Novel IL-6 inhibitor largely reduces hsCRP in CKD with elevated hsCRP
Effects of Interleukin-6 Inhibition with Ziltivekimab on Biomarkers of Inflammation Among Patients at High Risk for Atherosclerotic Event
Presented at ACC.21 by Paul Ridker (Boston, MA, USA)
Introduction and methods
Upon inflammation, IL-1β and IL-18 are activated in the NLRP3 inflammasoom resulting in upregulation of the central player IL-6 which then leads to upregulation of CRP, the biomarker of inflammation in atherosclerosis.
The CANTOS trial demonstrated that inhibition of inflammation by targeting the central IL-1β to IL-6 to hsCRP pathway reduced CV event rates independent of LDL-c lowering. Moreover, an additional analysis showed that the magnitude of clinical benefit in the CANTOS trial was directly related to the magnitude of IL-6 reduction achieved by individual patients in the trial, thereby suggesting that IL-6 may be the primary target to CV protection. There are abundant experimental data studies in human vascular biology models and murine intervention studies suggesting that IL-6 is a pivotal cytokine of innate immunity in vascular biology. This is supported by human translational findings.
This study examined whether direct inhibition of IL-6 by ziltivekimab provides maximal anti-inflammatory atherosclerotic benefit. Ziltivekimab is a narrow spectrum fully human monoclonal antibody targeting the IL-6 ligand and has been specifically developed to reduce ASCVD. A randomized, double-blind, placebo-controlled phase 2 trial (the RESCUE trial) was conducted to examine the effects of ziltivekimab on biomarkers of inflammation and thrombosis. Patients with CKD (stage 3-5) and elevated hsCRP (≥2 mg/L) at high CV risk were enrolled. 264 Patients were randomized to SC ziltivekimab 7.5, 15 or 30 mg every 4 weeks or SC placebo. Primary endpoint was the percentage change in hsCRP from baseline to 12 weeks.
- Large dose-dependent reductions in hsCRP were observed in the ziltivekimab groups (77%, 88% and 92% in the 7.5, 15 and 30 mg groups) compared to no change in the placebo group.
- Significant changes in ≥50% reduction in hsCRP and on-treatment hsCRP <2 mg/L were found for the ziltivekimab groups compared to placebo.
- Waterfall plots showed dose-dependent effects of ziltivekimab and almost all patients on 15 or 30 mg ziltivekimab achieved large reductions in hsCRP.
- The biomarkers fibrinogen, haptoglobin, serum amyloid A, sPLA2, and lipoprotein(a) were reduced by all doses of ziltivekimab compared to placebo at 12 weeks. No change in ApoB/ApoA ratio was observed by ziltivekimab compared to placebo.
- There were no reports of serious injection-related reactions, no ALT or AST >3x ULN, no serious infections, no anaphylaxis, no sustained neutropenia grade 2 or more, and no sustained thrombocytopenia grade 2 or more.
In the phase II RESCUE trial, treatment with ziltivekimab resulted in reduction of biomarkers of inflammation and thrombosis, including hsCRP, fibrinogen, SAA, sPLA2 and Lp(a). The magnitude of hsCRP reduction by ziltivekimab was almost 2-fold larger compared to the reduction in CANTOS (in which CV events rates were reduced by 15-20%). The safety profile of ziltivekimab appeared to be good.
Ridker concluded that the results of this phase II study support the evaluation of ziltivekimab in future CV outcome trials. He then announced the launch of the ZEUS trial (Ziltivekimab Cardiovascular Outcomes Study), a phase 3 trial that will be conducted in 6200 ASCVD patients with CKD (stage 3-4) and elevated CRP ≥2 mg/L . They will be randomized to standard care plus ziltivekimab 15 mg once monthly or to standard care plus placebo. Primary endpoint is time to first MACE. The focus is on the patient population with CKD and elevated hsCRP, because there is large unmet need in these patients. Also, these patients have a very high CV risk in whom LDL-c is less relevant for outcomes and inflammation is more relevant. Moreover, therapy with the anti-inflammatory colchicine is relatively contraindicated in CKD patients.
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