IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial

Patients with end-stage kidney disease (ESKD) have high mortality and morbidity, with cardiovascular disease accounting for over half of deaths despite dialysis. Traditional risk factors do not fully explain this burden and conventional therapies such as statins have shown little benefit in dialysis populations. Systemic inflammation, particularly signaling through the interleukin-6 (IL-6) pathway, is implicated as a causal contributor to cardiovascular risk. Inflammatory biomarkers including IL-6 and C-reactive protein (CRP) are elevated in ESKD and predict adverse cardiovascular outcomes. The study aimed to test whether targeted IL-6 ligand inhibition with clazakizumab can reduce inflammation, as measured by hs-CRP and downstream biomarkers, in patients receiving maintenance dialysis with evidence of baseline inflammation (hs-CRP ≥2 mg l−1).

Prior large-scale trials in the general population and those with CKD have demonstrated links between inflammation and cardiovascular risk. The CANTOS trial showed that IL-1β inhibition reduced cardiovascular events, with benefits associated with downstream reductions in IL-6. Mendelian randomization studies support a causal role of IL-6 pathway activation in atherosclerosis. In dialysis populations, inflammation is common and predicts mortality and cardiovascular events; however, lipid-lowering therapies have not yielded substantial benefits. Anti-inflammatory agents such as colchicine have reduced cardiovascular events in non-dialysis populations. IL-6 ligand inhibition with ziltivekimab in high-risk patients with moderate CKD reduced hs-CRP and several cardiovascular biomarkers, motivating outcomes trials in CKD. A pilot randomized trial of anakinra in hemodialysis reduced hs-CRP non-significantly versus placebo. Collectively, these data support evaluating IL-6 pathway inhibition in ESKD.

Design: Parallel-group, double-blind, randomized, placebo-controlled phase 2b trial (POSIBILESKD) at 56 sites in the United States, Canada, Belgium, Germany and Australia (ClinicalTrials.gov NCT05485961). Ethics approval obtained; all participants provided written informed consent. Participants: Adults (≥18 years) on dialysis ≥12 weeks with cardiovascular disease and/or diabetes and hs-CRP ≥2 mg l−1 by central lab. Key exclusions: HIV, HBV surface antigen, HCV, or TB positivity; clinically significant infection within 14 days; neutropenia, thrombocytopenia, marked liver enzyme elevation; recent (<90 days) MI or acute decompensated heart failure; planned major surgery including kidney transplant; high GI perforation risk; chronic immunosuppressant use. Randomization: 1:1:1:1 to placebo or clazakizumab 2.5 mg, 5 mg, or 10 mg, stratified by screening hs-CRP 2–6 mg l−1 vs >6 mg l−1. Blinding: Participants and investigators blinded. Intervention: Intravenous clazakizumab or placebo administered every 4 weeks as a 3-minute bolus via the hemodialysis return venous line (≥1 h after start and ≤1 h before completion of session). Minimum planned treatment 12 weeks (three doses); up to six doses (24 weeks) permitted. End-of-treatment visit 4 weeks after last dose and safety follow-up 8 weeks thereafter. Outcomes: Primary—change from baseline to week 12 in serum hs-CRP, expressed as geometric mean ratio (GMR). Secondary—proportion achieving hs-CRP <2 mg l−1 at week 12; changes from baseline to week 12 in serum amyloid A, lipoprotein(a), fibrinogen, secretory phospholipase A2, hemoglobin, ferritin, iron, transferrin saturation, hepcidin; change in serum albumin. Safety—treatment-emergent adverse events, serious adverse events, laboratory safety parameters (liver enzymes, lipid parameters, complete blood count). Sample size: 30 participants per group (total 120) to provide >97% power to detect 80% reduction (GMR to placebo 0.2) in hs-CRP at one-sided α 0.025/3, assuming SD 1.4 on log scale. Analysis populations: Modified intention-to-treat (mITT)—all randomized who received any treatment; per protocol (PP)—mITT without major intercurrent events before week 12; safety—any exposed. Baseline hs-CRP defined as average of screening and baseline. Statistical analysis: Mixed model for repeated measures (MMRM) of log-transformed change from baseline in hs-CRP through week 24; model terms included treatment, baseline, visit (categorical), and interactions, with unstructured covariance. Week 12 GMRs vs placebo expressed as percent difference; t-tests from MMRM for P values (two-sided, nominal, no multiplicity adjustment). Downstream biomarkers analyzed similarly (log-transform as needed) with additional factor for hs-CRP stratum. Analyses performed in SAS 9.4; primary efficacy independently verified by Stanford Quantitative Sciences Center.

Participants: 298 screened; 127 randomized (mITT and safety). Baseline characteristics were balanced; mean age 62.4 ± 13.0 years, 33% women, 46% non-White, 28% Hispanic/Latina/Latino; diabetes was the most common cause of ESKD (71%). Median baseline hs-CRP was 8.3 mg l−1 (IQR 4.8–19.1). Primary outcome: At week 12, clazakizumab reduced hs-CRP relative to placebo by 86% (2.5 mg), 90% (5 mg), and 92% (10 mg); placebo increased by 19% (PP analysis; all P < 0.001). In mITT, corresponding values were −86%, −90%, −91% versus +20% for placebo (all P < 0.001). Approximately 79%, 82%, and 79% of patients in the 2.5 mg, 5 mg, and 10 mg groups achieved hs-CRP <2 mg l−1 at week 12 compared with 0% on placebo. Secondary biomarkers: Significant reductions versus placebo in serum amyloid A, fibrinogen, secretory phospholipase A2, and lipoprotein(a) (all P < 0.001). Serum albumin increased by a mean of 0.28, 0.25, and 0.21 g dl−1 in the 2.5 mg, 5 mg, and 10 mg groups, respectively, versus 0.04 g dl−1 with placebo (all P < 0.01 vs placebo). Safety: No sustained CTCAE grade 3–4 thrombocytopenia or neutropenia. Transient grade 3 thrombocytopenia (n=2) and grade 3 neutropenia (n=2) resolved within 4 weeks after drug interruption. Serious infections occurred in 4 (12.5%) at 2.5 mg, 3 (9.4%) at 5 mg, 9 (28.1%) at 10 mg, and 2 (6.5%) with placebo; led to treatment discontinuation in 2, 0, 4, and 1 patients, respectively. Deaths: 2 (6.3%) at 2.5 mg, 2 (6.3%) at 5 mg, 1 (3.1%) at 10 mg, and 1 (3.2%) with placebo; none were adjudicated related to study drug.

Targeting IL-6 signaling with clazakizumab in inflamed patients on maintenance dialysis produced rapid, large, and sustained reductions in hs-CRP and multiple downstream markers of IL-6 activity, and increased serum albumin levels. These biomarker improvements address the hypothesis that IL-6–mediated inflammation contributes substantially to residual cardiovascular risk in ESKD, a population in which conventional lipid-lowering strategies have shown limited benefit. Safety findings were consistent with IL-6 inhibition; rates of serious infections were similar to placebo at the 2.5 mg and 5 mg doses but higher at 10 mg, supporting dose selection that balances efficacy and safety. The results align with prior evidence from anti-inflammatory therapies and Mendelian randomization supporting IL-6 pathway involvement in atherosclerosis and suggest that IL-6 ligand inhibition could be a viable strategy to reduce cardiovascular risk among patients receiving dialysis. These data justify progression to and completion of the phase 3 cardiovascular outcomes component.

In adults receiving maintenance hemodialysis with elevated hs-CRP, clazakizumab administered every 4 weeks substantially reduced hs-CRP and other inflammatory biomarkers and increased serum albumin, with an overall acceptable safety profile, particularly at 2.5 mg and 5 mg doses. These findings support IL-6 ligand inhibition as a promising therapeutic approach to mitigate inflammation-associated cardiovascular risk in ESKD. Future work should focus on long-term safety, optimal dosing, and definitive evaluation of cardiovascular outcomes in the ongoing phase 3 trial, including broader dialysis populations (for example, peritoneal dialysis).

The trial had a modest sample size and relatively short treatment and follow-up duration; adverse effects such as infections may be more frequent with longer exposure. Residual kidney function data were not collected, and the study was underpowered for subgroup analyses (for example, by sex, diabetes status, or type of vascular access). No peritoneal dialysis patients were enrolled in this phase 2b component. Multiplicity was not adjusted for secondary endpoints.