Thrilled to have with me Professor Kausik Ray. He's a professor of public health, head of commercial trials, and deputy director of the Clinical Trials Unit at Imperial College London. He's also the president of the European Atherosclerosis Society. We also have with us today Curtis Rambaran, MD, vice president of Clinical Sciences at Silence Therapeutics. Just for us to set the scene, elevated lipoprotein little a, also known as Lp(a), is increasingly recognized as an important inherited genetic risk factor for cardiovascular disease, impacting potentially more than 1 billion people worldwide. In today's webinar, we'll be discussing the history of Lp(a), the unmet need, the importance of testing, and the current state of the drug development landscape. So let's get the discussion started. So, Kash, just starting with you. Let's just start with some background. For those not as familiar with Lp(a), what is Lp(a), and why does it matter? Thanks, Surani. So lipoprotein(a), Lp(a), is an inherited risk factor for heart disease, and when we think about heart disease, we think about lots of different things, but in particular, this is the process that we call atherosclerosis, which is the furring of the blood vessels over time. It increases your risks of heart attacks and strokes. In addition, lipoprotein(a) increases the risk of narrowing of one of the major valves in the heart, the aortic valve, so it puts a strain on the heart. What is lipoprotein(a)? Well, essentially, it's... I said it was an inherited factor. In humans, we produce a protein called Apo(a), and it tags what we call the traditional cholesterol LDL particles, and that's what creates this compound that we called lipoprotein(a). Okay, and, Kausik, you know, said that around 20%-25% of the global population have high Lp(a). Are you expecting all of them to be candidates for treatment? That's an interesting question. So I think that where this number has come from, I think it's important for the audience to understand a little bit about the background. So lipoprotein(a) levels aren't changed by diet and lifestyle. They remain remarkably constant throughout your life. It will go up slightly more in women after the menopause, and that number of 1 billion has come from the observation that people who have levels of lipoprotein(a), if you measure in terms of weight, mass, milligrams per liter, levels above 30 mg/dL, which is equivalent to about 70 nmol, 75 nmol/L, then roughly one in five of the population essentially has a high level. The higher your level, the higher the risk, and in particular, it starts to go up above that level. So the problem that we have is that if you think about people who have a genetic condition, if you find them at the age of 40, 45, you've missed 45 years of this process. So in that scenario, many individuals will have elevated or will have accelerated furring of the blood vessels, and so our traditional methods that we've had so far were to control conventional risk factors. You know, a typical example is like a smoker who refuses to stop smoking, but I can de-risk them a lot by controlling blood cholesterol, and that's how we've managed it. But the person that smokes will have this additional risk factor that I'm not able to modify. So if you think about that subtlety in a bit more detail, then a significant proportion of that 1 billion will be eligible and potentially will require some of the treatments that are under development. Okay. Curtis, do you have anything to add on those two points? No. I think that sounds good. Okay. And, Kausik, just with, you know, LDL-C, or what many call bad cholesterol, is a well-known risk factor for cardiovascular disease. How is Lp(a) different from LDL-C? Thank you, and that's again, an important clarification that's needed. So what we typically call the, the cholesterol-containing particles, when you get a blood sample, a routine lipid panel, what we call LDL cholesterol actually includes lipoprotein(a) within that, and you can only really detect lipoprotein(a) if you measure it separately. So in some people who've got a strong family history of heart disease early in life, where you think or the LDL cholesterol is high, they've actually got this lipoprotein(a) that we are kind of misrepresenting, and we think it's LDL cholesterol. The reason it's different is that lipoprotein(a) has this additional part called Apo(a) that's added to it. Looks like Danish kringles, basically. It's a, it's a repetitive sequence that seems to change the properties of what we would otherwise call an LDL particle. So in blood, you've got LDL cholesterol, you've got lipoprotein(a), and then you've got other particles that are more common in people with obesity and diabetes that we call remnant cholesterol... and lipoprotein(a) seems to behave in a very different way. It seems to be a lot more toxic, if you like, molecule for molecule. So when it gets into the vessel wall, it does much more harm in terms of how aggressively you get furring of your blood vessels. So that's really how it can be distinguished from LDL cholesterol. But more importantly, for LDL cholesterol, we've got a whole group of treatments that have been around, multiple classes of therapies that lower LDL cholesterol, and there's a component from diet and lifestyle. But at the moment, we have nothing that lowers lipoprotein(a) meaningfully. Okay. Thanks, Kausik. And Curtis, since you're leading a drug development program at Silence for high Lp(a), can you share what is considered a high level of Lp(a) and what units it is reported in? Thank you, Surani. I think first I'd like to say I'm very much delighted to be participating in the webinar for what is a common risk factor that's often missed. So we know that Lp levels varies widely between individuals, and if you look at, say, the Danish general population, from where a lot of our epidemiology on Lp levels have been derived, the distribution is highly skewed. It's right shifted with a long tail stretching to high and extremely high levels. Now, when we talk about high Lp levels, it can differ depending on a few factors. One, Kausik mentioned the assay and the units of measurements. We have milligrams per deciliter and nanomoles per liter. Two, the population ancestry also influences what you consider to be high, and then the underlying diseases, of course, the clinical characteristics of patients. So let's talk about the units of measurement. So we have milligrams per deciliter that measures the mass, the Lp mass, and then we have nanomoles per liter that measures the Lp particle numbers. So ideally, Lp should be measured in the molar units because the Lp particles, they do differ in composition and size. It's a lot of different isoforms, and this ensures that, you know, an Lp particle is recognized just once. And I think even with the limitations of the Apo(a) isoforms, we accept that the current masses that reports in nanomoles per liter is probably a very good approximation of the true values. This is emerging and being used more and more. So in terms of high levels, I think I would like the audience to remember two values, and Kausik mentioned one already. So we know that 30 mg/dL, which is roughly said to be about 70 nmol/L, has been considered your historical normal. So any level above 30 mg/dL is considered to be high. The other important number to remember is 50 mg/dL, and that is because, as, as Kausik touched on, 1/5 of the global population has high levels. So that's a large number of people have levels of 50 mg/dL and above, and it's a, it's a number that's fairly easy to remember. So 30 mg/dL, your cutoff from normality to slightly high, 50 mg/dL, 1/5 of the global population. Okay, and now that we know what is considered to be high Lp(a), Curtis, what do we know about the link between high Lp(a), high Lp(a), sorry, and cardiovascular events? Okay, that's an important question that we get, you know, almost every day. So there's a lot of evidence. We have the Mendelian randomization studies, which is really essentially consider lifelong genetic exposure to high or low levels of Lp concentrations, and that's demonstrated, importantly, a causal relationship between high Lp concentrations and events. So atherosclerotic cardiovascular disease, you know, strokes, coronary events, peripheral events. And this relationship is continuous, so there's no threshold effect. So the higher the concentration, the higher the risk. That's an important point to remember. And I mentioned before, 50 mg/dL, or what we consider to be about 125 nmol/L. We know at this level, your increased risk is about 1.4-1.5 times the normal of an event. That's predominantly coronary events or aortic valve stenosis. That's why the 50 mg is important to remember. Above that, when you get to around the 90th percentile, and that's levels around 65 mg/dL and above, you have an approximate two to three-fold increased risk in coronary disease events and aortic valve stenosis. What is also important to remember is your baseline risk is important. So we know that Lp is a risk amplifier. So whatever your baseline risk is, if you have high Lp, and that's to be driven by, say, blood pressure, diabetes, obesity, other lipid parameters, if you have Lp on top of that, we know your risk is amplified. I wanted to mention that, many people may not be aware, but a new risk calculator was introduced under the umbrella of the, European Atherosclerosis Society 2022 consensus statement, considering Lp together with a range of cardiovascular risk factors, and that's available online. I think it's worth, looking at. I don't know if, Kausik, you wanted, as the EAS president, wanted to say anything else about it. Yeah. Thanks, Curtis. So yes, so one of the things is about the calculator, and when we created this, one of the problems that we have is that both for doctors and patients, you're talking about a condition that's asymptomatic, largely, like the furring of the blood vessels. And from the point when you first make a diagnosis of a high Lp(a). The question is, okay, so firstly, who do I measure it in? And what do I do with the results? And there's no one risk factor that we've got that will be absolute in terms of your risk of having a heart attack or so in the future. You've got to take context with traditional risk factors. And so what we're able to do with the calculator is I could use conventional risk factors, and I might say, "Okay, your ten-year risk of cardiovascular disease is only 7%." If I measured the Lp(a), for example, and let's say it's 225 nmol/L, well, your ten-year risk might now go up to 15%, 17%, 18%, for example. So that person, I don't want to manage them in the way that I would want to manage somebody with a ten-year risk of 7.5%. And what that calculator also enables you to do is, currently, obviously, we don't have treatments, but how much of that risk could I offset by better controlling conventional risk factors like blood pressure and LDL cholesterol, for example? And so what we provide in that is an opportunity to see from 17%, can I bring somebody down to 14% or 13% or 12% through controlling blood pressure and lipids? But remember, because Lp is high, it's not going your way down to 2%, 3% or 4%. So it enables you to work out what you can do now and what we also need to do in the future. Great. Great. Thanks, Kash. Let's transition into testing. Curtis, how does someone get tested for their Lp(a) level? Another important question. We have said it's a common risk factor, it's causal, and it's off this. We really need to be testing. Based on the genetic epidemiological evidence, consensus statements from the EAS and some guidelines from the Canadian societies, it is recommended that you should be tested at least once in your lifetime as an adult. It's a simple blood test, as you measure for other similar parameters. Ideally, it's recommended it should be part of your initial lipid. That would probably be the best time. The challenge we have currently is that, in most labs, maybe even all, Lp(a) is not part of your standard lipid profile, so often it has to be asked for separately. In some ways, a simple blood test, it's relatively inexpensive, and ideally, it should be part of your full lipid profile. I think it probably doesn't matter. Even though we have talked about different levels, I think whatever levels or units that are used in your local lab, I think it's important really to get tested. Great. Kash, can you add to that? Who should you measure it in, and who's most at risk? Sure. So I think, an ideal scenario is everybody should have it. So the question then becomes, all right, well, with 8 billion people, I've got to work through those 8 billion. So who do you prioritize? The people that you'd want to prioritize are, if there is a family history, for example, of a high Lp(a), because it's passed on in what we call an autosomal fashion. If it runs in families, you have a high chance of being affected, so it's not gonna change later on. So if you measure it and your parent has it, but you don't, you don't need to recheck it again, 'cause it's not going to shoot up later on. You know, it's not like your waist circumference going up if you've eaten a bit more and you've gained weight or so forth over the years. So that's a good rule-out. If you've got a strong family history of early-onset heart disease, heart attacks and strokes, and we define that as men before the age of 55 and women before the age of 60. If you're somebody who, let's say, had a bypass operation or a stenting procedure, and you've been on the usual gamut of medications, but then... The numbers should obviously protect you going forward for progression of disease, and you've gone through two to three years, and now all of a sudden, the numbers look okay, but why have I got new progressive disease? In that situation, that might unmask somebody who has got high lipoprotein(a), as that driver of that progression, even what we think are traditional risk factors being well controlled. The other thing, the other group, the fourth group, is when we use traditional cholesterol-lowering medications like statins, for example, it's a class that we use, other drugs as well. There's a certain percentage reduction you would expect and an improvement in those numbers in LDL cholesterol. If a large proportion of what we think is LDL cholesterol is really Lp(a), and we think we should get 50% lowering, but we only get 30, again, one possibility is the patient's not taking the medication. But once you've kind of excluded that by talking to the patient, you should measure Lp(a) because you may unmask the bit that you can't change with the medications you think is LDL, and you're getting a suboptimal, you know, result, is really Lp(a) in the background. So those are the four groups. Okay. And, Kash, from a practitioner perspective, can you share any personal experiences of how Lp has played a role as a risk factor in certain patients, and how have you been able to address that with no approved treatments? Yeah. So that's as a practicing clinician, it's probably what I've got over the last five years with increasing awareness of Lp(a), so there's clearly increasing testing. Availability of testing. People go to the Internet, and we've made a lot of resources available, so people now are becoming more aware of it. So when you basically have that, you know, it is what it is. It's there. What do you do about it? So you probably want to have that global assessment. Obviously, having a conversation with the patient, explaining to them what it is, what we can do now, and getting the best measures of what is the amount of damage, and furring, and atherosclerosis that I have in the vessel wall right now. That gives me an idea of how aggressively I need to treat, 'cause even with the same level of Lp(a), I will see a huge difference in patients between the amount of furring in the blood vessels. So the people that have a lot of furring, I've got to be a lot more aggressive, so I have to drive down risk factors much, much lower than you might do in somebody where the number's high, but there's not much furring. So there are other factors that are giving them some protection. So what we typically do is, you look at diet and lifestyle, because that's always a part, even though the numbers may not be changing, you know, that's always foundational. If there are additional risk factors, like somebody smokes, then we want to try and bring them down and stop that eventually, gradually move towards smoking cessation. 1 mmol or 38 mg/dL of LDL lowering reduces risk by about 22%. So you might want 2 mmol -3 mmol of LDL lowering with oral agents, and sometimes we're using PCSK9 injectable therapies, which when you add those to statins, they give you about 75%-80% LDL lowering. They can reduce lipoprotein(a) a little bit. We're not completely sure how much additional benefit one gets from that. That's kind of how we manage that and control things like blood pressure. If somebody has diabetes, you want to control their blood sugar level because all of those things count. They're all additive. Okay, great. So we've heard a lot about the risk of high Lp(a) and how the levels are measured. So let's transition into what is being done to address this unmet need. So in your role at Silence, you're leading the development of an siRNA being studied to treat high Lp(a), but there are multiple therapies in development. Can you give an overview of the different types of drugs in development and how they work? Yeah, sure. So currently we have the oligonucleotides that consist of the siRNAs and ASO, which is the antisense oligonucleotides. siRNA is the short interfering RNA. We have oral molecule, and on the horizon, emerging gene editing. So I'd say first that one of the reasons I joined Silence Therapeutics and got to learn about the very exciting platform of GalNAc conjugated molecules was because of the great promise of oligonucleotides, especially siRNA, its ability to hit previously undruggable targets. It's really entering that exciting realm of true precision-type medicines and targeting, you know, those targets that historically was not amenable to see small molecules or biologics. So the siRNA and the ASO, they are both platforms, are intended to modulate gene expression, so referred to as gene silencing. Both are nucleic acids with an antisense strand that's intended to recognize a target messenger RNA. You know, you really should describe them as precision-type medicines. This is the important thing because they engage and they silence the messenger RNA targets via the precise mechanism of Watson-Crick base pairing, which is very, very important. You have very much precision targeting. Now, coupled with that, both the ASOs and the siRNA in development are conjugated to GalNAc. What is GalNAc? That's an amino sugar molecule, and these attach to the ASGPR receptors, which are located on the hepatocytes. If you conjugate your siRNA molecule with GalNAc, after injection, it goes directly to the ASGPR receptors, and that's a high-affinity, rapidly internalizing receptor. It's a very efficient process that circulates about every 15 minutes, probably lends to the long, partly to the long duration of action. So what you have is precision medicine in terms of targeting via Watson-Crick base pairing, but you also have highly specific delivery. So this is probably, you know, as good as it really gets in terms of a precision-type targeting. So that's the similarities, but there are also important differences between the ASOs and the siRNAs. The ASOs, for example, are single-stranded, usually about 12-22 oligonucleotides, and they are complementary to the target messenger RNA and lead to sequence-specific inhibition of gene expression. And the binding of the ASO to the target messenger RNA, sorry, leads to the induction of the enzyme called RNA, RNase H. Now, one of the challenges with the ASOs has really been stability, and to improve that, they have undergone modifications, some to the phosphate backbone. Now, in part, this has resulted in nonspecific protein binding, so there's sort of a broad tissue distribution. For the ASOs, potentially in some molecules, you are of that risk in terms of binding to a greater degree in terms of tissues. The siRNAs, on the other hand, they are double-stranded RNA molecules, and again, leads, as I mentioned, the sequence-specific messenger RNA degradation of single-stranded targeted RNAs. Now, after injection, the molecule gets into the endosome, the passenger gets broken down, and then it gets out into the cytoplasm, and it goes into what is called the RISC complex, the RNA-induced silencing complex. This is very important. It's been around evolutionarily for thousands of years and essentially is an endogenous machinery designed to degrade messenger RNA. So by designing the molecules with specific sequences complementary to your target, you're basically using this endogenous machinery ready to degrade our messenger RNA. So what we are seeing is because of that, and we know that also the RISC mechanism and the degradation has been a very, very little variability. So it's a very, very strong process that we have seen, and that process gets repeated and is really lends to what we have seen in the clinic for a longer duration of action. So the ASO is single-stranded, the siRNA is double-stranded. Then you have possibly with the ASOs in some molecules that broader tissue distribution, less so for the siRNAs. But that's the word of caution. The technology, the science, continuously improve every day, so we really have to interpret each molecule in its own merit and really dive much deeper into the chemical modifications, but really very exciting times for the oligonucleotides, you know, heralding really precision-type medicine. Then we have oral molecule. We have a specific inhibitor Lp(a) formation that disrupts really the non-covalent, covalent binding between the Apo(a) and the ApoB. As Kausik mentioned, the Lp(a) is a very dynamic molecule. You have a LDL-like particle combined with a very polymorphic glycoprotein, Apo(a), with a disulfide bond. This oral molecule is designed to really break that, disrupt that non-covalent interaction. And we're certainly awaiting more data and more information to really see how that plays out into the clinic. And then so those are the three main ones. On the horizon, of course, we have our gene editing that's emerging as a potential once-in-a-lifetime treatment. It is potentially exciting. When we think of Lp(a), it's probably you could consider to be a very good target for these kinds of modalities because it's increasingly synthesized in the liver, and we know that it is predominantly genetic determined. So it, it could potentially lend itself to this technology. So we certainly await, you know, exciting times. I think it's a great thing to have multiple therapies in development, and it's really, really important as we take our knowledge in the field and certainly that ability to bring our patients to medicines rather quickly. Great. Thanks, Curtis. Kausik, as a practitioner, do you anticipate a need to have multiple drugs to treat high Lp(a)? I think absolutely, because as somebody, not just as a, as a clinician that's been involved in developing cholesterol-lowering therapies and trials or cholesterol modification therapies for the last 20 years, you know you need a lot of shots on goal, and there'll be advantages of different approaches. They've got to go through all the regulatory hurdles and show efficacy and safety and all of those things. But assuming you've got that, we have scenarios of patient preference, availability, and, and so, you know, our, our patients are very different from person to person, and there will be different considerations. And, you know, we've, we're really lucky, as Curtis said, we've got this wealth of, of potential therapies on the horizon. We're all itching to get them to our patients. But some of them, you not all of them may make it through, some of them may not, and there may be different things that you know that people will decide that this is more effective and this is less or so forth. So that's what's happened over the years in other areas for LDL lowering, for example. So I think it's, do my patients need it? Absolutely. And do we want, at this stage, to be really broad? Absolutely. Because we don't know what will be the advantages of one approach over another. So, you know, one bit is the amount, but then you've got other things as well. Patient preference, for example, is a big part of that. Curtis, siRNAs seem similar to the ASO technology. Are you able to explain how they're different? Yes. I think I touched on it, before. So structurally, they're different. So if you have the siRNAs are double-stranded, molecules, possibly tend to be more stable. ASOs are single-stranded. Because of some of the chemical modifications to make the ASOs, more stable, it has often led to a broader tissue distribution. So you potentially have that risk of binding to additional tissues, and we can see from a lot of the siRNAs in development, this very good safety profile and very, very specific, and I think that's what's attractive about it. I can say in my experience in drug development, this is the first time I've seen a platform that's precise, that's got a long duration of action, and very targeted, all in one. You know, so often you may get a molecule, and it's very powerful, but it is toxic, or it's probably not hanging around in the systemic circulation very long. We have seen with the siRNAs in development that after you inject them, about 36-48 hours, the drug is virtually gone from the systemic circulation, so you can't measure it. That's probably a good thing because it's not hanging around to bind to other tissues, and it's probably in part one of the reasons that the siRNAs to date has been very, very safe. So I said broadly, the nucleic acids has, have been pretty safe. The exciting thing about it is really that precision targeting. So like for the siRNAs, you know, all the action is within the hepatocytes, and we are not seeing it off-target effects. So we certainly need to generate more data, longer-term data. But I think to, to date, it's been very, very promising, and, yeah, I can tell you that there's a lot of excitement, there's a lot of, enthusiasm into the field. I have, you know, investigators calling us every day asking whether you're continuing studies. And I think, you know, for my colleagues in development and in other areas, I think it's been very much the same. Mm-hmm. Okay, and you mentioned a peptide in development. How do you think this will be used versus injectables? Right. So I think as Kausik said, not only do the practitioners like options, but I think patients, we all like choices. So I think, oral—the advantage for, I guess, would be oral, ease of administration, ease of use. But, but we know even from the statins, that there's a high degree of non-compliance. You know, I can tell you from running blood pressure clinics for, for many years, patients do not like taking tablets, particularly ones that may give them, you know, some transient, side effects. So that could be something we need to look at. We certainly need more data. It's early development days. The peptides, of course, will be, injections, but less frequently, possibly, you know, a couple times, three or four times a year. So I think each modality will have pros and cons. I think it'll be great to have options because, you know, we all like different options that may play to the needs of different patients. And I think, you know, it's... we have a lot of work to do. But it's an exciting time, and I think every drug development program, it's only going to be certainly helping the field and moving us forward, not only from the science, but I think clinically from the patient perspective. And as we have seen from, you know, for the last year and a half, certainly grown as well of enthusiasm and support, particularly for Lp around testing, around awareness. So there's a lot of very good work being done by lots of different groups. So it's, I think it's very, very exciting and gratifying time. Okay, and Kausik, to round out the discussion on the drugs in development, where does gene therapy and gene editing fit in here? Yeah, no, I think that's certainly I mean, I'm at the AHA at the moment, and that's obviously very topical, and there are a number of people looking at that. What's the real advantage of gene editing for Lp(a)? Well, if you're, for example, looking at LDL cholesterol, let's imagine how we lower it by 80% or 90%. Because of the number of different pathways that regulate LDL cholesterol, that's actually impossible with gene editing, 'cause there's no single thing that will do that by 80% or 90%. There's always another pathway, and that's why we use combination therapies. So what we've seen, for example, with the Lp(a) RNA-based therapies, you've got a gene, you've got a message, and then you've got the protein. You can reduce that by over 90%. So, virtually, there's one source coming from the liver, and there is one message. So if you know the gene that is making the message, and you edit that out, and when your cells replicate, what they do is they pass on that edited gene, so your daughter cells don't continue to make that message. And so in theory, that could be a once-in-a-lifetime approach. Now, the only thing that, with any new therapeutic option, is, all right, that's one side, then there are the unknowns. Then, you know, so what don't we know at the moment? Well, we don't know about long-term what the safety profile would be of those approaches. We don't know, for example, what would happen if there was off-target editing at the level of the genome. So it's slightly different with a small molecule, where we take something daily, and it's also slightly different with an RNA-based therapy, where even though there's a longer duration of action, it's twice a year or three times a year, or four times a year, or, you know, however often. So those are the unknowns with that approach. But the pros are that if that safety profile and, and all of that is, is, forthcoming and reassuring, that could ultimately be a once-in-a-lifetime approach. Great. Thanks, Kausik. So before we move on to questions, do each of you have any final thoughts on what we've been discussing? I think the key thing here is raising awareness for how common this is. I mean, this is more common than- if you think about, you know, one in five individuals have this inherited, which means it's there from birth. It's there from the first decade of life, first year of life. If you don't look, you don't find. This is more common, for example, than the global prevalence of diabetes, you know, seven in 100.... less than one in 10. It's less frequent than familial hypercholesterolemia, a genetic condition that raises LDL cholesterol levels from birth, one in 311. So the most important thing that I think that we have to do, in addition to developing those treatments, is raise awareness and understanding that the tests are available routinely around the world, and that people do get tested, then, you know, not just have it available. And then we work towards how we incorporate this as part of our clinical decision-making and try to personalize that. And hopefully, by the time we do that, some of these therapies coming through will essentially helped—Having helped identify the people that may benefit, we can then offer these to those patients to help reduce their long-term risk. Okay, great. Curtis, anything to add? Yeah, I mean, I, I echo those sentiments. I'll also, also say another important thing with testing, it's, it's, it's also an important way where we find patients. We know it's genetic, so it runs in families. So once we test someone at very high levels, it's a very nice way that we can work backwards to find other potential relatives or siblings that may have high levels, and that's proven to be pretty effective when you hear anecdotal reports. Also, I just wanted to emphasize from a therapeutic perspective, I mentioned the word precision medicines. When I started my cardiology fellowship research, many years ago, at that time, we were talking about precision-type medicines. I think we were just skimming the surface. I think we are now getting into the realm of true precision-type medicines. I think it's very exciting. I think, patients and, people out there should, really, you know, keep their eyes and ears open because I think, we have good therapies potentially coming in the near future. Great. Well, thank you both for this really insightful discussion. I do see some really good questions coming in. So just a reminder to the audience, if you haven't had a chance yet, remember, you can hit the Q&A button on the bottom of your screen to submit a question, and we'll get started with the first few. So the first one I have here is: It's a simple test, but when the results come back high risk, there is nothing you can really do to address them, so some specialists are not measuring it yet. If it's a statement. I think that's a misconception that there's nothing that we can do about it. So you can take somebody with diabetes, you can take a smoker, and you don't suddenly, overnight, change them from having diabetes to no diabetes or from being a smoker to a non-smoker. And even if those risk factors are there, we know that we can reduce the diseases called atherosclerosis, furring of your blood vessels, and that's what you're targeting. So our conventional risk factors go some way to offsetting that risk. It might be we can't get rid of all of that risk, and we can't. We know that, but we can get rid of a substantial portion of it. So... And how much of those you need to do depends upon how high your Lp(a) is and also how late you've identified those people. You start early, you need a little bit less. It's a bit like interest in a bank account. If you start saving for your pension early, it accumulates. You start late, you're gonna have to put more away. That's the basic principle of our consensus statement, and I'd encourage everybody to have a look at that. It's open access in the European Heart Journal. Thanks, Kash. Nice analogy there. Next question is, could you please speak to off-target effects of SI? Are these a big concern with siRNA therapeutics, and if so, how are they mitigated? So I think to date, we have not seen from a safety perspective, they have been pretty clean. As I touched on before, highly specific in terms of the targeting is very precise and specific delivery to the hepatocyte. So I guess the two organs that you would think may be important would be the liver, because that's where all of the pharmacodynamic effect occurs, and also the kidneys, because that's where you get excretion of the drugs. And if you look across the siRNAs that are approved, albeit the first four were niche indications, and then the ones in later, like inclisiran, in later development, with more extensive numbers of patients, we to date, we have not seen any, any significant, safety signals related to the liver or to the kidneys, anything that's needed, any dose adjustment or any modification. So I think it's very, very promising to date. And, and that's why I think it's, we're in a different realm now. We're in a different realm of being able to, to target very, very precisely. The other thing we are seeing is that, you know, in a trial study, we have been using the siRNAs experimentally on top, I should say, investigationally on top of standard of care, because we are not really seeing any significant drug-drug interactions, particularly with transporter disorders, as you would see, for example, with small molecules and other modalities. So mechanistically and clinically to date, I think that it's proven to be a very, very effective and safe delivery mechanism based on the data available. Okay, great. The next question is: If a treatment for Lp(a) will be approved in the future, do you think it will replace the statins, or will it be an add-on? So I think that, the trials that are being done at the moment are in people with established cardiovascular disease. If you've got established cardiovascular disease, you will always have blood pressure lowering and platelets, statins in the background. What you're picking up here are those additional things that, or that additional factor that will drive up excess risk beyond that level of control. So the initial approval will be as an add-on, and there'll be some people that can't tolerate statins, so there are other alternatives that we use in that scenario. In the future, what we might do is if we look at the drug development of statins, started very high levels of LDL in the presence of heart disease, a history of heart attacks, then gradually we dropped the threshold for those LDL levels, and we found that even going to lower levels, people still benefited. Then we went to primary prevention, where people didn't yet have heart disease, but at high risk, and that's when we will move to Lp primary prevention. And that will be interesting because we won't have the answers. It will depend upon the design of the trials, and we might, that actually for people, if you start early enough with no other risk factors, where Lp is the only risk factor, then you will just think about a single treatment that offsets that single inherited risk factor. But there's a long way to go before that, because it's a sequential process. Thanks, Kausik. Next question is: It was interesting to hear the LDL-C conversation. If LDL-C sits on zero, yet high Lp is still present, what could the consequences be? There appears to be conflation of LDL with Lp in the general discussions out there. You can still have elevated Lp whilst having effectively no LDL. I'm an example of this, currently 0.0. So, I think the thing about those very low LDL levels is that when you use a calculation called Friedewald, at such a low level, it's actually never zero. There is something that's measured. So you can use what we call non-HDL, which measures all of the other particles as well, or count them with something called ApoB. So ApoB will likely be low. We're absolutely right, that when you have so-called LDLs of zero, the LDL portion will be modest, and whatever is left will likely be in the Lp particle. So at the moment, what we have is there are two things. It's not just the risk factor. There are some people, their natural history will be, I've driven down LDL cholesterol level. There isn't much more left that I have, but I have another particle that I can't change at the moment, and there'll be some people that will be more vulnerable to retention of that particle in the blood vessel wall, and also to progression of that. So there will be some people, even when your traditional risk factors are really well controlled, and you think they're well controlled, but their natural history, because they've got this additional variable, is still for further disease progression. They are the ones we absolutely need these treatments for. Thanks, Kash. Next question is: Could you explain, please, how Lp metabolism works? How is it naturally removed from the blood? Is the LDL receptor involved? We don't really know how it is removed, and that's why. So when you look at blood levels of different factors, typically, you either work on improving clearance or you reduce production. So for example, LDL cholesterol, all pathways lead to having more LDL receptors functioning. So statins, ezetimibe, bempedoic acid, those classes, will make more LDL receptors, and the injectable PCSK9 therapies keep them alive longer. There's because the Lp particle is a bit like the LDL particle, except that these kringle repeats on them, they contain a protein on the surface called ApoB, which is able to bind to the LDL receptor. What we have seen is that in some scenarios where you've driven LDL down, particularly where you've got a lot of LDL receptors now available, you don't have the natural competition for removal of a traditional LDL particle, which is the preferred substrate for the LDL receptor and the Lp particle. If you like, think about that as an LDL plus. So now, a less efficient process of removal may actually, in the presence of enough LDL receptors, help to remove the so-called Lp particles. But we don't really know how, how they're removed, and maybe that's why your blood levels are constant, because you've got this constant turnover of Apo sticking onto the LDL particles, and, you know, you've basically got no way to remove it. So you work on reducing production. Great. Thanks, Kausik. Next question is: Other than PCSK9 modulators, what other pharmacological targets may hold promise in terms of Lp lowering, other than direct modulators of gene mRNA expression? I think at the moment, I mean, Curtis, it would be good to get your thoughts on this. I mean, at the moment, what we know with PCSK9-directed therapies, doesn't matter what class you use, monoclonals or siRNA, you get roughly 20-25%, maybe even up to 30% Lp lowering. You've got a much bigger LDL lowering, 50%. You know, that's the sort of amount of reduction in Lp that we had seen previously with a drug called niacin, which generally is not available or used around the world. And the only alternative way that you had of removing lipoprotein(a) was essentially to connect people up to machines called apheresis, where you clean the blood every two weeks to remove what you couldn't remove in any other ways. There are some therapies that have emerged which give you some additional reduction in lipoprotein(a). There are CETP inhibitors in development, where there is some reduction in lipoprotein(a) levels, but nowhere near the order of magnitude that we are seeing with the siRNAs, the ASOs, for example. Yeah. And, and I think the other good thing is that because, you know, the awareness and the testing for Lp and the development has very much come into the spotlight, a lot of people are now actually working backwards and probably looking at previous trials, looking at previous therapies, looking to see in their databases and so on, what, what's happened to Lp over time, it may have been missed. So I think, you know, we have to be just keep a watch. Other things may emerge, but as Kausik said, I think, you know, what the level of reduction we are seeing with the ones in development far seem to exceed anything else, that's currently available or approved. Okay. Next one is: What are some key barriers to identifying the correct patients for an Lp targeted therapy? And any trends in the community setting, campaigns that may be moving us towards widespread identification of the right patients for these targeted therapies. I think there's a lot more now. So one, one of the things I think that I've seen during my time in medicine is the need for patient advocate citizens, 'cause they're the ones that we're doing all of this for. When they have a voice, and when we engage with them, bring them to the table as part of those discussions, then when we make cases for screening and availability, care pathways, way more powerful than me as a scientist or Curtis, as somebody in, in development saying that, because they're the ones we should be doing all of this for. So there is definitely a momentum all around the world. Many of us that are leaders in academic societies, we spend a lot of time in different regions of the world trying to help advocacy in those regions. There's, of course, the other need among clinicians and physicians to become aware of Lp(a), what it is, how it's measured, what does it mean, and what do I do about it? So that's certainly happening, and the global community is actually fairly, not necessarily joined up, but they're all working towards that in every region of the world. You're on mute. Sorry about that. The next question is: How can we incentivize healthcare providers to test more, although there is no treatment available yet? Yeah, that's always a good question, but I think what we have to say is, well, so with healthcare providers, you have to give them the cost of not doing it. So if you measure, you can at least do something about it in terms of offsetting. So, you know, by finding what, what is the purpose of screening? Well, the screening is to think about risk in the future for that individual, but because it's genetic, if they have it, then you've got a first-degree relative with a high chance of having it. And if that person is then younger than your index case, the person you found it in the first place, you've got more chance of course-correcting through some of the interventions that we've got now. There's a whole problem with, for example, identifying something later on, is there's just more underlying disease. If you find things late, you have to do a lot more. You have to do a lot more. That's expensive, and that's the best argument that you can make for providers: a lot of the burden of disease that you have is explained by something that you're not looking for. By starting to shift the dial and find those individuals, and then move the healthcare system to finding them earlier, you are going to save a lot of potential healthcare costs and morbidity and improve quality of life by doing that earlier. That would be the argument I tend to use when I have those conversations. Okay. Thank you for that. And you may have touched upon this before, but I'll just read it anyway. What are your thoughts on using PCSK9s in high-risk patients, as they have demonstrated 20%-30% reduction in Lp(a)? Is this sufficient to move the needle, high-risk patients? So the answer is, we don't know what that additional value. We can model, and we've done that. We, others have published, and it looks fairly similar, that there probably is some additional benefit from whatever you can achieve. There'll be... Most of the benefit will probably be from the LDL lowering, but there will be some additional component. And if your baseline Lp is high, then those are the ones that are more likely, you know, to benefit, because 20% reductions at a very high level is a bigger absolute lowering of Lp... So we do do that for some patients. And the problem is that when you do that, I still feel slightly helpless because that's the best I can do now. By doing that, I'm clearly giving those patients some more benefit. We've seen that in the trial, but there's this sort of gut feeling and sinking feeling like, well, they're not a little bit better, and I feel a bit better, but what about in a year down the line, two years down the line, five years down the line? Usually, what the conversation you're having is, let's do this for now because it's better than not adding it in. But in the future, these treatments that are now being tested, if they show what we hope they show, and they have promised based on the biology, then actually we'll really be much more confident that we're treating all the harm that goes with this condition. Great. Thanks, Kausik. This one is also for you. Per Kausik's comment, when do you see Lp(a) therapeutics moving to primary prevention beyond what the original approvals will be targeting? As a practitioner, would you consider using it in a prevention setting upon initial approval for a patient with high risk and high CAC scores, but no history of cardiac events yet? Yeah. So I think there is always, so the label, the indication, will be for the people you study, and all the regulatory environments will only give you that. You can on a clinical basis, look at essentially what we call off-label, which will be primary prevention, if somebody's using that. Now, the issue with that is that your health system and guidelines won't recommend that. So you're in a difficult situation of in your public health systems, that really won't be an option as far as routine clinical practice, not without those, those trials. But on an individual case-by-case basis, with shared decision-making, it would be off-label. One might consider it, but you can't answer that, because right now, because it would be on a case-by-case basis, and it might be, you know, somebody with, as you say, no cardiovascular disease, but clearly already has some evidence of some atherosclerosis, and you've got sky-high levels. And that would be off-label, but one could have a conversation. Great. Thanks, Kausik. And thanks to the audience. This has been a really engaged discussion with all the questions coming in. But that's all the, that's all the time we have for today. So thanks, everyone, for joining us for the important discussion. And thanks to Kausik and Curtis for sharing your valuable time and expertise. And thanks also to Silence Therapeutics for sponsoring this webinar. We hope that everyone in the audience has better understanding of Lp(a), its immense impact on the global population, and the importance of a vast drug development landscape to address this risk factor. If you would like to rewatch the webinar or share it with colleagues, a link for on-demand viewing will be sent tomorrow. But for now, I'm Surani Fernando. On behalf of Endpoints News, thanks for joining us, and we hope to see you at a future Endpoints webinar.