ziltivekimab (COR-001) / Novo Nordisk - LARVOL DELTA

Targeting Inflammation in Chronic Kidney Disease: Pathophysiological Insights and Emerging Therapeutic Strategies. (PubMed, J Clin Med) - "Renin-angiotensin system inhibitors, sodium-glucose cotransporter-2 inhibitors, finerenone, and glucagon-like peptide-1 receptor agonists improve cardiorenal outcomes and have plausible anti-inflammatory actions, although inflammatory mediation remains unproven...Interleukin-6 ligand inhibition produces marked human target engagement; however, headline results from the completed phase 3 ZEUS trial showed no reduction in three-point major adverse cardiovascular events with ziltivekimab despite biomarker suppression, while serious infections were more frequent. POSIBIL6ESKD continues to test clazakizumab in inflamed dialysis patients...Future progress requires inflammatory endotyping, repeated biomarker assessment, mechanistically aligned outcomes, and rigorous infection surveillance. ZEUS underscores that pathway suppression must deliver clinical benefit beyond contemporary standard therapy."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Fibrosis • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Nephrology • Renal Disease • IL6 • NLRP3

Pharmacokinetics of novel drugs for the treatment of Diabetic nephropathy. (PubMed, Expert Opin Drug Metab Toxicol) - "Evidence was synthesized for sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), dual incretin agonists, nonsteroidal mineralocorticoid receptor antagonists (nsMRA), endothelin receptor antagonists (ERA), aldosterone synthase inhibitors (vicadrostat, baxdrostat, and lorundrostat), avenciguat, and ziltivekimab, emphasizing exposure, clearance, metabolism, elimination, and dosing implications. In reduced kidney function, SGLT2i show modest exposure increases but attenuated glucose-lowering effects, finerenone shows modest exposure increases despite minimal renal clearance, and ERA may have larger increases that narrow the therapeutic window. Newer incretin therapies generally maintain stable exposure, while eGFR alone may incompletely capture PK risk because uremia, altered protein binding, and nonrenal clearance can influence exposure. The next advance is likely to be drug-specific decision support integrating estimated..."

Journal • PK/PD data • Review • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

HERMES: A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Heart Failure and Inflammation (clinicaltrials.gov) - P3 | N=4899 | Terminated | Sponsor: Novo Nordisk A/S | Trial completion date: Jul 2027 ➔ Sep 2026 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jul 2027 ➔ Sep 2026; No longer looking for participants.

Trial completion date • Trial primary completion date • Trial termination • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • CRP

Novo Nordisk has given up on two more phase 3 trials of ziltivekimab, further eroding the prospects for a molecule that analysts had once tipped as a potential blockbuster (FierceBiotech) - "The Danish drugmaker had been evaluating the IL‑6 ligand in the late-stage Hermes and Athena trials, which enrolled 4,900 and 673 patients, respectively, with heart failure with mildly reduced or preserved ejection fraction. Success in both trials was to be judged by ziltivekimab’s ability to delay death or hospitalization from heart failure. The original plan, according to the federal trials database, had been to read out Hermes in the first half of 2027. But Novo notified investigators on Friday that it was winding up both of the studies early. The pharma made the decision after the trials’ data monitoring committee had assessed 'the totality of the data'....Novo told Fierce that Artemis will 'continue as planned,' with a readout penciled in for the first half of next year."

DSMB • P3 data • Trial termination • Heart Failure • Myocardial Infarction

ARTEMIS - A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With a Heart Attack (clinicaltrials.gov) - P3 | N=10000 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Myocardial Infarction

Ziltivekimab in Acute Myocardial Infarction: Rationale, Design and Baseline Clinical Characteristics of the ARTEMIS Study (AHA 2026) - "Abstract is embargoed at this time."

Clinical • Cardiovascular • Myocardial Infarction

Novo Nordisk’s ziltivekimab, an investigational human monoclonal antibody that targets the IL-6 ligand, a pro-inflammatory cytokine, to reduce cardiovascular inflammation, did not reduce the risk of major adverse cardiovascular events (MACE) in a Phase 3 trial. (Drug Discovery & Development) - "The trial’s primary endpoint showed a hazard ratio (HR) of 0.99 for MACE with a 95% confidence interval of 0.88 to 1.11, indicating no significant difference between ziltivekimab and placebo...Overall rates of adverse events (AEs) and serious AEs were similar to those observed with placebo, the company said in the release...Full results of this trial will be presented at an upcoming scientific meeting in 2026...Two additional ongoing trials investigating ziltivekimab in people with heart failure (HERMES) and in people following an acute heart attack (ARTEMIS) are planned to continue, and data is expected in the first half of 2027."

P3 data • Cardiovascular • Chronic Kidney Disease • Heart Failure • Immunology • Inflammation

SPIDER: Specifying the Anti-inflammatory Effects of Ziltivekimab (clinicaltrials.gov) - P3 | N=40 | Active, not recruiting | Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) | Recruiting ➔ Active, not recruiting

Enrollment closed • Atherosclerosis • Cardiovascular • Inflammation • CRP

From Selye to ZEUS: inflammation as the adaptation syndrome's hidden machinery. (PubMed, Eur J Prev Cardiol) - No abstract available

Journal • Atherosclerosis • Cardiovascular • Inflammation

ATHENA: A Research Study Looking Into How Ziltivekimab Works Compared to Placebo in Participants With Heart Failure and Inflammation (clinicaltrials.gov) - P3 | N=680 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • CRP

Targeting Inflammation in Atherosclerotic Cardiovascular Disease: Mechanisms and Emerging Therapies. (PubMed, Immunol Rev) - "Specific approaches-such as IL-1β inhibition or low-dose colchicine-have shown benefit in reducing cardiovascular events, while other strategies have failed, underscoring the importance of targeting disease-relevant immune pathways and selecting patients that will benefit. Newer approaches-including IL-6 inhibitors, NLRP3 inflammasome inhibitors, and low-dose IL-2-offer promise for further risk reduction. Efforts to use inflammatory biomarkers to more precisely identify patients who may benefit may further improve the benefit-to-risk profile of emerging therapies."

Biomarker • Journal • Review • Atherosclerosis • Cardiovascular • Inflammation • CRP • IL18 • IL1B • NLRP3

ZEUS - A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Cardiovascular Disease, Chronic Kidney Disease and Inflammation (clinicaltrials.gov) - P3 | N=6385 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed

Trial completion • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Inflammation • Nephrology • Renal Disease • CRP

Biomarker-guided pharmacotherapy in cardiovascular-kidney-metabolic syndrome: A three-dimensional framework for precision drug selection and monitoring. (PubMed, Pharmacol Ther) - "The rapid convergence of multiple drug classes on CKM pathways-SGLT2 inhibitors, finerenone, GLP-1 receptor agonists, ARNI, and interleukin-directed therapies-has created an urgent need for pharmacologically grounded frameworks that guide drug selection, interpret biomarker responses, and monitor target engagement across interconnected organ systems...In the organ-specific dimension, we map key biomarkers to their corresponding drug targets and elucidate the molecular mechanisms underlying drug-biomarker interactions: SGLT2 inhibitors attenuate myocardial injury through metabolic substrate shifting toward ketone body utilization and, based on preclinical evidence, NHE1 inhibition; neprilysin selectivity of sacubitril/valsartan explains the differential natriuretic peptide response; and tubuloglomerular feedback mediates the renoprotective hemodynamic effects of SGLT2 inhibitors. In the pathway-specific dimension, we identify cross-system biomarkers-hs-CRP, IL-6,..."

Biomarker • IO biomarker • IO Companion diagnostic • Journal • Review • Cardiovascular • Metabolic Disorders • Oncology • FGF21 • GDF15 • IL1B • IL6 • NLRP3

HERMES: A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Heart Failure and Inflammation (clinicaltrials.gov) - P3 | N=4899 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • CRP

A quantitative method to estimate free interleukin-6 among patients treated with the interleukin-6 ligand inhibitor ziltivekimab: comparison to C-reactive protein with implications for the ZEUS, HERMES, and ARTEMIS cardiovascular outcomes trials. (PubMed, Atherosclerosis) - "Predicted reductions in estimated free IL-6 following ziltivekimab closely parallel directly measured levels of downstream hsCRP. Estimated free IL-6 decreased immediately after the first dose, was dose-dependent, and mirrored the timing of hsCRP reduction. These data support ziltivekimab's targeted anti-inflammatory effect through free IL-6 reduction and affirm hsCRP as the most clinically actionable biomarker of direct IL-6 pathway inhibition, findings relevant for the ongoing ZEUS, HERMES, and ARTEMIS phase 3 trials."

Biomarker • Clinical • Journal • Atherosclerosis • Cardiovascular • CRP • IL6

Persistent residual inflammatory risk at 1 month after contemporary PCI: rationale for routine hsCRP reassessment and dual-target therapy. (PubMed, Front Immunol) - "This biomarker-guided approach represents a hypothesis-generating framework to enable precision deployment of low-dose colchicine or IL-6 pathway inhibitors (e.g., ziltivekimab) in patients with persistent RIR, directly addressing the enrichment gap observed in neutral broad anti-inflammatory trials such as CLEAR-SYNERGY. We therefore propose consideration of routine 1-month hsCRP reassessment as a potential future Class IIa recommendation in ESC/ACC guidelines. This strategy may transform silent residual inflammatory risk into a precisely treatable immunologic target, pending prospective validation in dedicated trials."

Biomarker • Journal • Review • Cardiovascular • Inflammation • CRP • IL1B • IL6 • NLRP3

Ziltivekimab in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the ATHENA and HERMES trials (HEART FAILURE 2026) - "ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality."

Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • IL6

Ziltivekimab in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the ATHENA and HERMES trials. (PubMed, Eur J Heart Fail) - "ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • CRP • IL6 • NLRP3

ARTEMIS - A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With a Heart Attack (clinicaltrials.gov) - P3 | N=10000 | Recruiting | Sponsor: Novo Nordisk A/S | N=3884 ➔ 10000

Enrollment change • Cardiovascular • Myocardial Infarction

ARTEMIS - A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With a Heart Attack (clinicaltrials.gov) - P3 | N=10000 | Recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Sep 2026 ➔ Dec 2026 | Trial primary completion date: Sep 2026 ➔ Dec 2026

Trial completion date • Trial primary completion date • Cardiovascular • Myocardial Infarction

ZEPHYR: Effects of Ziltivekimab on Coronary Atherosclerotic Burden in Patients With Acute Myocardial Infarction (clinicaltrials.gov) - P3 | N=332 | Recruiting | Sponsor: ECRI bv | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Myocardial Infarction

SPIDER: Specifying the Anti-inflammatory Effects of Ziltivekimab (clinicaltrials.gov) - P3 | N=40 | Recruiting | Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Coronary Artery Disease • CCL2 • CD14 • CRP • TNFA

NN6018-8195: Effects of ziltivekimab on coronary atherosclerotic burden in patients with acute myocardial infarction (clinicaltrialsregister.eu) - P2/3 | N=249 | Not yet recruiting | Sponsor: Novo Nordisk A/S, ECRI-trials B.V.

New P2/3 trial • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Myocardial Infarction

Role of Interleukin-6 in Atherothrombosis and Myocardial Infarction. (PubMed, Curr Atheroscler Rep) - "Recent studies showed reduced inflammation, a reduction in Lp (a) and inhibitory effects on platelets by anti-IL-6 (ziltivekimab) therapy in patients at risk for CVD. Anti-IL-6 receptor therapy (tocilizumab) showed reduced inflammation and improved myocardial function in MI patients, involving reduced degranulation in neutrophils and modulation of monocytes...IL-6 plays an important and many-faceted role in atherothrombosis including MI and ischemic stroke, and the IL-6 system represent a promising but still evolving therapeutic approach. A comprehensive understanding of the complexity of IL-6 signaling is needed to improve such treatment strategies."

Journal • Review • Atherosclerosis • Cardiovascular • Hematological Disorders • Inflammation • Ischemic stroke • Myocardial Infarction • Thrombosis • IL6

RESCUE: Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition (clinicaltrials.gov) - P2 | N=264 | Completed | Sponsor: Novo Nordisk A/S | Phase classification: P2b ➔ P2

Phase classification • Chronic Kidney Disease • Inflammation • Nephrology • Renal Disease