Ziltivekimab for Cardiovascular Disease

(ZEUS Trial)

Recruiting at 1460 trial locations

Overseen By Novo Nordisk

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Novo Nordisk A/S

Disqualifiers: Active infection, Recent heart attack, Recent stroke, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing whether ziltivekimab can lower the risk of heart attacks and strokes in people with heart disease, kidney disease, and inflammation. Participants will inject the medicine regularly. The study aims to see if reducing inflammation can help prevent serious heart problems.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug Ziltivekimab for cardiovascular disease?

Research shows that Ziltivekimab, a drug targeting inflammation, significantly reduced inflammation markers in patients at high risk for heart disease, suggesting it may help lower cardiovascular risk. ^{1 2 3 4 5}

Is ziltivekimab safe for humans?

Ziltivekimab has been tested in clinical trials and is generally considered safe for humans, as it significantly reduced inflammation markers in patients with high cardiovascular risk and chronic kidney disease without major safety concerns. ^{1 2 3 4 6}

How is the drug Ziltivekimab unique for treating cardiovascular disease?

Ziltivekimab is unique because it targets interleukin-6 (IL-6), a protein involved in inflammation, which may help reduce cardiovascular risk, especially in patients with conditions like rheumatoid arthritis that are linked to increased cardiovascular risk. ^{7 8 9 10 11}

Research Team

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Eligibility Criteria

This trial is for people with both cardiovascular disease and chronic kidney disease, who also have inflammation. They must have a certain level of kidney function or protein in their urine, signs of heart-related artery issues, or peripheral artery disease. Pregnant women or those planning pregnancy are excluded.

Inclusion Criteria

My kidney tests show a high protein level in my urine but my kidneys are still functioning well.

Your kidney function, measured using a test called eGFR, is between 15 and 60 mL/min/1.73 m^2.

Your blood test shows a high level of a protein called hs-CRP, which is a sign of inflammation.

Exclusion Criteria

I might have an infection, as per my doctor's assessment.

I have not had a heart attack, stroke, or severe chest pain requiring hospitalization in the last 2 months.

I am scheduled for a procedure to improve blood flow to my heart or other areas.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either ziltivekimab or placebo subcutaneously once monthly

Up to 4 years

Up to 20 clinic visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Placebo (ziltivekimab) (Other)
• Ziltivekimab (Monoclonal Antibodies)

Trial Overview The study tests if ziltivekimab can prevent heart attacks and strokes better than a placebo in patients with heart and kidney diseases plus inflammation. Participants will inject either the drug or placebo monthly for up to 4 years, with regular clinic visits and cardiovascular assessments.

Participant Groups

Group I: Ziltivekimab Experimental Treatment 2 Interventions

Participants will receive Ziltivekimab B or Ziltivekimab C subcutaneously once monthly for up to 4 years.

Group II: Placebo Placebo Group 2 Interventions

Participants will receive either placebo (Ziltivekimab B) or placebo (Ziltivekimab C) subcutaneously once monthly for up to 4 years.

Who Is Running the Clinical Trial?

Novo Nordisk A/S

Lead Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Findings from Research

In a study involving 1681 patients with rheumatoid arthritis who had inadequate responses to previous treatments, tocilizumab showed rapid and sustained efficacy, with significant improvements in disease activity scores over 24 weeks.

The treatment was generally safe, with a low discontinuation rate of 5.1% due to adverse events, although patients who had recently used TNF inhibitors experienced a higher rate of adverse events compared to those who had never used them.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. Bykerk, VP., Ostör, AJ., Alvaro-Gracia, J., et al.[2021]

In a 12-week phase 2 trial involving Japanese patients with chronic kidney disease, ziltivekimab significantly reduced inflammatory markers, with median hsCRP levels decreasing by 96.2% in the 15 mg group and 93.4% in the 30 mg group compared to placebo.

Ziltivekimab was well tolerated, showing no adverse effects on cholesterol ratios, although there was a small increase in triglyceride levels, indicating its potential as a safe treatment option for patients at high atherosclerotic risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of interleukin-6 inhibition with ziltivekimab in patients at high risk of atherosclerotic events in Japan (RESCUE-2): A randomized, double-blind, placebo-controlled, phase 2 trial. Wada, Y., Jensen, C., Meyer, ASP., et al.[2023]

In a subanalysis of the RESCUE trial involving 264 adults with chronic kidney disease (CKD) stage 3-5, treatment with ziltivekimab significantly increased hemoglobin levels after 12 weeks compared to placebo, indicating its potential efficacy in managing anemia associated with CKD.

Ziltivekimab also led to significant improvements in iron homeostasis, including increased serum iron levels and transferrin saturation, with no major safety concerns reported, suggesting it could be a safe option for anemia management in patients with systemic inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Ziltivekimab on Determinants of Hemoglobin in Patients with CKD Stage 3-5: An Analysis of a Randomized Trial (RESCUE). Pergola, PE., Davidson, M., Jensen, C., et al.[2023]

In a phase 2 trial involving 264 participants with chronic kidney disease and elevated high-sensitivity CRP, ziltivekimab significantly reduced high-sensitivity CRP levels by up to 92% compared to only 4% in the placebo group, demonstrating its efficacy in lowering inflammation related to atherosclerosis.

Ziltivekimab was well tolerated with no serious adverse effects reported, indicating a favorable safety profile for patients at high cardiovascular risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Ridker, PM., Devalaraja, M., Baeres, FMM., et al.[2022]

Jakinibs have been shown to be effective in improving rheumatoid arthritis symptoms, with significant increases in American College of Rheumatology response rates (ACR20, ACR50, ACR70) at both 12 and 24 weeks in a review of 28 trials involving 14,500 patients.

While jakinibs are generally well tolerated, they are associated with a higher risk of infections, although there was no increase in serious adverse events or discontinuations compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of jakinibs in rheumatoid arthritis: a systematic review and meta-analysis. Yin, Y., Liu, M., Zhou, E., et al.[2021]

Sarilumab, an IL-6 receptor antagonist, has been shown to significantly improve rheumatoid arthritis symptoms compared to both placebo and adalimumab, with ACR20 response rates of 56-72% and DAS28 remission rates of 20-34%.

While sarilumab carries a higher risk of neutropenia compared to tocilizumab, it has a lower risk of other side effects like dyslipidemia and gastrointestinal perforation, making it a viable alternative for patients who haven't responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sarilumab: Review of a Second IL-6 Receptor Antagonist Indicated for the Treatment of Rheumatoid Arthritis. Boyce, EG., Rogan, EL., Vyas, D., et al.[2019]

In a study of 2,101 rheumatoid arthritis patients, the use of TNFα inhibitors was linked to a significantly lower risk of developing coronary artery disease (CAD), with a hazard ratio of 0.45 compared to those not using these medications.

Long-term use of TNFα inhibitors (over 16.1 months) further reduced the risk of CAD to a hazard ratio of 0.18 and cardiovascular disease (CVD) to 0.31, suggesting that these medications may provide protective cardiovascular benefits for RA patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor necrosis factor α inhibitor use and decreased risk for incident coronary events in rheumatoid arthritis. Bili, A., Tang, X., Pranesh, S., et al.[2014]

In patients with rheumatoid arthritis and a history of atherosclerotic cardiovascular disease (ASCVD), the risk of major adverse cardiovascular events (MACE) was significantly higher with tofacitinib compared to tumor necrosis factor inhibitors (TNFi), with a hazard ratio of 1.98.

For patients without a history of ASCVD, the risk of MACE with tofacitinib was similar to that of TNFi, suggesting that tofacitinib may be safer for this group, although the analysis was exploratory and lacked sufficient statistical power to draw definitive conclusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Charles-Schoeman, C., Buch, MH., Dougados, M., et al.[2023]

In a study of 8689 rheumatoid arthritis patients across Hong Kong, Taiwan, and Korea, interleukin-6 inhibitors (IL-6i) and Janus Kinase inhibitors (JAKi) showed no significant increase in cardiovascular events compared to tumor necrosis factor inhibitors (TNFi).

The pooled analysis indicated that both IL-6i and JAKi have a similar cardiovascular safety profile to TNFi, suggesting that these newer treatments do not pose additional cardiovascular risks for patients with rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular risk in rheumatoid arthritis patients treated with targeted synthetic and biological disease-modifying antirheumatic drugs: A multi-centre cohort study. Tong, X., Shen, CY., Jeon, HL., et al.[2023]

In a study of 13,492 rheumatoid arthritis patients treated with JAK inhibitors (JAKi), TNF inhibitors (TNFi), or other biological drugs, the incidence of major cardiovascular events (MACE) was similar between those using JAKi and TNFi, indicating comparable cardiovascular safety profiles.

The analysis showed that JAKi treatment did not increase the risk of MACE compared to TNFi, with a hazard ratio of 0.71, suggesting that JAKi can be safely used without heightened cardiovascular risk in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative cardiovascular safety with janus kinase inhibitors and biological disease-modifying antirheumatic drugs as used in clinical practice: an observational cohort study from Sweden in patients with rheumatoid arthritis. Bower, H., Frisell, T., di Giuseppe, D., et al.[2023]

In a study involving 36 patients with rheumatoid arthritis, treatment with tocilizumab significantly reduced arterial stiffness (measured by pulse wave velocity) at 3 months, while rituximab showed a significant reduction in arterial stiffness at 12 months.

Both tocilizumab and rituximab were effective in lowering cardiovascular disease risk markers, indicating their potential benefits beyond managing rheumatoid arthritis symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Impact of Newer Biological Disease Modifying Anti-Rheumatic Drugs on Cardiovascular Risk Factors: A 12-Month Longitudinal Study in Rheumatoid Arthritis Patients Treated with Rituximab, Abatacept and Tociliziumab. Provan, SA., Berg, IJ., Hammer, HB., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and safety of interleukin-6 inhibition with ziltivekimab in patients at high risk of atherosclerotic events in Japan (RESCUE-2): A randomized, double-blind, placebo-controlled, phase 2 trial. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Effect of Ziltivekimab on Determinants of Hemoglobin in Patients with CKD Stage 3-5: An Analysis of a Randomized Trial (RESCUE). [2023]

4. England pubmed.ncbi.nlm.nih.gov

IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of jakinibs in rheumatoid arthritis: a systematic review and meta-analysis. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Sarilumab: Review of a Second IL-6 Receptor Antagonist Indicated for the Treatment of Rheumatoid Arthritis. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Tumor necrosis factor α inhibitor use and decreased risk for incident coronary events in rheumatoid arthritis. [2014]

8. England pubmed.ncbi.nlm.nih.gov

Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Cardiovascular risk in rheumatoid arthritis patients treated with targeted synthetic and biological disease-modifying antirheumatic drugs: A multi-centre cohort study. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Comparative cardiovascular safety with janus kinase inhibitors and biological disease-modifying antirheumatic drugs as used in clinical practice: an observational cohort study from Sweden in patients with rheumatoid arthritis. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

The Impact of Newer Biological Disease Modifying Anti-Rheumatic Drugs on Cardiovascular Risk Factors: A 12-Month Longitudinal Study in Rheumatoid Arthritis Patients Treated with Rituximab, Abatacept and Tociliziumab. [2022]