Canakinumab Anti-inflammatory Thrombosis Outcomes Study Research Articles

Update on the Inflammatory Hypothesis of Coronary Artery Disease.

The pathogenesis and progression of coronary artery disease (CAD) is now known to be largely driven by inflammation on top of the well-accepted role for the disequilibrium between cholesterol deposition and removal from the arterial wall. Recent clinical trials have supported the inflammatory hypothesis of CAD and will be discussed in this review. The clinical trial Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) found that treatment with canakinumab, an anti-interleukin-1β agent, resulted in a reduction in non-fatal myocardial infarction, non-fatal stroke, or death. This provided evidence for the inflammatory hypothesis of CAD. However, canakinumab is not cost-effective for widespread therapy and more cost-effective treatments are warranted. The Cardiovascular Inflammation Reduction Trial (CIRT), Colchicine Cardiovascular Outcomes Trial (COLCOT), and Low-Dose Colchicine 2 (LoDoCo2) are recent clinical trials that increased the understanding of the inflammatory hypothesis of CAD. Cost-effective therapies targeting inflammation are the future of preventative CAD treatment. Additional clinical trials with anti-inflammatory and anti-cytokine agents would help delineate the most beneficial target for CAD prevention.

Inhibition of IL1β by Canakinumab May Be Effective against Diverse Molecular Subtypes of Lung Cancer: An Exploratory Analysis of the CANTOS Trial

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of the IL1β inflammatory pathway by canakinumab has been shown to significantly reduce lung cancer incidence and mortality. Here we performed molecular characterization of CANTOS patients who developed lung cancer during the study, including circulating tumor DNA (ctDNA) and soluble inflammatory biomarker analysis. Catalogue of Somatic Mutations in Cancer (COSMIC) database ctDNA mutations were detected in 65% (46/71) of the CANTOS patients with lung cancer, with 51% (36/71) having detectable ctDNA at the time point closest to lung cancer diagnosis and 43% (29/67) having detectable ctDNA at trial randomization. Mutations commonly found in lung cancer were observed with no evidence of enrichment in any mutation following canakinumab treatment. Median time to lung cancer diagnosis in patients with (n = 29) versus without (n = 38) detectable COSMIC ctDNA mutations at baseline was 407 days versus 837 days (P = 0.011). For serum inflammatory biomarker analysis, circulating levels of C-reactive protein (CRP), IL6, IL18, IL1 receptor antagonist, TNFα, leptin, adiponectin, fibrinogen, and plasminogen activator inhibitor-1 were determined. Patients with the highest level of baseline CRP or IL6, both downstream of IL1β signaling, trended toward a shorter time to lung cancer diagnosis. Other inflammation markers outside of the IL1β pathway at baseline did not trend with time to lung cancer diagnosis. These results provide further evidence for the importance of IL1β-mediated protumor inflammation in lung cancer and suggest canakinumab's effect may be mediated in part by delaying disease progression of diverse molecular subtypes of lung cancer. SIGNIFICANCE: These findings suggest that targeting the IL1β inflammatory pathway might be critical in reducing tumor-promoting inflammation and lung cancer incidence.

Repurposing Colchicine to Combat Residual Cardiovascular Risk: The LoDoCo2 Trial

Over the last decades, our understanding of inflammatory processes involved in atherogenesis advanced considerably, with elements of R. Virchow's concept on atherosclerosis as a chronic inflammation induced by cholesterol appearing highly topical. Indeed, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) taught us that specifically targeted anti-inflammatory therapy can confer protection from recurrent cardiovascular (CV) events without affecting lipid levels.

Immunity, inflammation and the vasculature in the COVID-19 era

Immunity, inflammation and the vasculature in the COVID-19 era

Coronavirus 2019 Disease (COVID-19), Systemic Inflammation, and Cardiovascular Disease.

Acute respiratory failure associated with the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread worldwide and presents critical challenges for the public health and medical communities The World Health Organization (WHO) has declared SARS-CoV-2 a public health emergency of international concern, with a global estimate of over 7 million human infections and more than 400000 deaths worldwide as of June 12, 2020 A 2020 report by the China Medical Treatment Expert Group for Coronavirus disease 2010 (COVID-19) (2) showed that the clinical spectrum of the viral infection is dominated by fever (up to 88 7% of patients during hospitalization) and cough (67 8% of patients) followed by symptoms such as headache, fatigue, or shortness of breath

Effects of Interleukin-1β Inhibition on Incident Hip and Knee Replacement : Exploratory Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial.

Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear. To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR). Exploratory analysis of a randomized trial. (ClinicalTrials.gov: NCT01327846). 1091 clinical sites in 39 countries. 10061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants. Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases. Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80]; P= 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis. Because the parent trial was not designed to examine the efficacy of IL-1β inhibitors in osteoarthritis, information on structural joint outcomes was not collected. Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1β inhibition for treatment of large joint osteoarthritis. Novartis Pharmaceuticals.

Inflammation and cardiovascular diseases: lessons from seminal clinical trials.

Inflammation has been long regarded as a key contributor to atherosclerosis. Inflammatory cells and soluble mediators play critical roles throughout arterial plaque development and accordingly, targeting inflammatory pathways effectively reduces atherosclerotic burden in animal models of cardiovascular (CV) diseases. Yet, clinical translation often led to inconclusive or even contradictory results. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) followed by the Colchicine Cardiovascular Outcomes Trial (COLCOT) were the first two randomized clinical trials to convincingly demonstrate the effectiveness of specific anti-inflammatory treatments in the field of CV prevention, while other phase III trials-including the Cardiovascular Inflammation Reduction Trial one using methotrexate-were futile. This manuscript reviews the main characteristics and findings of recent anti-inflammatory Phase III trials in cardiology and discusses their similarities and differences in order to get further insights into the contribution of specific inflammatory pathways on CV outcomes. CANTOS and COLCOT demonstrated efficacy of two anti-inflammatory drugs (canakinumab and colchicine, respectively) in the secondary prevention of major adverse CV events (MACE) thus providing the first confirmation of the involvement of a specific inflammatory pathway in human atherosclerotic CV disease (ASCVD). Also, they highlighted the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome-related pathway as an effective therapeutic target to blunt ASCVD. In contrast, other trials interfering with a number of inflammasome-independent pathways failed to provide benefit. Lastly, all anti-inflammatory trials underscored the importance of balancing the risk of impaired host defence with an increase in infections and the prevention of MACE in CV patients with residual inflammatory risk.

Selective role of Nck1 in atherogenic inflammation and plaque formation.

Although the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) established the role of treating inflammation in atherosclerosis, our understanding of endothelial activation at atherosclerosis-prone sites remains limited. Disturbed flow at atheroprone regions primes plaque inflammation by enhancing endothelial NF-κB signaling. Herein, we demonstrate a role for the Nck adaptor proteins in disturbed flow-induced endothelial activation. Although highly similar, only Nck1 deletion, but not Nck2 deletion, limited flow-induced NF-κB activation and proinflammatory gene expression. Nck1-knockout mice showed reduced endothelial activation and inflammation in both models, disturbed flow- and high fat diet-induced atherosclerosis, whereas Nck2 deletion did not. Bone marrow chimeras confirmed that vascular Nck1, but not hematopoietic Nck1, mediated this effect. Domain-swap experiments and point mutations identified the Nck1 SH2 domain and the first SH3 domain as critical for flow-induced endothelial activation. We further characterized Nck1's proinflammatory role by identifying interleukin 1 type I receptor kinase-1 (IRAK-1) as a Nck1-selective binding partner, demonstrating that IRAK-1 activation by disturbed flow required Nck1 in vitro and in vivo, showing endothelial Nck1 and IRAK-1 staining in early human atherosclerosis, and demonstrating that disturbed flow-induced endothelial activation required IRAK-1. Taken together, our data reveal a hitherto unknown link between Nck1 and IRAK-1 in atherogenic inflammation.

Mendelian randomization in COVID-19: Applications for cardiovascular comorbidities and beyond.

Mendelian randomization in COVID-19: Applications for cardiovascular comorbidities and beyond.

COVID-19 and myocardial injury: is there a role for interleukin-1 inhibition?

Coronavirus pneumonia 2019 (COVID-19) pandemic was declared on 11 March 2020 by the WHO, with more than 400 000 people infected and more than 18 000 died as of 26 March. Myocardial injury is common in COVID-19 patients, particularly in the ICU.1 Shi et al.2 recently reported myocardial injury in 20% patients with COVID-19 associated with a death rate of 51 vs. 4.5% (P < 0.001). Although the mechanism of myocardial injury is unknown, it may be caused by cardiac adrenergic hyperstimulation during cytokine storm syndrome. Arrhythmia was a cause of ICU admission in 44% patients with COVID-19 infection.1 Macrophage activation syndrome (MAS) is a frequently undiagnosed severe and fulminant form of cytokine storm syndrome, mostly observed during viral sepsis and caused by overwhelming release of pro-inflammatory cytokines. Indeed, increased plasmatic concentrations of cytokines resembling MAS phenotype were found in ICU patients with COVID-19, along with higher levels of troponin I; NT-proBNP stands for N-terminal pro-Brain Natriuretic Peptide and C-reactive protein.2,3 In MAS, T-cells and antigen-presenting cells are hyperactivated through Toll-like receptors with repeated stimulation causing a massive autocrine loop of interleukin (IL)-1 and a subsequent, uncontrolled release of pro-inflammatory cytokines, including IL-6, IL-18, interferon (IFN)-γ, tumour necrosis factor alpha (TNFα) and ferritin, further precipitating clinical conditions, leading to endothelial dysfunction, multiple organ dysfunction and death (Fig. 1).4Fig. 1: Cytokine storm with sympathetic nervous system activation, myocardial lesion and endothelial damage leading to multiple organ failure. ANS, autonomic nervous system.IL-1 blockade gave encouraging results in similar clinical settings. Indeed, a posthoc analysis of a phase III randomized trial on the IL-1 receptor antagonist anakinra in septic patients showed improved 28-day survival (35 vs. 65%, P < 0.001) in patients with MAS phenotype. Furthermore, IL-1 blockade with anakinra in septic patients is currently being assessed in PROVIDE (Personalized RandOmized trial of Validation and restoration of Immune Dysfunction in sEvere infections and sepsis; ClinicalTrials.gov NCT03332225).4 CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) showed that IL-1 inhibition in patients with a previous myocardial infarction and increased C-reactive protein effectively reduced recurrent cardiovascular events.5 In the setting of COVID-19 infection, the additive effect of overwhelming IL-1 production associated with cardiovascular comorbidities, MAS and incessant adrenergic stimulation may synergize in a deadly vicious circle. In specific settings, such as pericarditis, nonselective inhibition of IL-1, either alfa and beta is superior to the selective inhibition of IL-1 beta because of the blocking of IL-1 alfa that can be secreted by mesothelial cells.6 Considering the potential key role of IL-1 in COVID-19 infection, its inhibition may be proposed as a potential therapeutic option. Randomized trials are needed to clarify the potential usefulness of IL-1 blocking agents. Acknowledgements Conflicts of interest There are no conflicts of interest.

The Role of Suppressing Inflammation in the Treatment of Atherosclerotic Cardiovascular Disease

To review the 3 anti-inflammatory drugs, canakinumab, colchicine, and methotrexate, that have been investigated in major clinical trials for treating patients with atherosclerotic cardiovascular disease (ASCVD). An Ovid MEDLINE literature search (1946 to February 2, 2020) was performed using search strategy [(C-reactive protein OR ASCVD OR cardiac disease OR cardiovascular disease) AND (canakinumab OR methotrexate OR Colchicine)]. Additional references were identified from the citations. English-language studies assessing the impact of these 3 drugs on inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) or the association with reducing ASCVD events were included. Canakinumab and colchicine significantly reduced ASCVD events in high-risk patients with median baseline hs-CRP levels of ~4.0 mg/L. Methotrexate was ineffective at reducing ASCVD events in high-risk patients, but their baseline hs-CRP concentrations were a median of <2 mg/L. In subgroup analyses of the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), patients whose baseline hs-CRP was 2 to 4 mg/L had benefits from canakinumab therapy similar to those with baseline levels exceeding 4. Even with the best current drug therapies, patients with underlying inflammation can benefit from the addition of both colchicine and canakinumab to further lower CV events. Given its cost, colchicine is a more attractive option. Patients at high risk of recurrent cardiovascular disease events with an hs-CRP of 2 mg/L or greater can reduce the occurrence of ASCVD events with canakinumab or colchicine therapy. Colchicine is the preferable option, in particular for those with myocardial infarction, given its more reasonable cost.

Effects of Interleukin-1β Inhibition on Incident Anemia: Exploratory Analyses From a Randomized Trial.

Inflammatory cytokines, such as interleukin (IL)-1β, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1β can reverse these effects is unclear. To determine whether IL-1β inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia. Exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846). Many clinical sites in 39 countries. 8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry. Random assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. Primary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women). Anemia incidence increased with rising baseline levels of high-sensitivity C-reactive protein (hsCRP), and both hsCRP and IL-6 decreased among participants receiving canakinumab compared with the placebo group. During a median follow-up of 3.7 years, participants without baseline anemia who received canakinumab at any dosage had significantly less incident anemia than those who received placebo (hazard ratio, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). Compared with placebo, the greatest benefits of IL-1β inhibition on incident anemia were observed among participants with the most robust anti-inflammatory response, an effect corroborated in formal mediation analyses. Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment. Canakinumab increased the risk for infection and was associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher. CANTOS was not designed to assess the cause of anemia in individual trial participants. These exploratory analyses of randomized trial data provide proof of principle that inflammation inhibition, at least through the IL-1β/IL-6 signaling pathway, reduces the incidence of anemia and improves hemoglobin levels in patients with anemia. Novartis Pharmaceuticals.

A perspective on targeting inflammation and cytokine actions in atherosclerosis.

Atherosclerosis, a chronic inflammatory disorder of the vasculature that results in cardiovascular disease, continues to pose a significant health and economic burden on modern society. Whilst inflammation has generally been accepted as the key driver of all stages of the disease, it was not until recently that inhibition of a specific proinflammatory cytokine (IL-1β) yielded successful results in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study trial. This article offers a perspective on targeting inflammation for atherosclerosis, focusing on results of recent Phase III clinical trials, and discusses other potential candidates together with future challenges and prospects.

From CANTOS to CIRT to COLCOT to Clinic: Will All Atherosclerosis Patients Soon Be Treated With Combination Lipid-Lowering and Inflammation-Inhibiting Agents?

From CANTOS to CIRT to COLCOT to Clinic: Will All Atherosclerosis Patients Soon Be Treated With Combination Lipid-Lowering and Inflammation-Inhibiting Agents?

The Role of Toll-like Receptors in Atherothrombotic Cardiovascular Disease.

Toll-like receptors (TLRs) are dominant components of the innate immune system. Activated by both pathogen-associated molecular patterns and damage-associated molecular patterns, TLRs underpin the pathology of numerous inflammation related diseases that include not only immune diseases, but also cardiovascular disease (CVD), diabetes, obesity, and cancers. Growing evidence has demonstrated that TLRs are involved in multiple cardiovascular pathophysiologies, such as atherosclerosis and hypertension. Specifically, a trial called the Canakinumab Anti-inflammatory Thrombosis Outcomes Study showed the use of an antibody that neutralizes interleukin-1β, reduces the recurrence of cardiovascular events, demonstrating inflammation as a therapeutic target and also the research value of targeting the TLR system in CVD. In this review, we provide an update of the interplay between TLR signaling, inflammatory mediators, and atherothrombosis, with an aim to identify new therapeutic targets for atherothrombotic CVD.

Atherothrombosis Prevention and Treatment with Anti-interleukin-1 Agents

Despite major advances in terms of prevention, diagnosis, risk-stratification, management and rehabilitation, atherosclerosis and atherothrombosis continue to have major morbidity and mortality implications worldwide. Since the unraveling of the pivotal role of inflammation in atherothrombosis pathophysiology, several focused treatments have been proposed with the ultimate goal of preventing or treating myocardial infarction, stroke, and peripheral artery disease. In particular, given the centrality of interleukin-1 (IL-1), targeted anti-IL-1 agents have attracted substantial attention and efforts. Yet, uncertainty persists on the real risk-benefit and cost-benefit balance of anti-IL-1 agents in patients with or at risk of atherothrombosis. Several trials have been recently completed on atherothrombosis prevention and treatment with anti-IL-1 agents, ranging, for instance, from the large Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial to the series of translational studies conducted within the Virginia Commonwealth University-Anakinra Remodeling Trial (VCU-ART) platform. In light of the present scoping umbrella review, it appears evident that anti-IL-1 agents can reduce systemic inflammation and improve surrogate markers of cardiac and vascular function, with potential benefits on the risk of new/worsening heart failure. One trial suggested an increased risk of major adverse events with anti-interleukin-1 agents, possibly due to a rebound phenomenon, but this was based on a post-hoc analysis of a small number of events, and it was not supported by all other pertinent trials. The CANTOS study showed a potential hazard due to an increased risk of fatal infections, but the effect size was rather small. In addition, cost issues limit the foreseeable scope of these treatment strategies in unselected patients, calling instead for more refined prescribing. The evidence base on the risk-benefit and cost-benefit profile of anti-IL-1 agents for atherothrombosis prevention and treatment has expanded substantially in the last decade. While largely dominated by the landmark CANTOS trial, effect estimates also including the VCU-ART trials suggest complex short- and long-term effects which may prove favorable in carefully selected patients with acute or chronically sustained inflammation. Conversely, more liberal use appears less promising, and further studies with currently available agents or novel ones are eagerly needed to better define their role in the era of precision molecular medicine.

Effects of Interleukin-1β Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory Risk: A Secondary Analysis of CANTOS.

While hypertension and inflammation are physiologically inter-related, the effect of therapies that specifically target inflammation on blood pressure is uncertain. The recent CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) afforded the opportunity to test whether IL (interleukin)-1β inhibition would reduce blood pressure, prevent incident hypertension, and modify relationships between hypertension and cardiovascular events. CANTOS randomized 10 061 patients with prior myocardial infarction and hsCRP (high sensitivity C-reactive protein) ≥2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo. A total of 9549 trial participants had blood pressure recordings during follow-up; of these, 80% had a preexisting diagnosis of hypertension. In patients without baseline hypertension, rates of incident hypertension were 23.4, 26.6, and 28.1 per 100-person years for the lowest to highest baseline tertiles of hsCRP (P>0.2). In all participants random allocation to canakinumab did not reduce blood pressure (P>0.2) or incident hypertension during the follow-up period (hazard ratio, 0.96 [0.85-1.08], P>0.2). IL-1β inhibition with canakinumab reduces major adverse cardiovascular event rates. These analyses suggest that the mechanisms underlying this benefit are not related to changes in blood pressure or incident hypertension. Clinical Trial Registration- URL: https://clinicaltrials.gov. Unique identifier: NCT01327846.

2417Elevated interleukin-6 and interleukin-18 concentrations predict residual inflammatory risk both before and after interleukin-1beta inhibition with canakinumab

Abstract Background The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1b (IL-1b) inhibition can significantly reduce cardiovascular event rates in the absence of beneficial effects on cholesterol. Yet, CANTOS participants treated with both statins and canakinumab remain at considerable risk. Both interleukin-6 (IL-6, a central signaling cytokine) or interleukin-18 (IL-18, which like IL-1b requires the NLRP3 inflammasome for activation) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis. Purpose To assess the impact of canakinumab therapy on plasma levels of IL-6 and IL-18, and to assess the potential contributions of IL-6 and IL-18 to residual inflammatory risk both before and after treatment with canakinumab. Methods Plasma samples from 3,381 stable post-myocardial infarction patients assigned to active IL-1b inhibition within CANTOS underwent measurement of IL-6 and IL-18 both before and after initiation of canakinumab. All participants were followed over a 3.7 year period for major adverse cardiovascular events (MACE) and all-cause mortality. Results When compared to placebo, canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8, 36.3, and 43.2 percent for the 50mg, 150mg, and 300mg doses, respectively (all p-values &lt;0.001). In marked contrast, no dose of canakinumab significantly altered IL-18 levels measured at 3 months (all effects less than 1 percent, all p-values &gt;0.05). Yet, despite these differential plasma effects, both baseline and on-treatment levels of IL-6 and IL-18 associated with rates of future cardiovascular events and with all-cause mortality. For example, for MACE, each tertile increase in IL-6 measured 3 months after canakinumab initiation associated with a 42 percent increase in risk (95% CI 26–59%, P&lt;0.0001) while each tertile increase in IL-18 measured 3 months after canakinumab initiation associated with a 15 percent increase in risk (95% CI 3–29% P=0.015). Similar effects were observed for MACE-plus, cardiovascular death, and all-cause mortality. Conclusions These randomized trial biomarker analyses from CANTOS demonstrate that interleukin-1b inhibition with canakinumab significantly reduces plasma levels of IL-6 but not IL-18, yet that there remains substantial residual inflammatory risk related to both IL-6 and IL-18. As such, our data support further pharmacologic development of potential anti-cytokine therapies for atherothrombosis that simultaneously inhibit IL-1b and IL-18 (such as NLRP3 inhibitors) as well as agents that directly target IL-6 signaling. Acknowledgement/Funding Novartis

Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis

The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1β (IL-1β) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1β requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis. Plasma samples from 4848 stable post-myocardial infarction patients who were assigned to active IL-1β inhibition or placebo within CANTOS underwent measurement of IL-18 and IL-6 both before and after initiation of canakinumab using validated ELISA. All participants were followed over a median 3.7-year period (maximum 5 years) for recurrent major adverse cardiovascular events (MACE) and for all-cause mortality. Compared to placebo, canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8%, 36.3%, and 43.2% for the 50, 150, and 300 mg doses, respectively (all P-values <0.001). By contrast, no dose of canakinumab significantly altered IL-18 levels measured at 3 months (all effects <1%, all P-values > 0.05). Yet, despite these differential plasma effects, either baseline and on-treatment levels of IL-18 or IL-6 associated with rates of future CV events. For example, for MACE, each tertile increase in IL-18 measured 3 months after canakinumab initiation associated with a 15% increase in risk [95% confidence interval (CI) 3-29%, P = 0.016], while each tertile increase in IL-6 measured 3 months after canakinumab initiation associated with a 42% increase in risk (95% CI 26-59%, P < 0.0001). Similar effects were observed for MACE-plus, CV death, all-cause mortality, and the for the combination endpoint of all vascular events inclusive of revascularization procedures and hospitalization for congestive heart failure. In baseline as well as on-treatment analyses, risks were highest among those with the highest levels of both IL-18 and IL-6. There remains substantial residual inflammatory risk related to both IL-18 and IL-6 after IL-1β inhibition with canakinumab These data support further pharmacologic development of therapies for atherothrombosis that target IL-18 or IL-6 signalling, or that can simultaneously inhibit both IL-1β and IL-18 (such as NLRP3 inflammasome inhibitors). ClinicalTrials.gov NCT01327846.

Inflammation in atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular disease is a leading cause of death and morbidity globally. Over the past several years, arterial inflammation has been implicated in the pathophysiology of athero-thrombosis, substantially confirming what pathologist Rudolf Virchow had observed in the 19th century. Lipid lowering, lifestyle changes, and modification of other risk factors have reduced cardiovascular complications of athero-thrombosis, but a substantial residual risk remains. In view of the pathogenic role of inflammation in athero-thrombosis, directly targeting inflammation has emerged as an additional potential therapeutic option; and some early promising results have been suggested by the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), in which canakinumab, a fully human monoclonal antibody targeting the pro-inflammatory and pro-atherogenic cytokine interleukin 1 beta, was shown to reduce cardiovascular events.