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

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

New P3 trial • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Myocardial Infarction

Rationale, Design, and Baseline Clinical Characteristics of the Ziltivekimab Cardiovascular Outcomes Trial: Interleukin-6 Inhibition and Atherosclerotic Event Rate Reduction. (PubMed, JAMA Cardiol) - P3 | "The ZEUS randomized clinical trial will formally test the hypothesis that IL-6 inhibition with ziltivekimab will lower incident cardiovascular event rates and potentially slow kidney decline among participants with known ASCVD, CKD, and elevated hsCRP. If successful, the ZEUS trial would provide a fully novel approach for prevention of myocardial infarction, stroke, cardiovascular death, and kidney function decline among high-risk patients with CKD."

Clinical • Journal • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Dyslipidemia • Heart Failure • Hypertension • Inflammation • Metabolic Disorders • Myocardial Infarction • Nephrology • Renal Disease • Transplantation • CRP • IL6

Beyond Lipids and Platelets: A Review of Anti-Inflammatory Strategies in Secondary Prevention of Acute Coronary Syndromes. (PubMed, J Clin Med) - "Colchicine, now FDA-approved for cardiovascular risk reduction, lowered major adverse cardiovascular events in COLCOT and LoDoCo2. Canakinumab (IL-1β inhibition) reduced recurrent events in proportion to IL-6 and hsCRP suppression, while ziltivekimab (IL-6 inhibition) achieved profound biomarker reductions but remains investigational. Early-phase studies of anakinra (IL-1 receptor antagonist) and dapansutrile (oral NLRP3 inhibitor) showed anti-inflammatory effects in early trials, whereas varespladib and darapladib illustrated the challenges of targeting lipid-associated pathways...Additional emerging avenues include triptolidiol, dasatinib, and BTK or JAK/STAT inhibitors, while novel approaches, such as nanozyme delivery systems and CRISPR-based editing, extend the therapeutic horizon. This review highlights the potential of inflammation-targeted therapies to advance secondary prevention in ACS by integrating current evidence and perspectives on future therapeutic..."

Journal • Review • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Immunology • Inflammation • Myocardial Infarction • CRP • IL1B • NLRP3

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 | Trial completion date: Apr 2025 ➔ Oct 2026 | Trial primary completion date: Mar 2025 ➔ Jul 2026

Enrollment open • Trial completion date • Trial primary completion date • Atherosclerosis • Cardiovascular • Inflammation

Anti-inflammatory pharmacotherapy in patients with cardiovascular disease. (PubMed, Eur Heart J Cardiovasc Pharmacother) - "Colchicine has demonstrated potential in reducing cardiovascular events, though recent trial data have raised concerns regarding its overall benefit and optimal application after myocardial infarction. Alternative agents targeting inflammatory pathways-such as monoclonal antibodies against interleukins (e.g. canakinumab, tocilizumab, ziltivekimab)-have shown biological efficacy but are not yet approved for routine clinical use in CVD...Future approaches will likely adopt personalized, multi-targeted regimens that integrate inflammation control with lipid-lowering and antithrombotic therapies. As evidence accumulates, inflammation may transition from an adjunctive target to a central focus in CVD management."

Journal • Cardiovascular • Inflammation • Myocardial Infarction

IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk. (PubMed, Nat Cardiovasc Res) - "Here we develop a genetic instrument for IL-6 signaling downregulation comprising IL6 locus variants that mimic the effects of the anti-IL-6 antibody ziltivekimab and use it to predict the effects of IL-6 inhibition on cardiometabolic and safety endpoints...Unlike IL6R missense variants linked to bacterial infections, the IL6 instrument was associated with lower risk of pneumonia hospitalization. Our data suggest that IL-6 inhibition can reduce cardiovascular risk without major unexpected safety concerns."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Gene Therapies • Infectious Disease • Peripheral Arterial Disease • Pneumonia • Respiratory Diseases • IL6R

Direct Interleukin-6 Inhibition Blunts Arterial Thrombosis by Reducing Collagen-Mediated Platelet Activation. (PubMed, Arterioscler Thromb Vasc Biol) - "Direct IL-6 inhibition blunts thrombus formation by reducing collagen-induced platelet activation. These findings offer a potential mechanistic explanation for the results observed in the RESCUE trial and support the rationale of the ongoing ZEUS trial (Ziltivekimab Cardiovascular Outcome Study)."

Journal • Cardiovascular • Hematological Disorders • Inflammation • Thrombosis • IL6

Novo Nordisk Told to Increase Indian Patient Enrollment for Ziltivekimab Study (Medical Dialogues) - "In response to a proposal by Novo Nordisk, the Subject Expert Committee (SEC) under the Central Standard Control Organisation (CDSCO) has recommended increasing the number of Indian subjects from 700 to 1000 in the Ziltivekimab C 30 mg/mL/placebo study conducted under protocol No EX6018-4979. The recommendation was made during the SEC (cardiovascular) meeting held on 5th June 2025, after the company presented its updated protocol requesting an increase in the number of subjects from India 700 to 1000 protocol No EX6018-4979."

Trial status • Cardiovascular • Myocardial Infarction

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=6200 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Oct 2026 ➔ Jun 2026 | Trial primary completion date: Sep 2025 ➔ Jun 2026

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

Seeking and treating inflammation in ischaemic heart disease: are we ready? (PubMed, Eur Heart J Suppl) - "However, the evidence of colchicine's efficacy in this context remains conflicting and inconclusive. In addition, using new systemic markers (IL-6) and modern non-invasive CT or CT-PET imaging techniques will lead to better accuracy in the diagnosis of inflammation, not only systemic but also organ- and lesion-specific."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Heart Failure • Inflammation • CRP • IL6

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=6200 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2026 ➔ Oct 2026

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

Inflammation in atherosclerotic cardiovascular disease: From diagnosis to treatment. (PubMed, Eur J Clin Invest) - "Thus, the integration of interventions aimed at lowering the inflammatory burden in combination with aggressive lipid-modifying therapy in secondary prevention may hold the potential to further reduce the still substantial burden of ASCVD."

Journal • Review • Atherosclerosis • Cardiovascular • Inflammation • CRP • IL6

A Research Study of How the Medicine Ziltivekimab Works in the Body of Chinese Men and Women With Kidney Disease and Inflammation (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed | Trial completion date: May 2024 ➔ Sep 2024

Trial completion • Trial completion date • Chronic Kidney Disease • Inflammation • Nephrology • Renal Disease • CRP

Design of the ZEUS Trial: Interleukin-6 Inhibition With Ziltivekimab for Cardiovascular Protection in Chronic Kidney Disease (ISN-WCN 2025) - No abstract available

Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease • IL6

DESIGN OF THE ZEUS TRIAL: INTERLEUKIN 6 INHIBITION WITH ZILTIVEKIMAB FOR CARDIOVASCULAR PROTECTION IN CHRONIC KIDNEY DISEASE (ISN-WCN 2025) - P3 | "Although colchicine is effective at preventing CV events in patients with atherosclerotic CV disease (ASCVD), more targeted therapies are required, particularly for people with chronic kidney disease (CKD) who are at very high CV risk and for whom colchicine is contraindicated. Interim analyses for efficacy have been prespecified. Conclusions ZEUS will evaluate the effect of ziltivekimab on MACE and kidney outcomes in participants with CKD, ASCVD, and elevated hsCRP levels, as well as additional efficacy and safety endpoints, and is expected to be completed in 2026."

Late-breaking abstract • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Inflammation • Myocardial Infarction • Nephrology • Renal Disease • CRP • IL6

ATHENA: A Research Study Looking Into How Ziltivekimab Works Compared to Placebo in Participants With Heart Failure and Inflammation (clinicaltrials.gov) - P3 | N=680 | Recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Sep 2026 ➔ Jan 2027 | Trial primary completion date: Jun 2026 ➔ Oct 2026

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

"Anti-inflammatory Therapies in Atherosclerosis - Where are we going?". (PubMed, Curr Atheroscler Rep) - "Reduction in Inflammation in Patients with Advanced Chronic Renal Disease Utilizing Antibody Mediated Interleukin-6 Inhibition (RESCUE) was conducted using Ziltivekimab, an IL-6 ligand monoclonal antibody and found that it significantly reduced high-sensitivity C-reactive protein, an inflammatory surrogate marker. Colchicine is by far the only one that has the potential to be widely used due to its cost-effectiveness. Further research is needed on other novel anti-inflammation therapies and their real-world implementation."

Journal • Review • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Inflammation • Ischemic stroke • Myocardial Infarction • Nephrology • Renal Disease • CRP • IL6

What additional/alternative agents are in the pipeline (NsMRA, Ziltivekimab, ASI, Cagrisema, dual/triple Incretins, etc…)? (CVCT USA 2024) - No abstract available

Diabetes • Metabolic Disorders

Anti-inflammatory Agents and their Effect on Cardiovascular Disease: A Comprehensive Review of Literature (AHA 2024) - "Two RCT's evaluated immunomodulating agents, including the CANTOS trial which assessed canakinumab, an IL-1β inhibitor and the RESCUE trial which assessed ziltivekimab, an IL-6 inhibitor. The COLCOT and LoDoCo2 trials assessed colchicine while CIRT assessed methotrexate...The advancements in targeted immune therapies offer promising new avenues in cardiovascular medicine. Our systematic review of RCTs suggests that anti-inflammatory agents have a beneficial role in the reduction of cardiovascular events and the progression of CVD in patients with atherosclerotic disease. While the majority of the included RCTs support the use of these agents, the heterogeneity in the individual studies emphasize the need for further research to investigate the role of immunomodulating agents on CVD outcomes."

Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • IL1B

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 | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Myocardial Infarction

Effect of IL-6 Inhibition on Lipoprotein(a) Levels: A Systematic Review and Meta-Analysis (CMHC 2024) - "The analyses included ten studies with 1,201 total participants (876 rheumatoid arthritis, 325 chronic kidney disease) receiving either an anti-IL-6/IL-6R mAb (311 tocilizumab, 153 sarilumab, 247 ziltivekimab) or comparator (78 placebo, 412 TNFi). This meta-analysis indicates significant reductions in Lp(a) levels with anti-IL-6/IL-6R mAbs compared to controls. The potential clinical relevance for ASCVD prevention warrants further investigation in outcome trials"

Retrospective data • Review • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Dyslipidemia • Immunology • Inflammatory Arthritis • Nephrology • Oncology • Renal Disease • Rheumatoid Arthritis • Rheumatology • IL6R

Ziltivekimab for anemia and atherosclerosis in chronic kidney disease: a new hope? (PubMed, J Nephrol) - "These trials have shown that ziltivekimab does not increase the risk for cytopenia or infectious complications as has been described for other interleukin-6-targeting monoclonal antibodies, like tocilizumab. In addition, ziltivekimab has shown efficacy in improving anemia parameters, including hemoglobin levels and iron studies. Ziltivekimab deserves full scale clinical development, and to this aim, large-scale clinical trials are under way."

Journal • Review • Anemia • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Dyslipidemia • Epilepsy • Hematological Disorders • Hypertension • Inflammation • Nephrology • Oncology • Renal Disease • Solid Tumor • IL6

Direct IL-6 inhibition prevents arterial thrombosis by reducing collagen-mediated platelets activation (ESC 2024) - "The recent phase 2 RESCUE trial reported that direct inhibition of IL-6 ligand by the monoclonal antibody (mAb) Ziltivekimab is safe in patients with elevated cardiovascular risk... The direct inhibition of IL-6 reduces platelets reactivity to collagen, thereby blunting arterial thrombosis upon endothelial damage. These results provide a potential mechanism to explain the reduction of cardiovascular risk associated to direct IL-6 inhibition."

Cardiovascular • Coronary Artery Disease • Thrombosis

Recent Advances in Targeted Management of Inflammation In Atherosclerosis: A Narrative Review. (PubMed, Cardiol Ther) - "Evidence suggests that high-sensitivity C-reactive protein (hsCRP), and potentially other inflammatory biomarkers, can be used to identify the inflammatory residual ASCVD risk phenotype and may serve as future targets for the development of more efficacious therapeutic approaches. We review the biological basis for the association of inflammation with ASCVD, propose new therapeutic strategies for the use of inflammation-targeted treatments, and discuss current challenges in the implementation of this new treatment paradigm for ASCVD."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • CRP

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

Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation