Juan Carlos Kaski: Welcome, everyone. I'm JC Kaski, Professor of Cardiovascular Science at St. George's University of London. My guest today is Dr. Paul Ridker, whose contribution to the field of inflammation in cardiovascular disease has been, and continues to be, absolutely fantastic. Paul, thank you very much for joining us today. Dr. Paul Ridker: It's an absolute pleasure and I look forward to the second part of our video presentation. Juan Carlos Kaski: The relationship between inflammation and atherosclerosis, and the development of cardiovascular disease and renal impairment is very complex, I know, but I wonder whether you could, in the short time we have today, explain the links that exist between inflammation and atherosclerosis. And particularly, why has your research, and the development of therapeutic agents, focused mainly on IL-6 and the NLRP3 inflammasome. Dr. Paul Ridker: Sure. So we've known now for almost 25, 30 years, that there's a relationship between certain biomarkers of inflammation in particular, C-reactive protein and interleukin-6 with the onset of vascular disease and with unstable angina and with all the complications of atherosclerosis. But about 10 years ago, it became apparent that a certain particular inflammatory pathway, now there are many inflammatory pathways of both innate and acquired immunity that I'm certain are involved in this process, but at least one of them, one that goes from the NLRP3 inflammasome, which is a central signalling centre where exogenous toxins and crystalline structures are recognised as being foreign. And of course, cholesterol crystals are recognised as being foreign and inside that inflammasome, a enzyme called caspase activates pro-interleukin-1 beta to locally secrete IL-1 beta and locally secrete interleukin-18. Now these two cytokines have very interesting properties. Dr. Paul Ridker: One of which is that they upregulate the central signalling cytokine, which is interleukin-6 and all three of those cytokines. IL-18, IL-1 and IL-6 have many direct effects on the vascular endothelium that we as cardiologists deal with every day in practise. They're augmenting thrombosis, they're increasing atherosclerosis and they're causing vascular event rates. Now IL-6 itself, of course, upregulates the liver to produce our biomarker, the CRP, which is not a causal agent. It's simply a very convenient clinical way of assessing this pathway. And of course the CANTOS study, the Canakinumab Anti-Inflammatory Thrombosis Outcome Study, showed that if we gave an IL-1 beta inhibitor, we lower IL-6 and we lower cardiovascular event rates. But the hypothesis in front of us now is, well what if we go directly to IL-6, might that give us a greater risk reduction than we saw in CANTOS? Juan Carlos Kaski: Right. Now, CANTOS results were extremely important. There were some side effects, which I guess would actually minimise the application of these sort of therapeutic intervention, which neutralises IL-1 beta. And colchicine has very recently appeared as a potential treatment in inflammation and atherosclerosis. It is cheaper than monoclonals, but perhaps problematic in certain subgroups. Can I have your sort of views on this? Dr. Paul Ridker: Well, colchicine is a very interesting drug, which I think has multiple different kind of anti-inflammatory effects. Remember colchicine effectively is a microtubule inhibitor. So it slows the bringing together a certain protein structures. And one of those protein structures, I think, is the NLRP3 inflammasome. So I'd say an indirect inhibitor of that process, but you should be aware it does many other things as well. But it does lower CRP and we have two clinical trials with LoDoCo2 and COLCOT telling us it does lower cardiovascular event rates in chronic stable atherosclerosis. But as you point out correctly, this is not a drug I'm comfortable giving to patients with chronic kidney disease because it's renally excreted and we can get in some trouble here. So the question is, are there other therapies that we believe would be safe and effective that also target the central NLRP3 to IL-1 to IL-6 pathway and Juan Carlos, I want to remind you of a very important observation within CANTOS. Dr. Paul Ridker: And that is that the most potent predictor of the magnitude of benefit for an individual patient was in fact, the magnitude of the IL-6 reduction that patient received. So regardless of which dose of Canakinumab they got, we found that the patients with the largest IL-6 reductions had an almost 36% reduction in major vascular event rates. That's a big reduction in risk. What we're trying to do now is say, can we focus specifically on these chronic kidney disease patients who again, we cannot give them colchicine because it's renally excreted, who clearly have residual inflammatory risk and we need more potent therapy. So we recently embarked on a clinical trial called ZEUS. This again is the Ziltivekimab Cardiovascular Outcomes Study. That's using a novel IL-6 ligand monoclonal antibody, Ziltivekimab, that unlike Tocilizumab for example, which is an IL-6 receptor antagonist, does not have adverse effects on lipids. Dr. Paul Ridker: So I'm comfortable giving it to atherosclerosis patients. We've shown that it is very powerful at lowering CRP levels, 85, 90% reductions, which is substantially larger than we saw with Canakinumab. So if the data holds up, we should get larger risk reductions as well. But of course, what is unknown in any clinical trial is safety and efficacy. That's why we do the large clinical outcome trials. I hope the drug is safe. Certainly IL-6 inhibitors have been safe when they're used to treat Crohn's disease or rheumatoid arthritis, but we have to see in an atherosclerosis setting. And of course we have to see whether the theory holds up in humans who are taking the drug, but in the ZEUS trial, half the patients will get Ziltivekimab at 15 milligrammes subcutaneous once a month, the other half will get very aggressive care plus placebo. All these patients will already have residual inflammatory risk because the entry criterion are known atherosclerosis on a high dose statin, with a CRP that's still above two. Dr. Paul Ridker: And we'll learn together in a global trial, whether or not we can directly apply this biology to this exceptionally high risk group of patients. I want to emphasise again, I said earlier that the nephrology community is also well aware of how this same NLRP3 inflammasome is involved in progression of kidney disease. And so we have a second hypothesis in the same trial, focusing specifically on rates of decline of GFR, incidents of renal failure, incidents of going on dialysis. So we're trying to find out in one study, if these very high risk patients are atherosclerotic events who have progressive kidney disease, will benefit on both of their major comorbid problems with a single intervention, that being inhibition of interleukin-6 itself. It's very exciting. Juan Carlos Kaski: Well, I'm afraid we have actually reached the time that was allocated to us today. So I would like to thank you very much indeed for joining me today for this extremely interesting update you have given us, and also thank you very much for really engaging so, with such commitment in actually trying to find new therapies and new avenues to actually help our patients live a better life. Thank you very much. Dr. Paul Ridker: Oh, Juan Carlos, thank you for having me and thank you for all your contributions and leadership in cardiovascular medicine. We obviously do all these things together, hopefully for the benefit of our patients. It's a pleasure to be here.