All right, thanks so much. I'm really excited to be here live with all of you guys and with my friends. And what we, you know, everything I'm going to say is going to piggyback exactly off of what Dr. Gulati and Dr. Ballantyne just said. This is not going for some reason. These are my disclosures. Okay, so I'm going to talk about a new therapy. So you heard about statins, our mainstay. We love them. You heard about other non-statins that we currently use. I'm going to talk about a new kid on the block, which I'm really excited about, and glycerin. So again, we know LDL is the main lipoprotein we are trying to reduce to reduce atherosclerotic cardiovascular disease. And just like Dr. Gulati showed you around the right, statin therapy has been very effective. So you see a number of statin trials over there, and the mean treatment LDL on the x-axis versus the event rate on the y-axis. The lower you get the LDL, the lower the event rate. But as you also heard, there's really good data for getting the LDL even lower. And you heard about the PCSK9 inhibitors. I just think the PCSK9 story is fascinating. It's a secreted protein that targets the LDL receptor for degradation. And it was found in two different labs across the world. Basically, there was a lab in France. The clinicians had been following patients who had all the world what looked like familial hypercholesterolemia. And as you know, that's an LDL receptor abnormality. They had very high LDLs in the 500 range. They had early coronary events. And so their clinician said, I want to do their genome and figure out exactly what the LDL receptor abnormality is. When they did that, lo and behold, it was stone-cold normal. They did a whole genome sequencing. The only abnormality they found was a gain-of-function mutation in PCSK9. About the same time in Dallas with the Dallas Heart Study, that's an epidemiologic study where they had been following a number of families in the Dallas area over time, measuring their lipids, their blood pressure, everything, and seeing who got events. They'd been following these families who had really low LDL cholesterol in the 30s and the 50s. They were fine. They had no pathology. But they wondered, hmm, what's causing these low LDL levels? So when they looked at their genome, they saw a loss-of-function mutation in PCSK9. Gain-of-function causes high LDL. Loss-of-function causes low LDL. The pharmaceutical industry figured out they could capitalize on that, and that's how we got PCSK9 inhibitors. So this is how they work. I like cartoons. This is a schematic of the hepatocyte. Every cell in your body can make LDL, but the only cells that can get rid of LDL out of the system are hepatocytes. So there's a hepatocyte on the right, the LDL receptor is the blue T, the LDL, the little asteroid, and the PCSK9, the little worm. So you have LDL receptors that go around grabbing LDL out of the systemic circulation, and then through a process called receptor-mediated endocytosis, for which Brian Goldstein got the Nobel Prize. The whole thing is internalized, and this is a very important step. The two vesicles have to split apart, because what you want to do is destroy the LDL and recycle the LDL receptor. Now what happens in the presence of PCSK9 is you get this whole little complex kind of gets stuck together. So you internalize everything, but then it can't split apart. So when you destroy the LDL, you also destroy the LDL receptor, and then you start depleting the cell surface of LDL receptors. Whenever that happens, you can't go around grabbing more LDL out of the systemic circulation, so it starts to build up. The whole idea behind PCSK9 inhibitors is that you're going to intercept the PCSK9. So the LDL and the LDL receptor can interact like normal, and then you get your whole system back to where it should be. As you saw from Dr. Valentine, the PCSK9 inhibitors in clinical trials have shown benefit. So we know this mechanism works. So how can we make it better? Well, some very smart people said, why don't we look at gene silencing technology using siRNA, small interfering RNA? Give you a rudimentary reminder of what this means. So you remember you have your gene. It gets transcribed to mRNA, and then the mRNA gets translated to a protein. All is well if that protein is good, but if that's a disease-causing protein, then that'll cause a disease, and then you have to figure out how to inhibit it. Normally, we do it with medications such as monoclonal antibodies, et cetera. But what if you could work upstream from that? Say you get rid of the mRNA, and that's the idea behind siRNA interference, because this siRNA will glom onto the mRNA. The mRNA becomes dysfunctional. The mRNA gets degraded. Then you never produce that disease-causing protein, so you don't have to worry about having disease or having to inhibit it thereafter. So that's the whole idea behind the inclisirin, and again, we know this mechanism works because we have these PCSK9 monoclonal antibodies, and they've shown benefit. So we know inhibiting PCSK9 can confer benefit. The PCSK9 inhibitors are great, but you also heard from Dr. Gulati that there's been very low uptake. There are probably a number of reasons for that. Cost is clearly one, but they're also inconvenient. You have to do subcutaneous injections every two weeks, usually, or four weeks. So if you could inhibit, do RNA interference, you could get actually durable inhibition of PCSK9 with many fewer injections. In fact, that's why they thought of this. And again, the monoclonal antibodies are fantastic. We know they work. That's good. But there are some problems with it. And so thinking about a new mechanism like RNA interference could show benefit. And again, in the preclinical studies, they showed that inclisirin at a 300 milligram dose delivered subcutaneously every four to six months lowered LDL about 50%, and it stayed low. So this is what it looks like. You give an injection at time zero, and then again at 60 days. This is just their preclinical studies. If you were giving placebo, there was no change in the LDL. If you were giving inclisirin, there was a durable reduction in LDL. That was maintained. So then they studied more and more. And Orion 10 was really kind of their landmark proof of principle study that showed you could get durable LDL lowering with this mechanism, with twice yearly injections. So in Orion 10, they gave an injection at time zero, then another injection at three months. But then after that, it was just every six months. And with that, they got a 56% time average lowering in LDL, stayed low, every six months injections. The other thing that was very nice, it was incredibly clean. When you look at the safety and tolerability, the placebo side effects and the inclisirin side effects, really, really similar. So it looked like a really clean therapy. So one of the things that I know people are concerned, if I have a side effect, is it going to last six months? Well, the good news is there really are very few side effects. So this is the inclisirin, the first cholesterol lowering agent in the siRNA class. Twice yearly injections provides LDL reduction of over 50%. That's durable and sustained. That is just another option for our patients. And think about it. If you see your patients with atherosclerotic cardiovascular disease twice a year, they could come in, see you, get their evaluation, and get their injection. And then you pat them on the back, continue your healthy lifestyle, see you in another year, and wave goodbye. This is our dream, I think, of trying to get more options to our patients for more effective LDL lowering. Thank you.

inclisiran

cholesterol-lowering agent

siRNA class

PCSK9 inhibitor

LDL reduction