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

Abstract

Background: Chronic systemic inflammation is highly prevalent in patients with chronic kidney disease (CKD; measured as an elevated high-sensitivity C-reactive protein [hsCRP]) and independently associated with cardiovascular events and all-cause mortality. An interleukin-6 blocker to suppress inflammation represents a potential novel paradigm to reduce cardiovascular risk in CKD. Methods: A phase I trial of Ziltivekimab, a fully human monoclonal antibody against interleukin-6, was conducted in patients with moderate-to-severe non-dialysis dependent CKD (estimated glomerular filtration rate of 20-60 ml/min/1.73m^2) 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 (5mg, 15mg, and 50mg subcutaneous injection) and followed for 12 weeks for safety and pharmacokinetic/pharmacodynamic assessments, and an additional 20 weeks for safety and anti-drug antibody assessments. Results: Participants were 67+/-11 years; baseline estimated glomerular filtration rate: 40+/-13 ml/min/1.73m2; 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. 100% of participants achieved suppression of hsCRP to <2mg/L with the 15mg and 50mg dose, and several subjects had undetectable levels of hsCRP with the 50mg dose. The mean half-life ranged from of 45-65 days. Conclusions: In adults with moderate-to-severe CKD and evidence of chronic inflammation, a single-injection of the interleukin-6 inhibitor Ziltivekimab was safe and highly effective at suppressing hsCRP over 12 weeks.