Canakinumab: Promises and Future in Cardiometabolic Diseases and Malignancy

doi:10.1016/j.amjmed.2018.10.013

The American Journal of Medicine

Volume 132, Issue 3, March 2019, Pages 312-324

https://doi.org/10.1016/j.amjmed.2018.10.013 Get rights and content

Abstract

Inflammation has proven in multiple studies to be responsible for the progression of cardiometabolic diseases and malignancies. The interleukin family has been critically associated with progression of atherosclerosis, insulin resistance, and various malignancies. Given the advent of pharmacologic interleukin-1 (IL-1) inhibition, this pathway can potentially be targeted to improve outcomes. In the recently concluded Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial, investigators looked at the potential role of IL-1 (especially IL-1β) inhibition in halting the progression of atherosclerosis. In the subset analysis of the data from this trial, IL-1β inhibition with canakinumab was found to have beneficial effects in other cardiometabolic diseases characterized by inflammation, like diabetes, stroke, and chronic kidney disease, and also in patients with lung cancer. In this article, we will try to review the current literature on the role of canakinumab in the treatment of cardiometabolic diseases and malignancies.

Introduction

The role of inflammation in the progression of cardiometabolic disease is being increasingly recognized through a multitude of research studies. Cardiometabolic syndrome is a combination of altered metabolic pathways primarily represented by insulin resistance, impaired glucose tolerance, dyslipidemia, hypertension, and central adiposity.¹ Another definition indicates that cardiometabolic disease constitutes the presence of at least 2 of the following pathologies: diabetes, coronary artery disease, and stroke.2, 3 Currently, 92.1 million US adults suffer from at least one type of cardiovascular disease. The total burden of disease is expected to increase by 43% by the year 2030. Inflammation is believed to be the key factor linking the pathologies and, perhaps, contributing to increased mortality.

The inflammatory model of the pathogenesis of these conditions, mediated by members of the interleukin (eg, interleukin-1 [IL-1]) family has been the focus of many studies. In the recently concluded Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial, investigators looked at the potential role of IL-1 (especially IL-1β) inhibition in halting the progression of atherosclerosis.⁴ In the subset analysis of the data from this trial, IL-1β inhibition with canakinumab was found to have beneficial effects in other cardiometabolic diseases characterized by inflammation, like diabetes, stroke, and chronic kidney disease, and also in patients with lung cancer.5, 6, 7 In this article, we will try to review the current literature on the role of canakinumab in the treatment of cardiometabolic diseases and malignancies.

Section snippets

Canakinumab: Mechanism of Action and Indications

The inflammatory process induced by IL-1 follows multiple pathways, but the one most studied involves its 2 major subunits, IL-1α and IL-1β.8, 9 The process is initiated with the binding of IL-1α or IL-1β with the ligand-binding chain IL1-R1. This is followed by recruitment of IL-1 receptor accessory protein (IL-1RAcP), leading to the formation of a complex consisting of 3 components (IL-α/β, IL1-R1, and IL-1RAcP). This complex then recruits an adaptor protein, namely, myeloid differentiation

Canakinumab and Atherosclerotic Vascular Disease

The role of canakinumab in atherosclerotic vascular diseases has been the subject of extensive research in both the preclinical and clinical settings. Be it cerebrovascular, peripheral artery, or coronary artery disease, the clinical significance and efficacy of canakinumab have been at the heart of every debate. The potential mechanisms of the clinical effects of canakinumab in various disease conditions are presented in Table 2.

Preclinical studies were instrumental in exploring the link

Canakinumab and Diabetes Mellitus Type 2

The role of IL-1 in diabetes has been studied extensively in the past.8, 9^,25, 26, 27 Diabetes is often associated with obesity, which leads to ongoing inflammation, thus propagating the cytokine release. IL-1α and IL-1β, as well as IL-Ra, all have been implicated in worsening of insulin resistance.¹ Initial interest in IL inhibition in the treatment of diabetes was sparked after anakinra (IL-1R antagonist) showed sustained improvement in hemoglobin A1c (HbA1c) during a clinical trial in 2007.²⁸

Canakinumab and Chronic Kidney Disease

The pathogenesis of accelerated atherogenesis in chronic kidney disease is still an area of active debate. Presence of chronic kidney disease alone with or without diabetes has been implicated in the progression of large-vessel atherosclerosis.³⁶ Inflammation has been shown in the past to play a key role in predicting outcomes in patients with chronic kidney disease.³⁷ Latest studies indicate a significant role of the NLRP3 inflammasome in the progression of atherogenesis in chronic kidney

Canakinumab and Malignancy

Inflammation, especially the chronic type, has long been associated with the development and progression of various malignancies.⁴⁰ IL-1, an important proinflammatory cytokine, has often been suggested as a potential mediator in angiogenesis, tumor invasiveness, metastasis, and cancer cachexia in various preclinical studies, although the exact pathophysiological explanation for these findings remains unclear.41, 42 A recently published study showed that IL-1β promotes the stem cell properties

Conclusion and Future Directions

Rising incidence of cardiometabolic diseases has led to newer innovative strategies to decrease the morbidity and mortality associated with them. The role of targeted therapy against inflammatory mediators, though promising, needs to be approached with caution. The CANTOS trial helped forward our understanding of the role of inflammation in cardiovascular diseases. Canakinumab is promising in the secondary prevention of myocardial infarction and in patients with chronic kidney disease, but its

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Canakinumab is a monoclonal IL-1β antibody that is FDA-approved for the treatment of cryopyrin-associated periodic syndrome (CAPS) and systemic juvenile idiopathic arthritis (SJIA). Canakinumab is an anti-inflammatory therapy that has been evaluated in Phase II trials for the treatment of rheumatoid arthritis (RA) and type II diabetes [35,36] and in a Phase III trial (CANTOS) for atherosclerotic disease [37,38]. However, Novartis' application for canakinumab for the treatment of atherosclerotic disease was rejected by the FDA and the European Medicines Agency (EMA) because canakinumab increased high-sensitivity CRP (hs-CRP) levels and the risk of serious infection.
Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Traditionally, IL-19 was thought to be expressed in only immune cells, but studies revealed that IL-19 is also expressed in multiple atherosclerotic plaque cell types, but not normal arteries, in humans and mice. IL-19 reduces the development of atherosclerosis via multiple mechanisms, including balancing cholesterol metabolism; enhancing Th2 immune cell polarization; reducing the inflammatory response; and reducing the proliferation, migration and chemotaxis of vascular smooth muscle cells (VSMCs). Clinical and/or animal studies have primarily aimed to achieve regression and/or stabilization of atherosclerotic plaques, with regression in particular indicating a very good drug response. Most antiatherosclerotic drugs in current clinical use, including atorvastatin and alirocumab, target hyperlipidemia. Several other drugs have also been investigated in clinical trials as anti-inflammatory agents; the development of some of these agents has been terminated (canakinumab, darapladib, varespladib, losmapimod, atreleuton, setileuton, PF-04191834, veliﬂapon, and methotrexate), but others remain in development (ziltivekimab, tocilizumab, Somalix, IFM-2427, anakinra, mesenchymal stem cells (MSCs), colchicine, everolimus, allopurinol, and montelukast). Most of the tested drugs have shown a limited ability to reverse atherosclerosis in animal studies. Interestingly, recombinant IL-19 (rIL-19) was shown to reduce atherosclerosis development in a time- and dose-dependent manner. A low dose of rIL-19 (1 ng/g/day) reduced aortic arch and root plaque areas by 70.1% and 32.1%, respectively, in LDLR^-/- mice. At 10 ng/g/day, rIL-19 completely eliminated atherosclerotic plaques. There were no sex differences in the effects of rIL-19 on atherosclerotic mice. Thus, low-dose rIL-19 is an effective antiatherosclerotic agent, in addition to its efficacy in intimal hyperplasia, spinal cord injury, stroke, and multiple sclerosis. We propose that IL-19 is a promising biomarker and target for the diagnosis and treatment of atherosclerosis. This review considers the role and mechanism of action of IL-19 in atherosclerosis and discusses whether IL-19 is a potential therapeutic target for this condition.
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: Conflicts of Interest: None.

: Authorship: All authors had access to the data and a role in writing the manuscript.

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ReviewCanakinumab: Promises and Future in Cardiometabolic Diseases and Malignancy

Abstract

Introduction

Section snippets

Canakinumab: Mechanism of Action and Indications

Canakinumab and Atherosclerotic Vascular Disease

Canakinumab and Diabetes Mellitus Type 2

Canakinumab and Chronic Kidney Disease

Canakinumab and Malignancy

Conclusion and Future Directions

Cytokine

J Am Coll Cardiol

J Am Coll Cardiol

Blood

J Am Coll Cardiol

Diabetes Metab

Lancet

J Transl Med

Pathol Res Pract

J Thorac Oncol

Lancet

Lancet Oncol

Mayo Clin Proc

Am Heart J

Heart Disease and Stroke Statistics–2017 update: a report from the American Heart Association

Circulation

Cardiometabolic syndrome: pathophysiology and treatment

Curr Hypertens Rep

Antiinflammatory therapy with canakinumab for atherosclerotic disease

N Engl J Med.

Post-ischaemic administration of the murine Canakinumab-surrogate antibody improves outcome in experimental stroke

Eur Heart J

Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases

Nat Rev Drug Discov

Interleukin-1 and acute brain injury

Front Cell Neurosci

Molecular mechanisms regulating NLRP3 inflammasome activation

Cell Mol Immunol

Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1β monoclonal antibody

Clin Pharmacokinet

Bioequivalence of canakinumab injected subcutaneously via an autoinjector device or a prefilled safety syringe device in healthy subjects

Clin Pharmacol Drug Dev

Safety profile of the interleukin-1 inhibitors anakinra and canakinumab in real-life clinical practice: a nationwide multicenter retrospective observational study [e-pub ahead of print]

Clin Rheumatol

Review
Canakinumab: Promises and Future in Cardiometabolic Diseases and Malignancy