User:Boghog/Sandbox10
| Monoclonal antibody | |
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| Type | Whole antibody |
| Source | Humanized (from mouse) |
| Target | Interleukin 6 |
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Ziltivekimab is an investigational new drug being developed by Novo Nordisk for the treatment of various inflammatory diseases. It is a fully human monoclonal antibody that targets interleukin 6 (IL-6). Ziltivekimab is under investigation for its potential to reduce inflammation in conditions such as cardiovascular disease,[1] chronic kidney disease (CKD),[2] heart failure[3] with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF),[1] and anemia of inflammation.[3]
Administered subcutaneously or intravenously, ziltivekimab has demonstrated potential in clinical trials by lowering inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) and improving anemia-related parameters in CKD patients.[4][5]
As of May 2025, ziltivekimab remains investigational and has not been approved for clinical use. It is currently being evaluated in ongoing phase 2 and phase 3 clinical trials.[6]
Medical use
[edit]Ziltivekimab is being developed to manage inflammatory conditions associated with elevated IL-6 levels, including cardiovascular disease, CKD, heart failure (HFpEF/HFmrEF), and anemia of inflammation. It aims to reduce systemic inflammation, as measured by biomarkers like hsCRP, serum amyloid A, and fibrinogen, which are linked to adverse outcomes in these conditions.[7][8]
In CKD, Ziltivekimab has shown potential to improve anemia by reducing IL-6-mediated hepcidin expression, decreasing reliance on erythropoiesis-stimulating agents (ESAs). It is also under investigation for reducing cardiovascular events in high-risk patients, such as those post-myocardial infarction or with atherosclerotic disease. As of May 2025, it is not approved for any indication and is limited to clinical trial settings.>[7]
Mechanism of action
[edit]Ziltivekimab is a human IgG1, κ monoclonal antibody that binds to the IL-6 ligand, preventing its interaction with the IL-6 receptor and inhibiting downstream inflammatory signaling. By neutralizing IL-6, it reduces the production of acute-phase reactants like hsCRP, serum amyloid A, and fibrinogen, which contribute to systemic inflammation.[citation needed]
In CKD, Ziltivekimab lowers hepcidin levels, improving iron metabolism and alleviating anemia of inflammation. Its targeted IL-6 inhibition distinguishes it from IL-6 receptor blockers like tocilizumab, potentially offering a different safety profile with fewer immunosuppressive effects.[citation needed]
Clinical Trials
[edit]Phase 1/2 Trial in Hemodialysis Patients
[edit]A phase 1/2, randomized, double-blind, placebo-controlled trial (NCT02868229) evaluated Ziltivekimab in 61 hemodialysis patients with CKD, elevated IL-6 (≥4 pg/mL), and a TMPRSS6 gene polymorphism (rs855791) linked to IL-6-mediated inflammation.Patients received placebo or Ziltivekimab (2, 6, or 20 mg) intravenously every 2 weeks for 12 weeks.[9]
Key findings included:
- Significant reductions in hsCRP, serum amyloid A, and fibrinogen compared to placebo.
- Median ESA usage decreased by 15,000–33,000 IU/week in Ziltivekimab groups, with no change in placebo.
- Increased serum iron, total iron-binding capacity, transferrin saturation, and serum albumin.
- No dose-limiting toxicity, though four deaths (two each in 6- and 20-mg cohorts) were reported as treatment-emergent adverse events.
RESCUE Trial
[edit]The phase 2 RESCUE trial (NCT03926117), a double-blind, randomized, placebo-controlled study, enrolled 264 patients with CKD stage 3–5 and hsCRP ≥2 mg/L.[10] Patients received placebo or subcutaneous Ziltivekimab (7.5, 15, or 30 mg) every 4 weeks for up to 24 weeks.[11]
Results, truncated at week 12 due to the COVID-19 pandemic, showed:
- Significant hsCRP reductions (up to 96.2% in 15-mg group, p<0.0001 vs. placebo).
- Hemoglobin increases of 0.57–1.05 g/dL across doses (p<0.001 vs. placebo).
- Increased serum iron, total iron-binding capacity, and transferrin saturation.
- No major safety concerns, with similar rates of thrombocytopenia, neutropenia, and anemia across groups.
RESCUE-2 Trial
[edit]The RESCUE-2 trial (NCT04626505), a phase 2, randomized, double-blind study in Japan, included 36 adults with CKD stage 3–5 and hsCRP ≥2 mg/L.[12] Patients received placebo or Ziltivekimab (15 or 30 mg) subcutaneously at weeks 0, 4, and 8. Outcomes included:
- Median hsCRP reductions of 96.2% (15 mg, p<0.0001) and 93.4% (30 mg, p=0.002) vs. 27.0% for placebo.
- Significant reductions in serum amyloid A and fibrinogen.
- A small increase in triglycerides, but no change in cholesterol ratios.
- Well-tolerated, with no major safety signals.
HERMES and ZEUS Trials
[edit]The ongoing HERMES (NCT05636176) trial investigates Ziltivekimab (15 mg, monthly subcutaneous) vs. placebo in patients with HFpEF or HFmrEF, assessing cardiovascular death, heart failure hospitalization, or urgent visits.[7][13]
The ZEUS trial (phase 3) (NCT05021835) evaluates Ziltivekimab’s impact on cardiovascular events (e.g., heart attack, stroke) in patients with cardiovascular disease, CKD, and hsCRP ≥2 mg/L.[14]
Both trials are ongoing as of May 2025[update], with no published results.
Safety and side effects
[edit]Ziltivekimab has been well-tolerated in trials, with no dose-limiting toxicities reported. In the phase 1/2 hemodialysis trial, four treatment-emergent deaths occurred, but no clear causal link to Ziltivekimab was established. The RESCUE and RESCUE-2 trials reported no significant increases in thrombocytopenia, neutropenia, or infections compared to placebo, unlike other IL-6 inhibitors like tocilizumab. A small, statistically significant increase in triglycerides was noted in RESCUE-2, but cholesterol profiles remained unaffected.[citation needed]
History and legal status
[edit]Ziltivekimab was initially developed by Corvidia Therapeutics and later acquired by Novo Nordisk, and is in phase 2 and 3 trials for cardiovascular disease, CKD, and heart failure.[citation needed]
See also
[edit]References
[edit]- ^ a b Wołowiec Ł, Zukow W, Pęcherz J, Czaplińska D, Jaśniak A, Grześk G (October 2024). "Modulation of Inflammation in Heart Failure: The Role of Ziltivekimab and Canakinumab". Journal of Education, Health and Sport. 65: 55579. doi:10.12775/JEHS.2024.65.55579.
- ^ "Ziltivekimab for anemia and atherosclerosis in chronic kidney disease: a new hope?". Journal of Nephrology. 38 (2): 403–414. March 2025. doi:10.1007/s40620-024-02117-0. PMID 39453604.
- ^ a b "Targeting Inflammation and Iron Deficiency in Heart Failure: A Focus on Older Adults". Biomedicines. 13 (2): 462. February 2025. doi:10.3390/biomedicines13020462. PMC 11853203. PMID 40002874.
- ^ "IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial". Lancet. 397 (10289). London, England: 2060–2069. May 2021. doi:10.1016/S0140-6736(21)00520-1. PMID 34015342. S2CID 235073253.
- ^ "Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial". Journal of the American Society of Nephrology. 32 (1): 211–222. January 2021. doi:10.1681/ASN.2020050595. PMC 7894678. PMID 33272965.
- ^ Clinical trial number NCT05021835 for "ZEUS - A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Cardiovascular Disease, Chronic Kidney Disease and Inflammation (ZEUS)" at ClinicalTrials.gov
- ^ a b c "HERMES: Effects Of Ziltivekimab Versus Placebo On Morbidity And Mortality In Patients With Heart Failure With Mildly Reduced Or Preserved Ejection Fraction And Systemic Inflammation". Journal of Cardiac Failure. 30 (1): 126. January 2024. doi:10.1016/j.cardfail.2023.10.024.
- ^ "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". Journal of Cardiology. 82 (4): 279–285. October 2023. doi:10.1016/j.jjcc.2023.05.006. PMID 37211246.
- ^ Clinical trial number NCT02868229 for "Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001" at ClinicalTrials.gov
- ^ "Effect of Ziltivekimab on Determinants of Hemoglobin in Patients with CKD Stage 3-5: An Analysis of a Randomized Trial (RESCUE)". Journal of the American Society of Nephrology. 35 (1): 74–84. January 2024. doi:10.1681/ASN.0000000000000245. PMC 10786611. PMID 38088558.
- ^ Clinical trial number NCT03926117 for "Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition (RESCUE)" at ClinicalTrials.gov
- ^ Clinical trial number NCT04626505 for "Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition in Japan. (RESCUE-2)" at ClinicalTrials.gov
- ^ Clinical trial number NCT05636176 for "A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Heart Failure and Inflammation (HERMES)" at ClinicalTrials.gov
- ^ Clinical trial number NCT05021835 for "ZEUS - A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Cardiovascular Disease, Chronic Kidney Disease and Inflammation (ZEUS)" at ClinicalTrials.gov
Category:Experimental monoclonal antibodies Category:Anti-interleukin monoclonal antibodies