Ziltivekimab for Cardiovascular Disease

(ZEUS Trial)

Not currently recruiting at 1778 trial locations

Overseen By Novo Nordisk

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novo Nordisk A/S

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 20

Duration: Up to 4 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates whether a new drug, ziltivekimab, can reduce the risk of heart attacks and strokes in individuals with cardiovascular disease and chronic kidney disease who also have inflammation. Participants will randomly receive either ziltivekimab or a placebo (a dummy treatment) without knowing which one they receive. The trial includes monthly self-injections and regular clinic visits for up to four years. Suitable candidates for this trial have both chronic kidney disease and heart disease, such as a history of heart attacks or strokes. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ziltivekimab is generally safe for people. In earlier studies, patients who received ziltivekimab did not experience any serious side effects at the injection site. There was a small increase in triglyceride levels, a type of fat in the blood, but overall cholesterol levels remained stable. This indicates that while some changes in blood fats may occur, the overall impact on health appears manageable.

These findings suggest that ziltivekimab is relatively safe for people. However, as it is not yet approved for any condition, ongoing research will offer more information about its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Ziltivekimab for cardiovascular disease because it targets interleukin-6 (IL-6), a protein involved in inflammation, which is a novel approach compared to standard treatments like statins that focus on lowering cholesterol. Ziltivekimab is designed to be administered subcutaneously just once a month, providing a convenient option compared to daily medications. This unique mechanism and delivery method have the potential to reduce inflammation-related risks in cardiovascular disease more effectively, which could represent a significant advancement in treatment.

What evidence suggests that ziltivekimab might be an effective treatment for cardiovascular disease?

Research has shown that ziltivekimab might help reduce inflammation in the body, which is linked to heart issues like heart attacks and strokes. In one study, patients who took ziltivekimab experienced a significant decrease in levels of hsCRP, a marker of inflammation, compared to those who received a placebo. This trial will test ziltivekimab against a placebo to further explore its potential to lower the risk of heart-related problems by reducing inflammation. Although ziltivekimab is not yet approved, these findings offer hope for its potential in treating heart disease. ^{1 2 3 6 7}

Who Is on the Research Team?

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Placebo (ziltivekimab)
• Ziltivekimab

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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 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 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]

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 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 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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37211246/

A randomized, double-blind, placebo-controlled, phase 2 trial There was a small, but statistically significant increase in triglyceride levels with ziltivekimab 15 mg and 30 mg compared with placebo.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05021835

NCT05021835 | ZEUS - A Research Study to Look at How ... This study is conducted to see if ziltivekimab reduces the risk of having cardiovascular events (for example heart attack and stroke) in people with ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8861265/

From RESCUE to ZEUS: will interleukin-6 inhibition with ... A monoclonal antibody targeting IL-1β significantly reduced recurrent major adverse cardiovascular events by 15–17%.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0914508723001120

Efficacy and safety of interleukin-6 inhibition with ... At both doses tested, ziltivekimab significantly reduced levels of hsCRP and other inflammatory biomarkers from baseline compared with placebo. Importantly, ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05636176

NCT05636176 | A Research Study to Look at How ... This study will be done to see if ziltivekimab can be used to treat people living with heart failure and inflammation.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34015342/

IL-6 inhibition with ziltivekimab in patients at high ... Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03926117

Study Details | NCT03926117 | Trial to Evaluate Reduction ... The purpose of this trial is to determine a dose to select for a potential cardiovascular outcome trial with Ziltivekimab. Doses to be tested will be 7.5 mg, 15 ...