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Ziltivekimab

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Ziltivekimab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetInterleukin 6
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem SID
DrugBank
UNII
KEGG

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

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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, ailtivekimab 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

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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.[9][10] By neutralizing IL-6, it reduces the production of acute-phase reactants like hsCRP, serum amyloid A, and fibrinogen, which contribute to systemic inflammation.[11]

In CKD, Ziltivekimab lowers hepcidin levels, improving iron metabolism and alleviating anemia of inflammation.[12] Its targeted IL-6 inhibition distinguishes it from IL-6 receptor blockers like tocilizumab, potentially offering a different safety profile with fewer immunosuppressive effects.[11]

Clinical trials

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Phase 1/2 trial in hemodialysis Ppatients

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A phase 1/2, randomized, double-blind, placebo-controlled trial (NCT02868229) evaluated Ziltivekimab in 61 hemodialysis patients with chronic kidney disease (CKD), elevated interleukin-6 (≥4 pg/mL), and a TMPRSS6 gene polymorphism (rs855791) associated with IL-6–mediated inflammation. Patients received placebo or Ziltivekimab (2, 6, or 20 mg) intravenously every two weeks for 12 weeks. The trial assessed safety, pharmacokinetics, and pharmacodynamic endpoints, including inflammatory markers, iron parameters, and erythropoiesis-stimulating agent (ESA) usage.[13]

RESCUE trial

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The phase 2 RESCUE trial (NCT03926117) was a double-blind, randomized, placebo-controlled study that enrolled 264 patients with CKD stage 3–5 and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L.[14] Patients received placebo or subcutaneous Ziltivekimab (7.5, 15, or 30 mg) every four weeks for up to 24 weeks. The trial evaluated changes in hsCRP, hemoglobin levels, iron metabolism biomarkers, and safety outcomes.[15]

RESCUE-2 trial

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The RESCUE-2 trial (NCT04626505), a phase 2, randomized, double-blind study in Japan, enrolled 36 adults with CKD stage 3–5 and hsCRP ≥2 mg/L.[16] Participants received placebo or Ziltivekimab (15 or 30 mg) subcutaneously at weeks 0, 4, and 8. The study assessed changes in hsCRP, serum amyloid A, fibrinogen, lipid profiles, and treatment-emergent adverse events.

HERMES and ZEUS Trrials

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The ongoing HERMES trial (NCT05636176) is evaluating monthly subcutaneous Ziltivekimab (15 mg) versus placebo in patients with heart failure with preserved or mildly reduced ejection fraction (HFpEF or HFmrEF). The primary endpoints include cardiovascular death, heart failure hospitalization, and urgent visits.[7][17]

The ZEUS trial (NCT05021835), a phase 3 study, is assessing Ziltivekimab's effects on cardiovascular outcomes—including myocardial infarction and stroke—in patients with established cardiovascular disease, CKD, and hsCRP ≥2 mg/L.[18] Both trials are ongoing as of May 2025, and results have not yet been published.

Safety and side effects

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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]

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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

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References

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  1. ^ a b Wołowiec, Łukasz; Zukow, Walery; Pęcherz, Julia; Czaplińska, Daria; Jaśniak, Albert; Grześk, Grzegorz (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.
  2. ^ Kanbay, Mehmet; Copur, Sidar; Yilmaz, Zeynep Y.; Mallamaci, Francesca; Zoccali, Carmine (March 2025). "Ziltivekimab for anemia and atherosclerosis in chronic kidney disease: a new hope?". Journal of Nephrology. 38 (2): 403–414. doi:10.1007/s40620-024-02117-0. PMID 39453604.
  3. ^ a b Maidana, Daniela; Arroyo-Álvarez, Andrea; Barreres-Martín, Guillermo; Arenas-Loriente, Andrea; Cepas-Guillen, Pedro; Brigolin Garofo, Raphaela Tereza; et al. (February 2025). "Targeting Inflammation and Iron Deficiency in Heart Failure: A Focus on Older Adults". Biomedicines. 13 (2): 462. doi:10.3390/biomedicines13020462. PMC 11853203. PMID 40002874.
  4. ^ Ridker, Paul M.; Devalaraja, Matt; Baeres, Florian M M.; Engelmann, Mads D M.; Hovingh, G Kees; Ivkovic, Milana; et al. (May 2021). "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. doi:10.1016/S0140-6736(21)00520-1. PMID 34015342. S2CID 235073253.
  5. ^ Pergola, Pablo E.; Devalaraja, Matt; Fishbane, Steven; Chonchol, Michel; Mathur, Vandana S.; Smith, Mark T.; et al. (January 2021). "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. doi:10.1681/ASN.2020050595. PMC 7894678. PMID 33272965.
  6. ^ 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
  7. ^ a b c Petrie, Mark; Borlaug, Barry; Buchholtz, Kristine; Ducharme, Anique; Hvelplund, Anders; Ping, Carolyn Lam Su; et al. (January 2024). "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. doi:10.1016/j.cardfail.2023.10.024.
  8. ^ Wada, Yukihiro; Jensen, Camilla; Meyer, Anna Sina Pettersson; Zonoozi, Amir Abbas Mohseni; Honda, Hirokazu (October 2023). "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. doi:10.1016/j.jjcc.2023.05.006. PMID 37211246.
  9. ^ Ridker PM, Rane M (May 2021). "Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease". Circulation Research. 128 (11): 1728–1746. doi:10.1161/CIRCRESAHA.121.319077. PMID 33998272.
  10. ^ Ridker PM (September 2021). "From RESCUE to ZEUS: will interleukin-6 inhibition with ziltivekimab prove effective for cardiovascular event reduction?". Cardiovascular Research. 117 (11): e138 – e140. doi:10.1093/cvr/cvab231. PMC 8861265. PMID 34352102.
  11. ^ a b d'Aiello A, Filomia S, Brecciaroli M, Sanna T, Pedicino D, Liuzzo G (December 2024). "Targeting Inflammatory Pathways in Atherosclerosis: Exploring New Opportunities for Treatment". Current Atherosclerosis Reports. 26 (12): 707–719. doi:10.1007/s11883-024-01241-3. PMID 39404934.
  12. ^ Derman C (December 2023). "Ziltivekimab May Help Anemia Management in CKD Patients". HCPLive. Retrieved 2025-06-04.
  13. ^ Clinical trial number NCT02868229 for "Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001" at ClinicalTrials.gov
  14. ^ Pergola, Pablo E.; Davidson, Michael; Jensen, Camilla; Mohseni Zonoozi, Amir A.; Raj, Dominic S.; Andreas Schytz, Philip; et al. (January 2024). "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. doi:10.1681/ASN.0000000000000245. PMC 10786611. PMID 38088558.
  15. ^ 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
  16. ^ 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
  17. ^ 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
  18. ^ 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
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