Clazakizumab, an IL-6 Inhibitor, Could Reduce Cardiovascular Risk in Patients on Dialysis

A phase 2b trial of clazakizumab, an Il-6 inhibitor, found use of the agent could help in reducing cardiovascular risk among patients receiving maintenance dialysis.

Presented at the 61st European Renal Association Congress, results of the phase 2b portion of the POSIBIL6ESKD trial indicate use of clazakizumab was associated with clinically significant reductions in serum hs-CRP of 86%, 90%, and 92% at 12 weeks among those receiving the 2.5 mg, 5 mg, and 10 mg doses, respectively, with no unexpected safety outcomes based on previous research of the agent.

“Among patients receiving maintenance hemodialysis with documented inflammation, clazakizumab reduced inflammatory biomarkers associated with cardiovascular events and increased serum albumin. The safety profile of clazakizumab appeared acceptable and consistent with its mechanism of action," wrote investigators.

In recent years, the prognostic value of hs-CRP and its effects on cardiovascular risk have become clearer because of continued research. As a result, many have hypothesized IL inhibition could serve as a tool in the management of this risk in certain patient populations.^1,2

Led by Glenn Chertow, MD, of Stanford Medicine, the phase 2b dose-finding trial of clazakizumab was launched in 2021 with the specific intent of assessing the safety and efficacy of the IL-6 inhibitor on reducing inflammatory biomarkers among adult patients with cardiovascular disease or diabetes on maintenance dialysis who have serological evidence of inflammation. Of note, the POSIBIL6ESKD is designed as a phase 2b/3 trial and the phase 3 portion of the trial is designed as a cardiovascular outcomes trial.¹

Specific inclusion criteria for the trial required patients to:¹

• Have either known cardiovascular disease or diabetes
• Been on hemodialysis for at least 12 weeks
• Have an hs-CRP level of 2 mg/L or greater at screening

Participants in the trial were randomized in a 1:1:1:1 ratio to receive clazakizumab in 2.5 mg, 5 mg, and 10 mg doses or placebo therapy via intravenous bolus every 4 weeks for up to 6 doses. The primary outcome of interest for the trial was the geometric mean ratio (GMR) to baseline serum hs-CRP concentration at week 12. Secondary outcomes of interest for the trial included change from baseline to week 12 in the proportion of patients who achieved hs-CRP less than 2 mg/L at week 12, GMR to baseline in downstream IL-6 biomarkers, and mean change from baseline in serum albumin.¹

In total, 127 patients were randomized into the trial and included in the primary analysis, with 32 patients in each of the clazakizumab groups and 31 receiving placebo therapy. The overall cohort had a mean age of 62.4 (SD, 13.0) years, 33% were women, 46% were designated as non-White, 71% reported diabetes as the cause of kidney failure, and the median baseline serum hs-CRP was 8.3 mg (25–75%, range: 4.8 to 19.1 mg).¹

Upon analysis, results indicated use of clazakizumab was associated with statistically significant reductions in hs-CRP at week 12, with reductions of 86%, 90% and 92% relative to placebo in patients randomized to 2.5 mg, 5 mg, or 10 mg clazakizumab, respectively (all P < .0001). Further analysis revealed 0 patients in the placebo arm achieved a serum hs-CRP less than 2.0 mg at week 12. In contrast, a hs-CRP level less than 2.0 mg was observed among 79%, 82%, and 79% in the 2.5 mg, 5 mg, and 10 mg clazakizumab groups, respectively.¹

Additional analysis of secondary outcomes revealed use of clazakizumab was associated with improvements in serum fibrinogen, amyloid A, secretory phospholipase A2, lipoprotein(a) concentrations, and mean serum albumin concentrations. In safety analyses, investigators pointed out there were no cases of sustained grade 3 or 4 thrombocytopenia or neutropenia observed in the trial and infections occurred at a similar frequency among the clazakizumab and placebo arms. There were 6 deaths in the trial, but investigators noted 6 deaths these were similarly distributed across all groups and none were considered to be related to clazakizumab.¹

“The results of this trial indicate that in patients receiving maintenance dialysis, clazakizumab reduced inflammatory biomarkers associated with cardiovascular events,” investigators wrote.¹

References:

1. Chertow GM, Chang AM, Felker GM, et al. IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial. Nat Med. Published online May 25, 2024. doi:10.1038/s41591-024-03043-1
2. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-1131. doi:10.1056/NEJMoa1707914