My name is Paul Ridker. I have the pleasure of joining my colleagues today in this symposium about inflammation the next therapeutic frontier in targeting residual cardiovascular risk. And my task is really to look to the future. What can we expect, moving down the road? In particular, focusing on interleukin 6. A critical cytokine that dr. Libby has just mentioned as a therapeutic target in inflammation and in cardiovascular disease. These are my disclosures.

Now, the chair of our symposium, Peter Libby along with his colleagues, Göran Hansen and Russell Ross, really form the basis of much of the underlying molecular biology that you've been hearing about in the way that both innate and adaptive immunity combined to help us to understand a new biology of atherosclerosis that includes not just lipid-lowering, which remains crucial but the addition of this inflammatory process. I'm a clinical translational researcher though. So our entry into this field was at the point of saying could we begin to figure out how to make this clinically relevant for you, the physicians taking care of our patients.

So in a series of papers going back to the mid 1990s we were able to show, first that this biomarker downstream of the liver, that is activated by inflammation C-reactive protein, can be measured with great fidelity with an assay that is now called high-sensitivity CRP and that in a clinical trial of aspirin versus placebo were able to show that there might be some effect of anti-inflammatory therapies on this outcome and more importantly that CRP predicted future vascular events in otherwise healthy individuals, who had no ongoing inflammatory disorder. So that CRP becomes very much like blood pressure and LDL cholesterol as a predictor of future cardiovascular events. We also shown in the middle of this slide that a variety of different kinds of inflammatory biomarkers, high-sensitivity CRP, serum amyloid A, interleukin 6, that I'll come back to and an adhesion molecule called ICAM1 all added to lipids in terms of predicting future vascular risk. And the right-hand side of this slide the data showing, that you could predict outcomes with CRP just as well as you could with LDL cholesterol, but they are very different. You cannot predict your patients inflammatory profile from lipid profile. They both matter and they add to each other.

Now quite a few years ago and again with the cooperation from dr. Libby we did a large clinical trial globally known as JUPITER which showed that powerful statin therapy reduced the events of first heart attacks and strokes even if LDL cholesterol levels were low but you had an elevated level of C-reactive protein. Now, this trial was the largest study in primary prevention ever done and also showed the largest relative risk reduction. A 44% reduction in the primary endpoint and even a 20% reduction in all cause mortality. Now in the context of this symposium I think that's because we were able to exploit the fact that statins powerful lipid-lowering drugs are also anti-inflammatory agents. On the right hand side I show the subgroup data and I want to emphasize that even patients who only had an elevated CRP and no other risk factor at a highly significant reduction in ever having vascular events from being assigned statin therapy.

But remember, statins are lipid-lowering drugs that happen to have anti-inflammatory effects. This symposium is saying, what's the next step? How do we move forward? Well, you've heard from dr. Crea earlier about colchicine a generic anti-inflammatory that we've seen data on efficacy. And you heard dr. Libby talk about the canonical NLRP3 inflammasome which upregulates both IL-18 and interleukin-1 beta. Which in turn upregulates IL-6, goes to the liver and puts out the acute phase reactants and other things that matter for this process. So let's walk down that IL-1 to IL-6 pathway.

The CANTOS-trial, which is mentioned earlier by my colleagues was a very large study of over 10.000 patients, conducted in 39 countries worldwide

between 2011 and 2017 that really became the fundamental proof of principle test of the inflammation hypothesis of atherosclerosis in people. CANTOS took secondary prevention patients, who all had an elevated C-reactive protein aggressively treated already with all other therapies, including high-intensity statins and then gave three different doses of canakinumab. A monoclinal antibody that targets interleukin-1 beta and what CANTOS showed for the first time was statistically significant reductions in both MACE and MACE-plus which interestingly were just as large as the risk reduction seen in the very large scale PCSK9-trials. But remember in CANTOS we did not lower LDL cholesterol or apo-B at all and we did not change blood pressure. What we did is we targeted the immune system we've been hearing about. We lowered IL-1, we lowered IL-6 and we lowered vascular events just as much as if we had very aggressively lowered, LDL cholesterol.

One of the most important secondary findings from CANTOS I show you here. Which is that the magnitude of reduction in inflammation was probably the most important driver of the benefit patients get. I want you to focus on the right hand side of the slide which is the on treatment IL-6 levels. Whereas the left hand side is on treatment CRP. The story is very similar. What it says is that if you were a patient in CANTOS and had a very robust reduction in interleukin-6 there was a large benefit. A 36% reduction in major adverse cardiovascular events for those individuals who got after a single dose of canakinumab a greater than median reduction in IL-6. That's a big benefit on top of aggressive therapy. On the other hand you also see data that says, if the patients only had a moderest or less robust response they really were not that much better than placebo. This is a very direct signal that we want to target interleukin-6 to perhaps benefit our patients the most.

That story makes a lot of sense. I take you all the way back to 2000 when we published the first paper describing the fact that interleukin- 6 levels in humans predicts future cardiovascular events. On the right hand side this is repeated many times over the subsequent years showing very consistent data that IL-6 levels, like LDL, like blood pressure are powerful predictors of future vascular events.

There's also abundant supportive data for the hypothesis that lowering IL-6 directly might well benefit our patients. These data come in the upper left from GWAS-studies. Where the IL-6 loci turned out to be a very powerful predictor of outcomes for CRP. They come out of PHEWAS-data in the lower left where a variety of atheroscerotic events clearly line up with the IL-6 receptor pathway. And on the right hand side, the Mendelian randomization studies which showed concordance between lifelong CRP levels and lifelong risk based again on IL-6 signaling.

Further, we've seen data that in mice. That murine models of IL-6 inhibition also can support this hypothesis. I'd like you to focus on the right hand side of the slide. The red staining is atherosclerosis and what you see.is that when a murine anti-IL-6 receptor antibody known as MR16 is given to mice that have either a LDL receptor knockout or other models. A great reduction in that red staining. Less atherosclerosis in these mice when they're pre-treated with an anti-IL-6 receptor antibody.

The other exciting area going on here is an acute coronary ischemia. We believe that the ischemia in that setting is driving a lot of inflammation. We learned in our work many years ago, that levels of CRP at the time of an ACS can be very high. 10, 15, 20 milligrams per liter. Then over the next 25 days or so those levels will drop. We've seen in three different studies now that an IL-1 receptor antagonist and then two studies of tocilizumab, an interleukin-6 receptor antagonist, can have some small effects. Now these are small studies, experimental studies, suggesting maybe some benefit of myocardial salvage, maybe some benefit on troponin. But they taught us that this is a new direction we can go.

So, where are we heading? Well we worked with the development of a drug called ziltivekimab which is a narrow spectrum, fully human monoclonal antibody, that targets the IL-6 ligand, that we're working with a specifically developed drug for atherosclerosis. In a clinical trial called RESCUE we were able to show very dramatic, dose-dependent reductions, in CRP. That's the data in the upper left. But remember in CANTOS we only lowered CRP about 35 to 40 percent. even at the highest dose of canakinumab. Well here across three different doses of ziltivekimab from 7.5 milligrams, to 15 milligrams, to 30 milligrams. We were getting 70, to 80, to 90 percent reductions in CRP. You can see that in the waterfall plots, that almost everybody receiving the middle doses gets very dramatic reductions and the lower left that this is sustained over time.

We also saw, reflecting on what Peter Libby was talking about earlier how the liver is very responsive to IL-6. We saw reductions in fibrinogen, reductions in haptoglobin, reductions in serum amyloid A, an alternative contraxin as well as reductions in sPLA2. So, we're beneficially affecting multiple different inflammatory and coagulation markers here. What you see in a lower middle is quite interesting. We also had statistically significant reductions in Lp(a). This actually make sense because the loci driving IL-6 is involved in Lp(a) production and you're all well aware of novel directions were going with lowering Lp(a). Some of you may be aware that tocilizumab and other IL-6 receptor antagonists, have some adverse lipid effects that was not seen with ziltivekimab which is a IL-6 ligand inhibitor. And you can see that in the lower right-hand corner that we had no effect on the Apo A to Apo B ratio. In other words not having adverse effects on atherogenic lipids.

So all this leads up to a new clinical trial launched about four months ago now called ZEUS. The ziltivekimab cardiovascular outcomes study in which we're taking roughly 6.000 patients who have atherosclerosis disease. This is secondary prevention trial. We're doing this in chronic kidney disease stages three and four who also have an elevated C-reactive protein. So this is a very high risk group with large unmet clinical need and an unusual biologic state, where inflammation is very prevalent. Despite agressive lipid-lowering. And half of those patients are receiving ziltivekimab once monthly a 15 milligrams subcutaneous dose. The other half received placebo. And this trial has two primary endpoints really. The first is the cardiovascular endpoint. The second, my colleague Vlado Perkovic, who is a nephrologist many of you may know, is involved with the secondary endpoint. which is really dealing with the duration of renal dysfunction and progression of kidney disease. So, simultaneously in this trial we're addressing whether or not this novel IL-6 ligand monoclonal antibody can reduce cardiovascular events and perhaps improve outcomes for our patients with kidney disease.

Why kidney disease? Well there are several reasons for that. As this audience is well aware and you can see in the top of this slide as GFR falls below 60, rates of kidney disease obviously go up. But so too do cardiovascular mortality and all cause mortality. In fact the tragedy for our CKD patients is that the most common cause of death in fact is atherosclerotic. At the bottom half you see prevalence of common cardiovascular disorders. In the darkblue among those with normal renal function and in light blue among those with reduced GFR. And you can see again, very high risk in this setting.

What cardiologist may not be aware of however is that IL-6 itself is a very powerful predictor of outcomes. These data come from the CRIC-study, chronic renal insufficiency cohort. And you can see here that IL-6 is the most powerful marker of all these markers we talked about. And you can see on the right hand side that inflammatory score that really takes the CRP, the IL-6, the IL-1 and put it together it's a very powerful predictor in the setting of kidney disease. These data look very, very similar to what we saw many years earlier in the setting of atherosclerotic disease.

So, let me summarize for you. What we're talking about in this symposium is residual inflammatory risk. Where we have patients who already on aggressive lipid-lowering therapy might need residual inflammatory targeting rather perhaps, than residual lipid targeting. So in the cartoon on the left, you see two individuals very common in all of our clinics, who both have hyperlipidemia and elevated CRP. Certainly in my clinic they receive a high-intensity statin and then some of them still have a very high cholesterol level. Good, we know what to do there. Perhaps add ezetimibe, perhaps add bempedoic acid, perhaps add a PCSK9 inhibitor. We have many clinical trials, telling us that works. But there are three patients with residual, inflammatory risk for everyone patient with residual cholesterol risk. That's why we're having this symposium. If you're not measuring inflammation you don't know who they are. But those individuals are more likely to benefit from residual inflammatory reduction. You've heard in the symposium the data for canakinumab. You've heard this symposium the data for colchicine. And in the future we think you'll have data for ziltivekimab.

I'm also very excited. On the right-hand side of the slide you see the first guidelines internationally to go ahead and say, yes, we can now put inflammation inhibition into our guidelines. So I want to thank our European colleagues for being on the front end of this and hope that our North American colleagues also join us in this task. Last for those of you interested in more biology here, a recent review on interleukin-6 signalling and anti-IL-6 therapeutics is cited at the top. And a very nice paper about IL-6 and how you can actually think through the specific cytokine complexes and how they get inhibited on the bottom. It's a very exciting future and I think we're going to have some very interesting ways of moving forward. My prediction is that down the road, we'll be giving combination therapies very aggressive lipid-lowering on top of, very aggressive inflammation inhibition. And it'll be of terrific benefit for our patients. So thank you for joining us in this symposium.

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