Inflammation inhibition targeting the central NLRP3 inflammasome to IL-1 to IL-6 pathway of innate immunity is an emerging method for atherosclerosis treatment and prevention.1 This principle was first demonstrated in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) using IL-1β inhibition2 and has now been confirmed in two trials of colchicine, an agent that through microtubule disruption might indirectly inhibit NLRP3 function.3, 4 These trials share a common mechanistic mediator, which is downstream inhibition of the central signalling cytokine IL-6, in turn reducing the clinical biomarker high-sensitivity CRP.
In CANTOS, the magnitude of atherosclerosis prevention associated with canakinumab was proportional to the magnitude of achieved reduction in IL-6 and high-sensitivity CRP levels following treatment.5, 6 Further, the magnitude of residual inflammatory risk in CANTOS associated with IL-6 was substantially greater than that of IL-18, another cytokine activated by the NLRP3 inflammasome.7 By contrast, a contemporary inflammation reduction trial using low-dose methotrexate neither reduced IL-6 nor vascular event rates,8 suggesting that anti-inflammatory agents that do not reduce IL-6 are unlikely to be effective for atheroprotection.
Research in context
Evidence before this study
Recent randomised trials have demonstrated that anti-cytokine and anti-inflammatory therapies can reduce cardiovascular event rates, and evolving genetic, murine, translational, and human epidemiological data suggest that IL-6 might be a causal mediator of this process. However, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is largely unknown.
Added value of this study
The RESCUE trial data provides the first evidence that inhibition of IL-6 with the novel monoclonal ligand antibody ziltivekimab reduces in a dose-dependent manner multiple inflammatory and thrombotic biomarkers relevant for atherosclerosis, in a critical population of patients with chronic kidney disease and high cardiovascular risk who have considerable unmet need, yet are free of a clinically apparent inflammatory condition.
Implications of all the available evidence
Beyond aggressive lipid lowering, future treatment of atherosclerosis will probably include targeted anti-inflammatory therapy that inhibits the IL-1 to IL-6 pathway of innate immunity. On the basis of these phase 2 efficacy and safety data, a large-scale cardiovascular outcomes trial of ziltivekimab will be conducted among patients with chronic kidney disease, increased CRP, and established cardiovascular disease.
Beyond the internal consistency of these recent clinical trials, it has been known for two decades that IL-6 levels predict vascular events in primary and secondary prevention with at least as much fidelity as the downstream clinical biomarker high-sensitivity CRP.9, 10, 11, 12, 13, 14 Unlike CRP, mendelian randomisation studies indicate that genetic variants in the IL-6 receptor signalling pathway associate with lifelong risks of coronary heart disease, suggesting that IL-6 is likely to be a causal factor for atherosclerotic progression.15, 16 Genetic data have also affirmed a role of IL-6 signalling in multiple forms of atherosclerosis, including myocardial infarction, peripheral arterial disease, and aortic aneurysm formation.17 In parallel, experimental data have long implicated IL-6 directly in the atherosclerotic process.18, 19, 20 Moreover, genetically modified mice with high IL-6 levels have increased susceptibility to atherogenesis when fed a high-fat diet, yet have fewer atherosclerotic lesions after treatment with an anti-mouse IL-6 receptor antibody.21
On the basis of these data, we hypothesised that direct targeting of IL-6 might have the potential to maximise anti-inflammatory atherosclerotic benefit while minimising off-target effects among high atherosclerotic risk individuals who are free of a clinically apparent systemic inflammatory illness.1, 22, 23 One agent under investigation is ziltivekimab, a narrow-spectrum fully human monoclonal antibody targeting the IL-6 ligand that, unlike other clinically available IL-6 signalling inhibitors, is being developed specifically for atherosclerosis treatment. As a monoclonal antibody targeting the IL-6 ligand rather than the IL-6 receptor, ziltivekimab used at lower doses could have fewer adverse effects on lipid levels, haematological indices, and hepatic function than other approved IL-6 agents such as tocilizumab and sarilumab.
To address these issues, we conducted a phase 2 trial to assess the effects of ziltivekimab on multiple biomarkers of inflammation and thrombosis, and to address whether there might be dose response effects for safety or efficacy. The population selected for this trial was patients at high cardiovascular risk with chronic kidney disease and elevated high-sensitivity CRP, a group where previous studies indicate that IL-6 levels correlate with severity of renal impairment as well as level of atherosclerotic risk.24, 25, 26, 27, 28, 29, 30 Further, as shown within CANTOS, participants with chronic kidney disease and elevated IL-6 preferentially benefit from targeted anti-inflammatory therapy.31 In RESCUE, we assessed effects of antibody-mediated IL-6 inhibition on inflammation in patients with advanced chronic renal disease.
