A Phase 1 Randomized Dose-Escalation Study of a Human Monoclonal Antibody to IL-6 in CKD

• Published in: Kidney360 Vol. 2; no. 2; pp. 224 - 235
• Main Authors: Nowak, Kristen L, Kakkar, Rahul, Devalaraja, Matt, Lo, Larry, Park, Wansu, Gobburu, Joga, Kling, Douglas, Davidson, Michael, Chonchol, Michel
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 25-02-2021
• Subjects: Adult; Aged; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal, Humanized; Biomarkers - metabolism; Humans; Interleukin-6 - therapeutic use; Middle Aged; Original Investigations; Renal Insufficiency, Chronic - drug therapy; clinical trial; nephrology; cardiovascular disease; chronic kidney disease; phase 1; ziltivekimab; CKD; chronic inflammation; interleukin-6
• ISSN: 2641-7650; 2641-7650
• DOI: 10.34067/KID.0005862020

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.
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 m
) and evidence of chronic inflammation (hsCRP level >2 mg/L over two consecutive measurements). Three cohorts of
=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.
Participants were 67±11 years old; baseline eGFR: 40±13 ml/min per 1.73 m
; 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
ranged from of 45 to 65 days.
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.