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A Phase 1 Randomized Dose-Escalation Study of a Human Monoclonal Antibody to IL-6 in CKD
Kristen L Nowak1, Rahul Kakkar2, Matt Devalaraja2
1Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Insights
Ziltivekimab, an IL-6 inhibitor, effectively reduced high-sensitivity C-reactive protein (hsCRP) in patients with chronic kidney disease (CKD) and inflammation. This novel treatment shows promise for reducing cardiovascular risk in this high-prevalence population.
Area of Science:
- Nephrology
- Immunology
- Cardiology
Background:
- Chronic systemic inflammation, indicated by elevated hsCRP, is common in CKD patients.
- This inflammation is linked to increased cardiovascular events and mortality in CKD.
- Targeting IL-6 offers a potential strategy to mitigate cardiovascular risk in CKD.
Purpose of the Study:
- To evaluate the safety and efficacy of ziltivekimab, an IL-6 inhibitor, in patients with moderate-to-severe CKD and chronic inflammation.
- To assess the pharmacokinetic and pharmacodynamic effects of ziltivekimab in this patient population.
Main Methods:
- A Phase 1, randomized, double-blind trial involving patients with moderate-to-severe non-dialysis-dependent CKD and elevated hsCRP.
- Three cohorts received single subcutaneous injections of ziltivekimab (5 mg, 15 mg, or 50 mg) or placebo.
- Safety, pharmacokinetics, pharmacodynamics, and hsCRP levels were monitored over 12 weeks, with extended safety follow-up.
Main Results:
- Ziltivekimab was generally safe, with adverse events consistent with the CKD population.
- No serious adverse events were reported in active treatment groups.
- Significant reduction in hsCRP levels was observed, with 100% achieving suppression to <2 mg/L at 15 mg and 50 mg doses.
Conclusions:
- A single injection of ziltivekimab demonstrated safety and high efficacy in suppressing hsCRP in adults with moderate-to-severe CKD and inflammation.
- Ziltivekimab represents a promising therapeutic approach for managing inflammation-associated cardiovascular risk in CKD.
Background:
Chronic systemic inflammation is highly prevalent in patients with CKD (measured as an elevated high-sensitivity C-reactive protein, hsCRP) and independently associated with cardiovascular events and all-cause mortality. An IL-6 blocker to suppress inflammation represents a potential novel paradigm to reduce cardiovascular risk in CKD.
Methods:
A phase 1 trial of ziltivekimab, a fully human mAb against IL-6, was conducted in patients with moderate-to-severe nondialysis-dependent CKD (eGFR of 20-60 ml/min per 1.73 m2) and evidence of chronic inflammation (hsCRP level >2 mg/L over two consecutive measurements). Three cohorts of n=4 (3:1 active:placebo) were blindly randomized to a single dose of ziltivekimab (5 mg, 15 mg, and 50 mg subcutaneous injection), and followed for 12 weeks for safety and pharmacokinetic/pharmacodynamic assessments, with an additional 20 weeks for safety and antidrug antibody assessments.
Results:
Participants were 67±11 years old; baseline eGFR: 40±13 ml/min per 1.73 m2; baseline hsCRP: 5.0±2.5 mg/L. Dose escalation was approved, and all adverse events were within the expected range for a CKD population with chronic inflammation. No serious adverse events were reported in any active cohort. hsCRP levels were substantially reduced with ziltivekimab. Of participants, 100% achieved suppression of hsCRP to <2 mg/L with the 15 mg and 50 mg dose, and several patients had undetectable levels of hsCRP with the 50 mg dose. The mean t1/2 ranged from of 45 to 65 days.
Conclusions:
In adults with moderate-to-severe CKD and evidence of chronic inflammation, a single-injection of the IL-6 inhibitor ziltivekimab was safe and highly effective at suppressing hsCRP over 12 weeks.
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