stock decline of 27%. The company is developing MRT-8102 for IL-1β/NLRP3-driven inflammation, and its interim Phase 1 data showed an 85% suppression of hs-CRP levels, a positive inflammatory signal now questioned by the ZEUS trial's inability to translate hs-CRP reduction into cardiovascular benefits.

Ziltivekimab's Phase 3 ZEUS Trial Fails Cardiovascular Endpoints

Recent literature highlights significant findings for major drug classes in cardiovascular disease, particularly SGLT2 inhibitors and GLP-1 receptor agonists. A 2025 CARDIAB cohort study of over 138,000 patients with type 2 diabetes and atherosclerotic cardiovascular disease demonstrated substantial all-cause mortality reductions with SGLT2 inhibitors alone (HR 0.28), GLP-1 RAs alone (HR 0.39), and especially combination therapy (HR 0.17) versus no treatment. However, in the post-acute myocardial infarction setting, a 2025 meta-analysis of seven trials (n=11,405) found that SGLT2 inhibitors reduced heart failure hospitalizations (OR 0.71) but did not significantly impact mortality or MACE. Further nuancing this landscape, a 2026 propensity score-matched study directly comparing GLP-1 RAs to SGLT2is in post-PCI AMI patients reported superior 1-year outcomes for the GLP-1 RA class, including lower risks for acute heart failure (HR 0.415), MACE (HR 0.788), and all-cause mortality (HR 0.700).

Beyond glucose-lowering agents, recent meta-analyses have refined the understanding of lipid-lowering strategies and their economic implications. A 2026 meta-analysis of 11 trials involving 38,089 elderly patients (≥65 years) confirmed that intensive lipid-lowering therapy (ILLT) is associated with a lower risk of major adverse cardiovascular events (HR 0.85). The risk reduction was particularly significant in a primary prevention context (HR 0.66) and was driven by reductions in myocardial infarction (HR 0.84) and stroke (HR 0.71), though effects on mortality were not statistically significant. Complementing these clinical findings, a 2026 pharmacoeconomic analysis stratified cardiovascular therapies by cost-effectiveness. It identified low-cost interventions (<$20,000/QALY) like ramipril and generic statins; moderate-cost options ($3,000-$50,000/QALY) such as empagliflozin, liraglutide, and colchicine; and high-cost therapies ($80,000-$300,000/QALY) including PCSK9 inhibitors, providing a valuable framework for strategic decision-making.

Challenging hs-CRP as a Surrogate for Cardiovascular Outcomes

Ziltivekimab trials have consistently used high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L as the primary biomarker-driven inclusion criterion, layered onto populations with chronic kidney disease (CKD) and/or established atherosclerotic cardiovascular disease (ASCVD). The RESCUE trial (2022) enrolled adults with moderate-to-severe CKD and hsCRP ≥2 mg/L, while RESCUE-2 (2023) applied similar criteria in Japanese patients with stage 3–5 non-dialysis-dependent CKD. The phase 3 ZEUS trial (2025) extended this strategy to 6,376 participants with ASCVD, CKD, and hsCRP ≥2 mg/L, reflecting a residual inflammatory risk population characterized at baseline by a mean eGFR of 44.5 mL/min/1.73m², median hsCRP of 4.5 mg/L, median IL-6 of 4.9 pg/mL, mean age 69.5 years, and high comorbidity burden (92.0% hypertension, 65.7% diabetes, 41.3% heart failure). Across these trials, ziltivekimab produced dose-dependent reductions in hsCRP—up to 92% at the 30 mg dose in RESCUE and 93.4% in RESCUE-2—alongside parallel decreases in fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a), reinforcing hsCRP’s role as a pharmacodynamic marker of IL-6 pathway inhibition rather than merely a selection criterion.

Beyond hsCRP, investigators have explored complementary hematologic and inflammatory biomarkers to refine risk stratification and capture residual inflammatory risk more comprehensively. A 2023 post hoc analysis of RESCUE examined the neutrophil-to-lymphocyte ratio (NLR), a marker independently associated with atherosclerotic events, in a cohort where 71% had diabetes and 48% had known atherosclerosis. Ziltivekimab produced significant, dose-dependent reductions in NLR at 12 weeks (estimated treatment differences of -14.6%, -15.3%, and -23.6% for the 7.5 mg, 15 mg, and 30 mg doses, respectively; all P<0.004), accompanied by parallel reductions in absolute neutrophil count. This suggests that NLR may serve as an adjunctive biomarker for identifying patients with heightened residual inflammatory risk who could benefit from IL-6 pathway inhibition, complementing hsCRP-based selection.

A more recent methodological advance addresses a fundamental limitation of hsCRP monitoring during IL-6 antagonist therapy: conventional immunoassays cannot distinguish free IL-6 from ziltivekimab-bound IL-6, complicating direct pharmacodynamic assessment. A 2026 quantitative modeling study developed an approach to estimate free IL-6 concentrations, demonstrating reductions of 72%, 82%, and 90% from baseline to week 12 across the 7.5 mg, 15 mg, and 30 mg doses. Notably, these estimated free IL-6 reductions closely mirrored the timing and magnitude of proportional hsCRP reductions, with declines evident immediately after the first dose in a clearly dose-dependent manner. This concordance affirms hsCRP as the most clinically actionable surrogate of direct IL-6 pathway inhibition, supporting its continued use for biomarker-based patient selection and monitoring in the ongoing phase 3 ZEUS, HERMES, and ARTEMIS trials.

Repercussions for Emerging Inflammatory Cardiovascular Therapies

Recent research highlights a multi-faceted pipeline of emerging therapeutic targets for cardiovascular disease, with several candidates approaching late-stage development. Lipoprotein(a) [Lp(a)], a causal, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis affecting about 20% of the global population, is transitioning from an untreatable biomarker to an actionable target. Pivotal Phase 3 trials for RNA-targeted therapies and novel oral small molecules designed to lower Lp(a) levels are nearing completion. Similarly, in cardiac amyloidosis, amyloid-specific imaging agents are advancing, with the pan-amyloid-binding peptide Iodine [I]evuzamitide (AT-01) having completed a Phase 3 pivotal evaluation and receiving U.S. FDA Breakthrough Therapy designation.

In the preclinical space, novel inhibitors are being identified for targets implicated in pathological cardiac remodeling. Phosphodiesterase 9A (PDE9A) has emerged as a key target, with the natural compound Hederagenin (HED) identified as a novel inhibitor. HED directly binds to PDE9A, inhibiting its activity and activating the protective cGMP-PKG signaling pathway. In murine models of cardiac hypertrophy, oral administration of HED attenuated both hypertrophy and fibrotic responses. Another promising target is CREB5, a transcription factor central to pathological cardiac hypertrophy. The compound Xanthatin has been shown to exert protective effects by suppressing CREB5 signaling, with cardiac-specific knockdown of CREB5 synergizing with Xanthatin to enhance its suppressive actions on hypertrophy, oxidative stress, and fibrosis.

The discovery landscape is also rich with novel biomarkers and early-stage targets. microRNA-92a (miR-92a) is being investigated as both a diagnostic and therapeutic target in heart failure, as its levels are significantly elevated in CHF patients and its inhibition improved cardiac function in animal models (p < 0.05). Other targets being characterized include Kallistatin, a serine protease inhibitor with protective effects on endothelial function and inflammation, and ARNT2, a transcription factor involved in regulating stress adaptation and immune signaling pathways. Further understanding of the biology of these targets may open new avenues for designing future cardiovascular therapies.