Dr. Tom Ganz from the David Geffen School of Medicine at UCLA, who will discuss the key role of hepcidin in iron regulation and its therapeutic potential. From our London site, we have our Head of R&D and Chief Medical Officer, Dr. Giles Campion, who will provide an update on our SLN124 hepcidin regulation program. Additionally, we are excited to have Dr. Henry Ginsberg, Irving Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons. Dr. Ginsberg will share an overview of the medical need in cardiovascular disease. Following his presentation, Giles will give an update on our SLN360 program for cardiovascular disease due to high lipoprotein(a). Mark will provide some concluding remarks and moderate a Q&A session at the end of the presentation. If you would like to submit a question, you can do so at any time during the meeting by typing your questions in the Ask a Question field on the right side of your screen. For everyone here today in person, please scan the QR code on the table, and you'll be directed to the webcast where you can log in and submit your questions through that Q&A field. The meeting is scheduled to conclude around 11:30 A.M. Eastern Time. There will be a webcast replay available on the IR section of Silence's website following the event. Finally, as a reminder, we will be making forward-looking statements during this event. We encourage you to read our most recent SEC filings for a more complete discussion of our risk factors. With that, I'm pleased to introduce Mark. Thank you very much, Gem. Welcome everybody. It's so good to see the room here in New York full. We just didn't know what to expect with a semi-virtual meeting. Also delighted that so many can join us today virtually around the world. A great deal has happened at Silence Therapeutics over the last two years since the last R&D Day. We're really delighted to be able to share that with you during the course of today's meeting. At Silence Therapeutics, we have a very clear vision and strategy. What we're looking to do is to help patients around the world with our precision engineered genetic medicines. For that, we've developed over 20 years now what we call the GOLD platform. This is all about silencing or knocking down the expression of disease-causing genes in the liver. Our strategy is to maximize this GOLD platform that we've developed, we have a huge amount of know-how around this, through what we call the hybrid model, which is, on the one hand, building our own proprietary pipeline, and on the other hand, serving the needs of partners. That hybrid strategy is very deliberate. I think what's very attractive about this particular modality is that firstly, we can imagine that with simply two to four injections a year, you can help control somebody's chronic genetic condition. Secondly, as experienced not just by us, but our peers, Alnylam, Arrowhead, Dicerna, we've seen that this modality has a good safety profile. That you can envisage treating not just rare genetic conditions, but potentially very large indications using this modality. You'll see from our own pipeline an example of each. As Gem said, delighted to welcome the presenters today. To remind you, Giles has headed cardiovascular for Novartis and SmithKline Beecham and has also worked extensively with oligonucleotides. Marie has also an extensive background in oligonucleotides, most recently before joining Silence a number of years ago at Roche. I am, of course, delighted that we're welcoming some global thought leaders to our meeting today, Professor Tom Ganz and Professor Henry Ginsberg. Professor Tom Ganz is a Distinguished Professor of Medicine and Pathology at UCLA. He discovered and characterized hepcidin and erythroferrone, the principal hormones of iron homeostasis. He received the Marcel Simon Award of the International Bioiron Society in 2005 for the discovery of hepcidin and the American Society of Hematology E. Donnall Thomas Award in 2014 for groundbreaking research in iron homeostasis, including the discovery of the iron regulatory hormone hepcidin and investigation of its roles in iron metabolism. Also delighted to have Henry Ginsberg with us. Henry is the Irving Institute Professor of Medicine at Columbia University Irving Medical Center, New York. He is a world-renowned lipid expert and researcher who has also been involved in many major clinical trials, including ACCORD Lipid, where he was the lead investigator. In 2017, Dr. Ginsberg received an Outstanding Investigator Award from the NIH, providing $4 million in support over seven years. Dr. Ginsberg currently sees patients with severe lipid disorders in parallel with directing the Irving Institute's pre-doctoral and post-doctoral training programs in arteriosclerosis. Thank you for joining us today. As I mentioned at the opening, we've made a lot of progress since 2019. I'm not going to go through all of it, but I'm going to highlight three things. Firstly, we are now a clinical stage company. We had our 1st data from our clinical program in May earlier this year, the SLN124 healthy volunteer study. It exceeded our expectations. Giles will say more about that later on. Secondly, on the partnering side of our hybrid model, we've really made a lot of progress. We've signed up deals with AstraZeneca, with Mallinckrodt, and most recently, last Friday, with Hansoh Pharma, a major pharma company in China. We can say more about that later. That part of the hybrid model is working very well. Finally, we made a deliberate move to become a more global company, listing on the Nasdaq, after nearly 20 years or so in Europe, becoming listed on the Nasdaq, as I say, a year ago. Now, as we announced last Friday, actually choosing it to become our primary listing as we delist from AIM. Not only have we grown our infrastructure here, but we've also sort of aligned ourselves with our peers. Today, we set out a press release earlier today, and we're also sharing this new news with you. Firstly, of course, just to confirm for SLN124, we are on track for the single ascending dose data to come out in thalassemia and MDS in Q3 of next year. The focus of today is really on SLN124's ability to modulate hepcidin expression endogenously. We think that there is tremendous potential here for SLN124 to become an important hematology franchise. For SLN360, we will, with Professor Ginsberg, look at the unmet need in cardiology associated with elevated lipoprotein(a). With regard to our single ascending dose study, the phase I study, we are on track to share with you data in Q1 of next year. Giles will be sharing with you some new news that comes from our independent safety review committee that also helps us think about how this program is going to evolve. I'm very excited also to announce today the third program in our pipeline going into the clinic. SLN501, which is partnered with Mallinckrodt and is a complement C3 lowering agent, will initiate a phase I study in the 1st half of next year. Finally, we're going to reaffirm that we're on track to deliver two-three INDs per year by 2023. The GOLD platform stands for GalNAc Oligonucleotide Discovery platform. As I said earlier, this is about knocking down or silencing the expression of disease-causing proteins in the liver. Marie is going to spend some time really sharing with you the knowhow that we've been building in this domain for 20 years and how we're tracking to deliver on our goal. I think there's an enormous potential with the GOLD platform because if you look out there's 14,000 or so genes expressed in the liver. If you add up the number of programs that Alnylam, Arrowhead, Dicerna, and ourselves have in this field, it's less than 1%. We believe that there are many potential, really valuable and important medical targets for us to go with or go for in the future. We also believe that it's a worthwhile endeavor to invest in discovery. Of course, discovery is at the less expensive end of what we do. We think that the dollars we're investing in this domain is a worthwhile endeavor because if you look at the track record of GalNAc conjugated RNAi molecules in the clinic, when you have a validated target, it's substantially higher than the industry average. Alnylam quoted a 69% chance of getting a positive outcome at phase III, going into phase I, if you have a validated target. I think it's a really great modality that we're working with. To just spend one more moment on the partnered side of the equation. As you know, we have AstraZeneca with up to 10 targets, Mallinckrodt with up to three targets. They've optioned all three of them, Hansoh with three targets. What was great about that agreement is that two of those targets are essentially proprietary pipeline programs because we have global rights to those programs except for China. One of those targets, the rights are wholly Hansoh's. All in all, we're looking at about 16 programs here under the partnership umbrella with the potential for $7.5 billion in milestone payments plus royalties. Let me end this section by just showing you the current pipeline. It's rapidly growing. As you can see, it's also nicely balanced between proprietary and partnered programs. With that, I'm delighted to hand over to Marie in Berlin and hope that she can hear me well and the communication's working well. Marie? Yes. Thank you, Mark, for that. I want to move over to my 1st slide here and nothing is happening. There we go. I am going to spend 15 minutes just explaining to you what it is we are doing in our GOLD platform and how the 20 years of experience that this company has in siRNA has led up to this stage. This will also lead into an explanation of how we think this combined knowledge and capacity we have now can lead an increased output and why we are confident about to do this many INDs per year by 2023. I'm just going to start with a very simple biology 101 explanation what it is we are doing with these molecules. The RNAi approach or RNA interference, how does it work? It really is biology 101. DNA codes for RNA, codes for protein. If the proteins are disease-causing because we have too much of them, or we have a misfolded or just disease-causing mutation in a protein, of course, you can address that by removing the proteins. We think it's rather clever to instead reduce the amount of the mRNA that is coding for the protein. That's what we are doing with our molecules, and by doing so, we are harnessing a natural cellular mechanism. It's transient, so we don't have permanent effects on the cells, but it is long-lasting. As far as we and other people in the industry know, this is remarkably safe. Mark has mentioned that I have a quite long experience of oligotherapeutic development. I want to stress for those of you who are well familiar with the fact that there are several different kinds of oligonucleotide therapeutics, that not oligotherapeutics are created equal. I have 10 years of experience with early stage research and drug discovery with antisense oligonucleotides, and then I moved over to siRNAs. I think this Venn diagram can help to explain why I did that transfer. If we are looking at starting with the similarities between these two technologies, in both cases, the pharmacological effect is through a naturally occurring mechanism. We are using enzyme systems already present in the cells. We have a long or very long duration of action of the single injection, and it tends to be longer for siRNAs than for ASOs. We do have a risk for sequence dependent off-targets, but it can be mitigated by picking the right sequences already at the in silico stage. It can be further mitigated by chemical modification and molecular design. Now I'm going to go a little bit out in chemistry terminology here, because now we are getting over to the differences between these techs. ASOs have something called a phosphorothioate backbone. The only thing you need to know is that that makes them sticky. It's also something that needs to be there, otherwise, they are going to get degraded in the body. That PS backbone leads to a broad and non-specific distribution. We don't see that for the siRNAs. It also has been correlated in the clinic with safety risks such as nephrotoxicity and thrombocytopenia. No such effects has been documented for siRNAs. Finally, it seems as if these two technologies are responding differently to certain chemical modification. I'm using one example here, 2'-fluoro, which in ASOs can lead to hepatotoxicity. When we put it in an siRNA, no such toxicity has been noted. There are similarities, but not all oligotherapeutics are created equal, and I would like to say that the siRNAs have a tendency to be longer lasting and safer than the ASOs. When we design our molecules, we also add this thing called GalNAc. It's a sugar. It stands for N-acetylgalactosamine, and what it does is that it adds precision delivery to liver cells. This is a cartoon showing what's going on here. The only thing you need to bring with you when you recollect this slide is that the GalNAcs, these sugars, they are attached to the siRNA. As a cluster t hey bind with very high affinity to receptors that we have a lot of on the liver cells, and it is really specific for the liver cells. It's taken up into the cell, and then the siRNA is released, and the part of the siRNA, called the antisense strand, enters RISC, the RNA-induced silencing complex, and there it meets with a very high level of specificity, the target mRNA coding for a disease-causing protein. This is catalytic, so this in part explains why we have a long duration of action, because one strand, one molecule, can be active for a long time, targeting one after another molecule of mRNA. We've been at this for quite a while. The route to GOLD started with a company called Atugen, and it was a spin-off of Ribozyme Pharmaceuticals. Our first core patents in the siRNA industry were really remarkably early, already 2002. This company had a reverse takeover, was AIM-listed, and the name was changed to Silence Therapeutics. This company developed a really solid, I would say, world-leading knowledge about LNP, or lipid nanoparticle formulation, and did take LNP siRNA programs, or one program, into the clinic. However, five years ago, there was a strategic decision to move away from the LNPs. They work well, but not well enough. Since then, the company has been focusing on the GalNAcs, and that has now resulted in 10 technology patent families, and also resulted in the platform that has taken two programs to the clinic and a rapidly growing proprietary and partner pipeline. What is it? What are we talking about here? We have siRNA. That's two strands of two chains, if you want, of synthetic RNA that are wound around each other. There is a linker, and then there is the ligand. These molecules are designed to bind very specifically to the target gene only. We have a basic design, and it's something we refer to as the blunt and the 19-mers. On top of that, we are applying a toolbox of chemical modifications that are working optimally in a sequence-dependent manner. We are applying that toolbox at the lead optimization stage. This toolbox is considering all elements of the siRNA and the ligand. We are looking at modifications of the sugars. We are looking at stabilizing modifications on the internucleoside linkages. That's the linkages that we have between each nucleobase. We are looking at stabilizing modifications at 1 or more of the ends. I mentioned that was something that you had to have in the ASOs. We need them, but we need fewer of them. We are also having some modifications that increases how quickly we get activity and how long we get activity. We also have a small portfolio of linker chemistry that we can apply on the GalNAcs. When we apply these elements of the toolbox, we also reduce the overall content of unnatural sugar modification, and we are working on something that is called reducing the number of undefined stereogenic centers in the molecule. That is really quite advanced chemistry, but in short, that helps us both with analytics and has had some unexpected positive effects also on activity and duration of action in some of the molecules. One thing that we are really good at, and I would say is the core of the GOLD platform, is that we are good at picking the right target, the right sequence, and the right molecule. How do we do this? Well, with the knowledge we have about choosing a good target that is well-suited for siRNA interference, we have built a pipeline that balance risk. That's the starting point. We balance new targets with solid genetic evidence, where we are aiming to be first in class with well-validated targets where we can be a fast follower and where we think our chemistry and our knowledge gives us a chance to have best-in-class potential. To do this, and I will tell you more about exactly how we do this, we leverage big data and machine learning to accelerate target selection. As Mark just said, once we are in the clinic, the RNAi programs have a much higher success rate, particularly than the GalNAc siRNAs, compared to pharma industry average. The strategy is that we really focus on genetic validation because that gives us a clear line of sight from target to disease. We combine targets that we discover through the experience of our team members or that is mentioned to us in some other context that we look at, think it's going to be a good target, and then non-biased machine learning methods to find novel human genetics-derived targets. We also confirm that the disease-associated transcript is expressed in liver because that's the cell type we can get into today. We do a review. This is based on our 20 years of experience, where we prioritize targets with high disease burden and unmet need. We also evaluate the targets from a drug discovery perspective. Is it conserved across species? Are there good animal models? Is there a good understanding of the mechanism? Also, of course, we want to know if humans with low or no levels of the transcript that we want to downregulate are healthy. We have built now internally and continue to build a dedicated translational genomics team that is working on this, and that is what is going to supply us with, have already actually, to some extent, supplied us with new targets through these unbiased machine learning methods. The team is integrated across the R&D organization, is integrated in the matrix, and we are using big data, both from external sources but also from our internal sets of data where we have looked at structure function relationships for siRNAs for the last 20 years. We are using machine learning methods and the people in this team to pick the right targets and also to pick the right molecules. This is a dedicated effort that we really believe is bringing value to the company. That feeds into the drug discovery funnel. Really quick here, we start out with 2,000 - 8,000 sequences. The difference in size here depends on the size of the target transcript. We are using our proprietary in silico siRNA predictions to pick molecules which have a chance to be potent, developable, and safe. We boil that down to 150 to 200 sequences, synthesize them. We test them in vitro. We pick the best ones. We put a GalNAc on them. We put them in rodents. With a smaller set of molecules, three - five of the top candidates, we apply the toolbox lead optimization stage, and pick the really best molecules that gives us good activity, that are safe, and has got a long duration of action. This process typically takes about 12 months. After identifying a very small number of potential leads, we test them in disease models, and we test them in non-human primates. This is an example of what the lead optimization actually looks like. I thought it could be interesting to show what difference this toolbox at that stage can actually make. This is data from mice. We have one single sequence, and we are comparing three different chemical modification patterns for one single sequence. It's version 1, 2, and 3. To the left, you are seeing the target transcript, the mRNA levels in liver, in animals on day 14. You could see that there is some difference. These three sequences were all tested with 5 mg per kg, in how much we down-regulate this target transcript on day 14. The really interesting data came out when we also followed the biomarker of effect here, the serum protein, for a longer period of time, up to 42 days, in these animals. You could see here, this is quite a busy slide, that one of these versions of the molecules started to lose activity and go back to baseline for both those levels at the later time point, whereas the other two kept having a really good effect. This, I think, is an interesting example of what we discover when we do apply the toolbox at the lead optimization stage. The key takeaways here is that we think GalNAc conjugated siRNAs have a high clinical probability of success due to genetic validation of target genes, precision, that's the GalNAc delivery to liver cells, and also precision, that's the molecular design, that's the in silico stage, that's the big data, precision targeting of the disease-causing mRNA. We are confident that our GOLD platform can deliver two - three INDs per year by 2023 because of the translational genomics effort, a fine-tuned drug discovery process, and a mixed-risk portfolio where we are mixing up internal as well as partner-proposed projects, and we have them at different stages of drug discovery, which means that we have multiple shots on goal. So yeah. This is how the science, and what we have learned over the last 20 years, has led to the mRNA gold platform, and how this is maximizing the output through it so that we are rather confident that we will be able to hit this target of two - three new INDs per year. That's it with respect to the platform. I am now handing over to the SLN-124 project, and that will start with testimonies for a couple of our future patients. Dear Vera, I know you are in pain. I understand what you face every single day. You have bright hopes and big dreams that you worry might be limited by hospital visits, sick days, and a family that wants you to feel so secure that they might not push you that extra mile to see how far you can go. It's funny, working in a hospital translating other people's problems. They'd never know that sat next to them is someone who has never experienced a day without pain. I just wish I had someone that could've told me this when I was growing up, somebody who had experienced all this beforehand. How systemic iron homeostasis interacts with some of the diseases that are targeted by SLN124. A little bit about myself. I started my research career in the 1980s when I discovered the natural human antibiotic defensin and characterized its role in innate immunity. In that context, we studied then in the 1990s the role of defensins in urogenital tract immunity. While we were screening through the peptides that are present in urine, we accidentally discovered a new peptide that had not been described to date, and that we named that peptide hepcidin because it was antimicrobial and it was made in the liver. This turned out to be the long-sought iron regulatory hormone. I spent the next 20 years after that on trying to understand the role of this hormone in systemic iron homeostasis, and its role in innate immunity. About 10 years later, we discovered a second hormone, which I will not be able to spend much time on today, a hormone named erythroferrone. This hormone regulates hepcidin and also regulates iron metabolism in response to the changes in the blood-making cells, erythroblasts. First, the introduction to the iron cycle. Most of the iron in the body is present in hemoglobin of red blood cells. Red blood cells in the human live approximately 120 days, and when they outlive their lifespan, they land in the spleen, where they are ingested by macrophages. Their iron is extracted, it is returned to blood plasma, and then from the blood plasma, it enters the marrow to make new red blood cells. About 20-25 mg of iron a day, which is a large amount of iron, circulates in this recycling circuit. The liver functions as a storage organ, and the duodenum functions as the absorptive organ that absorbs iron from the diet and replaces the small losses. Only about one or two milligrams a day of iron need to be absorbed to replace the small losses from the body. The liver, which is the storage organ, takes up iron in times of iron excess and releases it back to the body when iron is needed. The main lesson from this graph is that most iron in the body is recycled, and that erythropoiesis, or the production of red blood cells, is dependent on the supply of iron. This is then summarized in a greater detail on the next slide. The red blood cells develop from precursors in the marrow called erythroblasts, and they go through a series of divisions and modifications, in which the 1st phase is dependent on the presence of the hormone erythropoietin, which is made by the kidney. Erythropoietin allows the very primitive precursors to develop into the erythroblast stage. Everything that happens after that, the differentiation of erythroblasts into red blood cells that contain hemoglobin, and the production of hemoglobin, is iron-dependent. The first phase depends on the presence of erythropoietin. It requires erythropoietin. The second phase, the substance that is absolutely required for the cells to proceed through the second phase, is iron. The amount of iron controls the rate and the amount of the production of red blood cells. Now, hepcidin is the iron regulatory hormone, which was discovered by my lab in 1998, as I mentioned before. It is secreted by the liver as a 25 amino acid peptide, and it regulates the absorption of iron. The sequence of the peptide is depicted below, and its three-dimensional structure was determined in collaboration with my laboratory. Here is what hepcidin does. Easiest way to remember what hepcidin does is to think of it as the equivalent of insulin to glucose. Hepcidin is to iron like insulin is to glucose. You take a mouse, you inject it with synthetic hepcidin, and you measure serum iron. Over the first hour or so after the injection, the iron levels drop from 30+ micromolar to less than 10 micromolar, and they stay down for 24 - 48 hours before they return back to normal. Again, this is a typical hormone, and its target is iron. The same relationship as insulin has to glucose, hepcidin has to iron. The target of hepcidin is a membrane transporter called ferroportin. Ferroportin is a molecule that exports iron from the cell to the extracellular space, and it works by a reciprocating mechanism. It binds iron when it's open to the inside of the cell, it flips around, and releases the iron to the outside. In the third part of that diagram, you can see hepcidin binding into the open cavity of this transporter. When hepcidin binds, iron export from the cell stops. Not only that, ferroportin is taken up by the cell. It's destroyed inside the cell, essentially removed from functioning as an iron exporter. Through this mechanism then, hepcidin, produced in the liver, regulates the influx of iron into blood plasma. It regulates the absorption of iron from the intestine, the duodenum. It regulates the release of iron from the liver to plasma, and it regulates the release of recycled iron from the spleen to blood plasma. Essentially, through this mechanism, it regulates the supply of iron to the bone marrow. When hepcidin is high, the iron influx into the plasma is low, and the iron supply to erythropoiesis is restricted. When hepcidin is low, iron flows into blood plasma, and the iron supply to erythropoiesis, or the production of red blood cells, is very abundant, and the erythrocytes and erythroblasts are produced in large amounts. Iron functions in this respect as a controller for erythropoiesis, and hepcidin functions as a controller for iron. Now, we could spend a lot of time today talking about how exactly hepcidin itself is regulated, just like it is quite a complex matter on how insulin is regulated. Hepcidin regulation requires two cell types. One is the hepatocyte, which is the primary cell in the liver, and the second one is the sinusoidal endothelial cell, which is the cell type that lines the vessels that course through the liver. These cells produce BMP2 and BMP6, which are locally acting hormones. These then act on the hepatocytes to regulate the production of hepcidin. Very relevant to today's discussion is then what happens in the hepatocyte. In the hepatocyte, the production of hepcidin is primarily regulated transcriptionally at the level of mRNA production by a receptor complex called bone morphogenetic protein receptor. It interacts with various iron sensors and other molecules to regulate the production of hepcidin. Of critical importance for targeting this area is that there is only one known negative regulator of the system, one known inhibitor of the system, and this is the molecule matriptase-2, encoded by the gene TMPRSS6, which we call TMPRSS6. Tempress6 or matriptase-2 are the negative regulators that down-regulate the production of hepcidin. When you remove TMPRSS6, as happens in patients who congenitally lack this protein, you get very high levels of hepcidin. The same can be done in mice. You can show in a mouse model that if you remove TMPRSS6, hepcidin levels rise. Now, we and others have tried to establish what consequences this would have on other physiologic processes, the removal of TMPRSS6. We know from the human patients that these patients become iron deficient and anemic. Surprisingly, in a mouse model of beta thalassemia, this is not what happens. When you remove TMPRSS6 in the mouse model of this blood disease, beta thalassemia, the disease improves. The mice become less iron overloaded, and their anemia improves. Similarly, in mice which suffer from hereditary hemochromatosis as a result of genetic manipulation, when they also are subjected to removal of TMPRSS6, they actually improve. They get less iron overload and depending on how severe the disease is, they can in fact normalize, become completely normal when TMPRSS6 is removed. Finally, in a mouse model of polycythemia vera, which is a disease in which red cells are present in excess, removing TMPRSS6 raises hepcidin, restricts the iron flow, and improves the exuberant production of red blood cells so that it becomes more normal. The strategy of silencing TMPRSS6 increases endogenous hepcidin production and restricts the flow of iron to erythropoiesis and the tendency of these patients to develop iron overload. The key to this drug is that it controls the single negative control element in the hepcidin iron pathway. Now, a little bit about the diseases that are involved here. One class of diseases, of which beta thalassemia is the poster child, are so-called anemias with ineffective erythropoiesis. I'm going to spend a little bit of time on explaining what these kinds of anemias are. During normal production of red blood cells, the precursor will divide three or four times so that each precursor will give rise to eight or 16 descendant cells, which become the mature red blood cells. In diseases with ineffective erythropoiesis, such as beta thalassemia, the cells divide, but they, in some cases, keep dividing and not generating red blood cells. Instead, these cells will die in the bone marrow so that very few of them reach the stage where they give rise to a normal red blood cell. Even those red blood cells are not really normal. They are damaged, and they only live a short time in blood circulation. In diseases with ineffective erythropoiesis, you have many more precursors generating many fewer mature red blood cells. These precursors secrete products. One of them is the hormone erythroferrone, which suppresses hepcidin and thereby causes more iron to flow into the system and creates a vicious cycle in which more and more iron flows into a system in which the red blood cells already have a tendency to uselessly proliferate. This seemed like a ripe target for a strategy that would inhibit the flow of iron into the system and maybe slow the system down so the red cells can mature and be more normal. Now, the hormone erythroferrone, that I mentioned before, is made in the bone marrow as a result of stimulation by the hormone I mentioned before, erythropoietin or EPO. EPO acts on the bone marrow, releases erythroferrone, which we abbreviate as EPO. That suppresses hepcidin, and that is the stimulus that releases more iron to the system and drives the production of red blood cells. It drives it uselessly because these red blood cell precursors will only proliferate and die instead of give rise to functioning red blood cells. One potential approach to this is to slow the system down by removing iron from the system, and in fact, this is beneficial in mouse models of this disease. Besides beta thalassemia, what other conditions are there in which iron plays a key role in the pathogenesis of the disease? I already mentioned beta thalassemia, but there are other diseases like beta thalassemia that are characterized by iron-dependent proliferation of red blood cell precursors. This can be seen in myelodysplastic syndrome, a variety of other rare anemias collectively called iron-loading anemias. In these diseases, hepcidin is too low, iron is high, and the production of red blood cell precursors is stimulated, but it does not necessarily, or not in these diseases, lead to the production of useful red blood cells. These patients suffer from iron overload, and they suffer from anemia. A different disease is Polycythemia Vera. In this particular entity, iron is very low because the red cells use up the iron as they are produced in larger and larger quantities. These patients have exuberant production of red blood cells. They get strokes and other complications from blood that is too thick in the clotting system that is activated. These patients then are a target for an iron-restrictive strategy that would slow down erythropoiesis and decrease the production of red blood cells. Another disease type is hereditary hemochromatosis, a genetic disease. In this, hepcidin is produced in amounts that are too small because of genetic defects in regulatory circuitry for hepcidin or genetic defects in hepcidin gene itself. These patients absorb too much iron from the diet, become iron overloaded, destroy their livers, hearts, endocrine organs, depending on the severity of the disease. The goal in this disease is to control the iron overload, is to prevent the absorption of iron. Manipulating hepcidin can do that. Sickle cell disease, another disease in which iron can become important, in that a mild iron restriction in this disease could potentially decrease this frequency of vaso-occlusive crisis, which are the main driver of the pathology of this disease. Sickling, obstruction of blood vessels, lack of blood flow to critical organs. Another kind of application is the transplantation of stem cells for hematopoietic stem cells, in which there is a period during which erythropoiesis is suppressed. The production of red blood cells is suppressed by myelotoxic agents that are given as part of the treatment of these diseases and pre-treatment for hematopoietic stem cell transplantation. During this period, iron is not consumed because red cells are not being made, and iron floods the system and provides inadvertent food for microbial infection, as well as drives inflammation because iron is present in forms that are toxic and exceed the ability of the system to buffer this iron. These patients, during the phase of treatment, develop frequent infections, which are the common cause of death in hematopoietic stem cell transplantation. Again, an iron-restrictive strategy is thought to be potentially useful in this condition. To summarize some of these ideas, if we have a drug that reduces the expression of TMPRSS6 or the corresponding protein, which is usually referred to as matriptase-2, this drug will increase endogenous hepcidin. The production of hepcidin will restrict iron flows. It will decrease the production of toxic forms of iron. It will inhibit the accumulation of toxic iron in the body. It will restrict the flow of iron to erythropoiesis. as the color code there indicates, these three different approaches, the color blue, red, and green can cooperate in treating the disease manifestations in specific diseases. in iron-loading anemias, all three of these mechanisms are in effect to improve red blood cell quality, prevent iron overload, potentially reduce anemia and transfusions, and reduce the need for chelators. In hereditary hemochromatosis, the decrease in non-transferrin bound iron and inhibition of iron accumulation prevents iron overload, reduces end organ damage, and makes these patients potentially completely normal because their only problem is iron overload. In Polycythemia Vera, the restriction of iron to erythropoiesis by hepcidin in acting in response to the drug that decreases TMPRSS6 and matriptase-2 levels. In Polycythemia Vera, the restricted flow of iron will reduce the production of red blood cells, reduce blood viscosity, reduce thrombotic risk. In sickle cell disease, it may reduce the frequency of sickle cell crises and potentially reduce organ damage, which accumulates over repeated episodes of sickling and hemolysis. In hematopoietic stem cell transplantation, a drug that manipulates TMPRSS6 by decreasing its production can prevent toxic iron release and reduce infections, and reduce the mortality associated with hematopoietic stem cell transplantation. To summarize the ideas behind my presentation, hepcidin is the master controller of iron. This regulation of iron distribution, which contributes to the adverse course and bad outcome in many hematologic diseases, can be manipulated by decreasing the amount of TMPRSS6 matriptase-2, which increases hepcidin, restricts iron, and leads to improved outcome potentially in all these diseases. It can normalize erythropoiesis, reduce inflammation, and reduce end organ damage. I would propose to you that the therapeutic avenues that increase endogenous hepcidin are a viable approach for the treatment of multiple hematologic indications, and we will, in the future, learn what the spectrum of these potential targets is. You will hear about some of them today later. With that, I will hand over to Dr. Giles Campion, who is the Head of R&D and Chief Medical Officer at Silence, and he will tell you more about how some of these ideas are being implemented. Thank you. Thank you very much, Tom. Good morning, New York from London. I'm sorry I couldn't be there in person. I guess it's just an example of social isolation in action. I'm very excited to be able to talk to you about, particularly today, our clinical programs and specifically now about SLN124. What I'm to do during this talk is, firstly, to talk about some of the profiles of the drug, take you through some of the pre-clinical data that supports our development strategies, go through the healthy volunteer study that we're doing, introduce some exciting new data that we've seen in Polycythemia Vera, model of that, and then take you through our further strategies. Starting with the next slide. As you've heard, silencing TMPRSS6 enables the body to increase endogenous hepcidin production and modulate iron distribution. An siRNA does that by hitting the hepcidin regulated TMPRSS6. We have now assembled strong pre-clinical data in a variety of animal disease models, demonstrating the therapeutic potential in different pathologies. The healthy volunteer study shows a long duration of action as SLN124, consistent with the profile of siRNA, combined with a favorable safety profile. You've heard about the potential for a broad mechanistic mode of actions approach, and I'll tell you about that in terms of our development plans. Importantly, the U.S. Rare Pediatric Disease Designation has been obtained for beta thalassemia, as well as Orphan Drug Designation for MDS and beta thalassemia. This is important because it gives us the opportunity to work very closely with the regulatory authorities as we chart our progress forward. Starting with some of the animal data. This is published data from collaborators in Australia, at the Hudson Institute of Medical Research. What this series of charts show is the ability of three mg per kg of SLN124 to ablate production of TMPRSS6 in the liver to increase endogenous hepcidin, to reduce systemic iron levels, and to lower transferrin saturation. This is important in terms of the disease model because of two effects that I show here. One is if you have a situation in which there's ineffective erythropoiesis in the bone marrow, the body attempts to make red cells in other organs, so-called extramedullary hematopoiesis, and the spleen is one of these. What we've done in this experiment is to look at two doses of three milligrams per kilogram of SLN124 in thalassemia mice. We've also included a group being treated with oral deferiprone, which is an oral chelating agent. you can see that there is a significant reduction in spleen weight, with SLN124 and with deferiprone, but interestingly not with deferiprone on its own. the ability to modify iron endogenously through hepcidin provides a distinct effect. that's also seen in the results in hemoglobin. you can see that there's a robust increase in hemoglobin in this experiment, of 2.5 grams per deciliter, which again, is not seen with oral iron chelating agents. to put that into clinical context, the increase of hemoglobin by 1.5 grams per deciliter is defined as a clinically relevant effect. 2.5 grams per liter reduces the need for transfusions and really reflects between two-three units of red blood cells. giving us confidence in terms of the registration endpoint we'd be looking for in that condition. that was beta thalassemia. Another disease you've heard about is hereditary hemochromatosis. This experiment, again published, shows animals with the knockout for HFE gene, administered SLN124. Again, you see very strong ablation of messenger RNA in the liver, increase in hepcidin, reduction of iron in the serum, and then redistribution of the iron out of tissues into the macrophages where it is normally stored. Showing evidence for application in this model as well. With those promising results in animal models, we then were very interested to see if this could be replicated in our healthy volunteer study. This was reported earlier on the year. The design is as follows. A single ascending dose study, three cohorts, eight subjects per cohort, six active, two placebo, three doses, in total 24 adults as part of our GEMINI program. We were very excited to see a really nice dose response. Obviously, we couldn't look at mRNA knockdown in the liver, but we could look at the effects on hepcidin. You can see a very nice dose response going up to nearly fourfold increase in hepcidin. You see the four dose groups there, the orange representing baseline, the dark blue representing day 29, and then the cerulean showing day 57. You can see an increase, as I say, up to fourfold at peak, but even at day 57, levels were double what we saw at baseline. Actually exceeding what we were expecting to see based on the animal model. That was very rewarding. As one might anticipate, the consequential reduction in serum iron up to around 50% at peak, again with substantial effect up to day 57. We were really encouraged by these data for a number of reasons. This was the first clinical data from our technology platform. It demonstrated proof of mechanism from SLN124. All three dose levels of SLN124 were safe and well-tolerated. As you saw, there was an up to fourfold increase after a single dose, with sustained effect and a significant reduction in iron, again after a single dose. Very pleased to announce that the abstract has been accepted for presentation at ASH, and so further details will be available at that time. Following on from that, we were very pleased recently to see new data in a model of Polycythemia Vera. Again, we saw the traditional impact of siRNA really showing very strong intensity of action in terms of knocking down the target messenger RNA, an increase in hepcidin. If you remember from what Tom said, the whole therapeutic hypothesis here is because you've got exuberant red cell production, what you want to do is to restrict iron at the level of the erythrocyte to control that expansion. That is what we see here in this animal model, with a reduction in hemoglobin and a reduction in hematocrit. This is an area where development is thoroughly indicated. It's a disease area of high unmet need. 96% of patients have a gain-of-function mutation in JAK2 in hematopoietic stem cells, so a homogeneous population. Mutation induces cell proliferation independent of erythropoietin. The symptoms that Tom talked about in terms of a fourfold increase of risk of death for cardiovascular causes or major thrombosis is related to the increase in red cell mass or hematocrit, so particularly over 45%. On diagnosis, patients are treated with phlebotomy to reduce and then maintain the hematocrit to less than 45%, and some patients requiring multiple procedures every year to manage the condition. Sometimes phlebotomy is not enough and then can be complemented with cytoreductive treatments, including hydroxyurea. About 30%-40% of patients who receive that have either a suboptimal response or they have issues with tolerability. A big unmet need, and we are announcing too that we will be starting a phase I study the second half of next year to look at the safety, tolerability, kinetic and PD responses of SLN124 in patients with Polycythemia Vera. In this study, the key clinical study endpoints will be focused on hematological measures, including red cell packed volume, hemoglobin content, TSAT, and hemoglobin. apart from the homogeneous characteristic of this population, the advantageous aspect of development in this indication is that early and late clinical studies use the same endpoints, simplifying development path to approval. As you've seen from Tom, we feel that SLN124, through its ability to down-regulate TMPRSS6 and increase hepcidin, has the potential to be useful in a number of indications, both in terms of iron-loading anemias, hereditary hemochromatosis, and Polycythemia Vera to start with. To put all that together in a summary, SLN124 modulates endogenous hepcidin, what we believe has multiple clinical applications. It down-regulates TMPRSS6, inducing endogenous hepcidin, the gatekeeper of iron in the body. We've shown that endogenous hepcidin regulation has been shown to control iron in a variety of disease models. Preclinical disease models show that SLN124 normalizes erythropoiesis, improves anemia, and SLN124 has demonstrated safety and proof of mechanism in our healthy volunteer study. As I indicated, these data will be presented at ASH in December. We have clinical studies ongoing in non-transfusion dependent thalassemia and MDS patients. In fact, we just heard yesterday that the IND has been passed in the U.S., so we'll be able to expand that study into the U.S. topline data from the singles ascending dose study will be anticipated in Q3 2022. A phase I clinical study with SLN124 in Polycythemia Vera patients is planned for the second half of 2022 as we seek to expand the possible areas in which this molecule could be helpful to patients. Now I want to introduce the coffee break. In 2015, I had an event and I wound up going to the hospital, and I wound up with, at the end of all treatment, five stents to clear some blockages in my arteries in my heart. When I tried to investigate this myself, I realized that I had a problem with my lipoprotein(a). I called my doctor and I wanted to be tested for lipoprotein (a), and had difficulty getting the doctor to order the test. I think he had difficulty because he had never ordered the test before. He said, "Why did I want to be tested for it?" I said, "I think this is a problem that I have, and it is causing a problem that could probably kill me." He said, "Well, there's not much we can do about it, but I'll give you the test." I had the test and I found out that my number of my lipoprotein(a) was 921, which is 12 times the high normal. Looking back on things, I've realized that I might have had some signs before this, where I was having some chest pains that I ignored, and all along it was this lipoprotein(a) problem. There's probably been in my family, I have a sister, Joan, who died at 44, and my sister Barbara just passed away recently after an attempted heart bypass operation at 55. It's been a problem in my family for quite some time, and I know there's a good chance that one or two or all three of my sons who are in their 20s now could have the same problem. There's a one in two chance that they also have this problem. I hope that some of the drugs that are in the pipeline now will be something that can cure this problem. I know it brings the numbers down to very controllable levels, and I'm hoping it's going to be the solution. just up the road a bit at The Columbia University Irving Medical Center and NewYork-Presbyterian Hospital on the Upper West Side. The video was a patient of mine who has had multiple events. If you heard, he had two younger sisters who have already died of cardiovascular disease. I'm going to explain to you today, I'm going to focus on two important aspects, maybe three, but one is obviously what is lipoprotein(a) and what it is not. Number two, why is it important? number three, how we can go about approaching it and taking it out of the picture of what we call the cardiovascular risk complex. That I'm an endocrinologist by training, but have focused my research and my clinical care in the area of metabolism and lipid and lipoprotein metabolism. I've been familiar with lipoprotein(a) for many years, and I'll touch on that a little bit as we move along. I've already told you about this. I've been at Columbia for 36 years. I've done a lot of administrative work supporting research across the campus. I do a lot of training, but I've been funded by the NIH successfully for over 40 years and have been awarded at times for my work. I've been personally and scientifically involved in lipoprotein(a) for about 30 years, and that's because I might have ended up as that video if I wasn't in the lipid and lipoprotein field. at the age of about 50, with absolutely no risk factors and having already run around the equator about one and a half times in my life, leading to a lot of titanium in my body now, but that's a sidebar. I went out to Long Island to St. Francis Hospital, which at that time had the first CT scanner that could look at coronary artery calcification, a test that's become commonplace in taking care of patients with cardiovascular risk. it can demonstrate calcification in atherosclerotic plaque in the coronary arteries, something that happens late in the game of the accumulation of cholesterol, the inflammation that follows. At the age of 50, with no risk factors, still running 30, 40 miles a week, running at least half marathon still at that point in time, as a lark, and because it was a friend of mine who was one of the pioneers in the field, I went out and had that test done, and I had a chunk of calcium right in the middle of my left anterior descending artery, which has been called the widow-maker artery, because it's the most commonplace for fatal myocardial infarctions. Knowing that, I was able to do some things about. My very good LDL became extremely good with medications, and I altered some other aspects of my lifestyle, although it was pretty good. I'm here today, but there are people who wouldn't be as lucky as I was to have understood what that meant, to have a test done and not have anything done until the individual you saw after the fact and after people in his family had already died of very premature cardiovascular disease. Now, because of a little bit of publicity, a The New York Times article, a couple of other things, I get patients every week who have gone to their doctor because someone in their family has had an event or because they've had an event and been lucky enough to survive, and they've asked for a lipoprotein(a) measurement. The response they get is often, as you heard there, the doctor said, "I don't know why you want this. I have nothing I can do about it, and I'm not sure what it is. People are getting it done. I have my small, little half-a-day a week practice is loaded with people who have this risk factor, and we absolutely need to get therapies through the process of regulatory agencies and get them to the patients. In order to tell you about lipoprotein(a), I'll start off by telling you about something you have heard of, LDL and LDL cholesterol, the "bad cholesterol," a major risk factor for cardiovascular disease. Although I'll show you how this is closely related to Lp(a), it is very different. This is the one that we all know for going back 60 years now. High LDL is bad for you, and lowering LDL is good for you, and that's what's shown on this. It's a standard type of slide in my field, but if you just pick one half of the slide, you have a dark, solid line down the middle that ends at the bottom at the number 1, then you have a box to the left of that number 1, down around 0.75. This is what we call a meta-analysis. It's an aggregate of a whole bunch of data from a number of studies with hundreds of thousands of people put together. These are all people who received statin therapy in various trials. The key message is the one just under the black area of the slide. If I can lower your LDL cholesterol by about 40mg per deciliter, I will reduce your risk over the next five years of having a fatal heart attack, a fatal stroke, non-fatal heart attack, non-fatal stroke by 22% or so. That doesn't matter where you are when I start the treatment. What matters is if you're very high, your absolute risk is very high, and I lower that by 22%. If your risk in five years is 20%, I can lower it to 15%. That's a really big risk. If your absolute risk is 5% and I lower it to about 4%, so what? Is that worth taking a pill and having co-pays and maybe thinking you can't find your keys anymore to your car? Which I hear all the time. I'm presenting it this way because there is absolute relative risk that comes into the play of any drug that we use. As you may, if you're in this field scientifically more, and this is what you focus on, you've heard number needed to treat, okay? It's good to have a number needed to treat that's under 100. It's great to have one that's under 25 or so. That person that I described maybe with a 20% five-year risk, and I can lower it 25%, I need 20 people to save one person from an event. That would be a great outcome. This we know. This is written in stone. Lowering LDL is good for you. Okay. Having said that, we have patients who either have multiple risk factors, they have diabetes, hypertension, they smoke, they're overweight, they're old. That's the number 1 risk factor, and that's the one we can't hopefully do anything about. We all want to get older. Well, two sides of the coin. All those have to be treated, but they're not treated optimally, and so we still have very high event rates. If you've been lucky enough to survive a heart attack, your five-year risk of having another one is about 20% unless you do something else. That's with getting all the drugs that are available. We need to find out why people are still having events, and there's a list here. Mainly, the best drug we have to lower LDL, the statins, and people just drop off them all the time, or they're not treated adequately. The other ones are very important as well, and under the little people figures there are a lot of other aspects of what we need to do. We also need to find the emerging risk factors, the biomarkers, and you probably go to meetings and you hear 1,000 biomarkers are out there, and if you tinker with them, you may get a little effect. I'm going to tell you about one, lipoprotein(a). It's actually discovered, the first publication, 1963. It's just been very hard for the scientific community to work with. It's only in humans, some of the great apes, and for who knows why, hedgehogs. We don't have the mice, and it's been even hard to genetically engineer the mice for this particular problem. It's hard to work with in cells because we don't have good human cell lines. There was this long period of 60 years where things crept along. Because of that, it wasn't measured and we didn't have Science moves in parallel with drug discoveries. Doctors' clinical practice depends on having something they can prescribe. If they can't prescribe something, they don't even want to know about it, which is a big mistake, as I'll get back to. This is the focus now. This is a little bit of a different version. I'm sorry I couldn't duplicate the LDL exactly, but I'll have them side by side in a moment for you. The big circle with all those little pockmarks is the LDL I showed you more colorfully in an earlier slide. It has this extra protein that's bound to it called covalent binding. It is stuck on very tightly, that is called Apo(a), and the gene is called capital L, capital P, capital A, Lp(a). I'll tell you about the complexity of this that's made studying it even that much harder. You can see all these little wiggly things that are called kringles, a Danish pastry, and that's because the protein amino acid makes it a whirl in a 3D dimensional structural sense. It is a lipoprotein. Lipoproteins, low-density lipoprotein, I described in detail. High-density lipoprotein, the so-called good guy, although it's gotten a little cloudy over the years. It's maybe not as good as we thought it was, but let's put that aside as just another lipoprotein. There's one called very low-density lipoprotein that carries the triglyceride that's in your bloodstream. On this slide, you can see down in between the LDL and the HDL, and they're listed by their size and also sort of their density. You have the lipoprotein(a), and then there's a blow-up of that kringle. Okay. These are the two side by side. We actually don't like the concept that much of calling this an LDL with an extra protein, because that extra protein changes the function of the LDL dramatically. Changes everything about it. Here's a little bit of genetics and evolution. Okay? The top line, the top structure is the gene for a protein called plasminogen. When plasminogen is activated, it becomes plasmin can break down a clot. When you have atherosclerosis, and you're building up cholesterol in the artery wall Well, let's focus on the coronaries, although this happens in the brain, it happens in the legs, they all can become symptomatic. In the coronary artery, our arteries are tubes, the wall of the tube is pretty thin. If it starts to accumulate cholesterol from LDL also from Lp(a), that cholesterol starts to cause a bulge, the body sees that as an infection, in fact. Probably because 100,000 years ago, nobody had enough LDL to get atherosclerosis, every time they cut themselves, they had bloodstream infections, bacteria entered their arteries. It's my view of the world. What we do know, though, is when there's cholesterol in the artery wall, the body sends in white blood cells, mainly monocytes, as we call them, mononuclear cells. They go in, and their job is to eat up the cholesterol and then leave. If your cholesterol is just up for a day or so, that would work. If it's up all the time, they get stuck themselves, the monocytes. They become another form of monocyte called the macrophage. You heard a little bit about macrophages from Tom Ganz. That creates an inflammatory process. Now you have all other sorts of biological processes going on, and you get this very complicated plaque. At some point, the bulging in starts to cut off the blood flow. When that happens and it reaches a certain point, you run up a flight of stairs, and you get this feeling like you're running up a flight of stairs with a suitcase on your chest. That's called angina. That tells you to go to a doctor and get tested to see if there's enough that they need to do something about this narrowing. You crack open, the plaque actually breaks open the inner lining of the tube, the wall, and now the bloodstream is exposed to this inflammatory collection of cholesterol and cells, and you form a blood clot. Cut yourself on the skin, you want a blood clot to form really fast. Cut yourself on the inside of an artery that's already narrowed by maybe 70%-80%, you don't want a blood clot, because suddenly you have no passage of blood. This can go from 50% or 60% to 100%, and that's an acute myocardial infarction, and that can be a sudden death event as well. This clot is forming, plasminogen is activated, becomes plasmin, and starts to break down the clot. What's that got to do with Lp(a)? Well, the bottom row there shows that genetically, this Lp(a) gene is part of the pieces of plasminogen, the color coding. Plasminogen has these K1, K2, K3, K4, K5. Lp(a) only has K4 and K5, and then it gets much more complicated, and I just have to briefly discuss it because it's very important in terms of the levels of Lp(a). The K4 has several flavors. In fact, as you see here, 10 of them, different DNA bases, and one of them, called K4-2, can repeat itself between one and 40 times. The gene has 40 versions of itself, from very small to very large. Most importantly, the white box that says P on it is when the gene becomes the protein, that P area is what breaks down fibrin. Okay. The Lp(a) white box has a mutation in it, and it's lost its ability to break down the fibrin as the protein, like Apo(a). Now you have Lp(a) circulating. It can find the clot and bind to it and interfere with plasmin breaking down the clot. This has not been proven to the point that I can say it's written in stone, but we think it's important, and it's an important component of the overall picture, and that's what I show you in the next slide. Uh-oh. It's showing up on one screen. It was a build. You may have to go by it if you can't figure that out fast. Okay. There it is. You have lipoprotein(a). Looks like an LDL with that extra protein on it. Very complicated protein, 40 sizes of that protein. It has then the ability to get into the artery wall just the way LDL does. The artery wall then accumulates cholesterol and all the downstream bad things happen. It can also, once you have an event, you crack open your plaque, the clot can become bigger. Instead of just getting sudden chest pain, getting to a hospital and getting something done, you may have not a chance. You may shut off the blood flow completely, and that's when people fall down in the street. Okay. These two factors we think play roles. Okay. Backing up a bit, this is what we call a bell-shaped curve. It's that statistical distribution of a lot of things in the world. This happens to be cholesterol. LDL looks the same way. I point this out because when you have a bell-shaped curve like that and you're looking for an association, for instance, between cholesterol and heart disease, you have a continuous variable, and you can look across that and see if people at the upper end have more heart disease. This is what the distribution of Lp(a) looks like in the population. 80% or so of the population is squeezed down to very low levels of Lp(a). It's not really dangerous to them. Maybe from the 40th to the 50th percentile, it is a continuous risk, but the risk is low. We have not only the top 20% having higher levels. It's what we call a skewed distribution. It's really my patient with a 1,200 or a 900. In the last 20%, and this is a different scale, from the last 20%, you can see here it's going from 50- 200, where the first 80% is going from 0%- 50%. I have patients who are 200. I'll stay in the milligram per deciliter here because we use two versions of different assays. I have patients who are at 50%. I have patients who are at 250 or 400. They're all stuck in this last 20%. There's a marked range of very high levels. It's all driven by the gene and going back to those kringles, those Danish whirls. If your gene has only a few repeats, you're going to have very high levels, and if the gene has a lot of repeats, you're going to have low levels. Everything about us is genetic, anywhere from 30% - 95% in certain diseases, single gene diseases. LDL is about 70% genetic. There's always room. You can change your diet. You can lose weight, exercise, so-so for LDL. There are things we can do. It led to a lot of also interventions with medications. The Lp(a) level is 95% driven by the Apo(a), which is the Lp(a) gene. It's left us with no environmental, no non-pharmacologic approaches that do anything. It's really unmet need for pharmacotherapy. These are three versions of large studies with hundreds of thousands of people showing that the higher the Lp(a) level, the greater the risk. We're in a big discussion in the field now. We know exactly, I told you, that for every 40 mg per deciliter of LDL cholesterol, your risk is 22% higher if your LDL is higher. If I lower it 40, your risk goes down 22%. For Lp(a) it's been more difficult to get that kind of number perfectly. Most of the data says that this is probably 1.5x -2x more damaging, more potent than LDL cholesterol is. These are just some estimates of the risk. This is using 90 mg per deciliter, which would be about, as you can see on the lower right or the middle right, the prevalence, the percentage of the population with an Lp(a) greater than 50. I'd already told you that was the top 20%. Greater than 90 mg per deciliter, the top 10%. The patient you saw would be in the top 1% or less. You're looking then at the number of people that fall in simple arithmetic, population times the prevalence, and on the left side, you're looking at the increased risk for having a 90mg per deciliter versus a 5 mg per deciliter Lp(a) level. We have heart attacks. We have heart failure, downstream effect of heart attacks. We have stroke. We have overall mortality. At the bottom, there's one that I wanted to step off to the side a moment and tell you about, that's aortic stenosis. The aortic stenosis is the aortic valve is at the top of the left side of your heart. Every time your heart beats, pressure builds up, the valve opens, and you pump blood out. Okay? That's when you feel your pulse. The heart pumps some blood out. Then as the heart then relaxes, the left side of the heart relaxes, the valve closes. If your LDL is high, or as I'll show you, your Lp(a) is high, and if you get older, you start to get calcification and plaque around the aortic valve. That's what's shown here. It's called the tricuspid valve because you can see the three thickened bars that make an upside-down Y. Around, at least particularly on the right side, but a little bit on the left, you see those ugly-looking nodules, okay. That's calcified plaque, and it's blocking the outflow. Your heart pumps and the blood shoots up and it can't get through. Maybe half of it gets through, a third of it gets through. We have easy ways to identify that risk by echocardiograms, and we know exactly when the risk of sudden death or stroke or simply symptomatic, like a syncopal episode, you pass out. We know what narrowing degrees lead to those. Okay. We always thought it was just good old-fashioned atherosclerosis, and it is to some degree. Several years ago, a large genetic study looking at people with aortic stenosis found that the only gene in the entire genome that was clearly associated with aortic stenosis was the Lp(a) gene. A whole second, partially atherosclerotic but partially unique downstream damage by Lp(a). Where are we now? As I said, this is a 60-year journey. By the '70s and certainly the '80s, we knew that Lp(a) was bad for people. It's just been hard to work with. There were groups that never gave up on it. Now we're at the point where, very recently, the Canadian Cardiovascular Society recommended everybody get an Lp(a) done once. I'll loop back for a minute and say, remember, it's 95% genetic and it doesn't change. It's not like LDL, where your doctor might want you to come in even if you were normal, quote-unquote, that once a year you should have your LDL done as an adult. Maybe something changes and your LDL is going to change. You get this once. You could get it any time, and that's what it is, and it'll tell you what your risk is over a lifetime. In the European Society of Cardiology, in the European Atherosclerosis Society, we're talking about also getting it once in each adult lifetime. In the good old USA, where our guidelines for cholesterol and cholesterol-related substances like Lp(a), we've been at least a decade behind the rest of the world. The guidelines say that it should be measured in people who have a family history of premature atherosclerotic cardiovascular disease. You have to have somebody in your family who's already had the event, or a personal history, you have to be lucky enough to survive. Maybe we'll move that forward. A recently published paper that I'm a co-author on came out from ASH. It's not a guideline, it's a scientific statement mentioning all the things I just talked about. Based on a very large database of half a million people, every time your Lp(a) goes up about 20 mg per deciliter or there's 15 nanomoles, your risk goes up about 10%. It's like interest at a bank. If you have 5 50s, you can go up almost double. We know that now. Importantly, the statins do nothing. This is risk of having an event with a high Lp(a), and whether you're on a statin or not, statins don't do anything. It may raise Lp(a) a little bit, but let's call them neutral. All the other drugs that might be available, there's niacin, there's an ApoB Antisense, PCSK9 inhibitors, they're modest at best. We need something to knock the heck out of this. We need something that's going to wipe it out in this 20% of people. This just shows from that 11% increase, it doesn't matter what your other risks are or who you are, if your Lp(a) would go down by 11%, if it go down by this 20 mg per deciliter, you'd decrease your risk by about 11%. I'll move by that. The profile of a new Lp(a) drug, it has to be potent. We're dealing with people with very high levels, and if they're 300, lowering them to 200 probably won't be enough. At least the 70% reduction of the level, long duration of action, safe and better compliance. Here we are. It's very potent. At least as potent, if not more potent as a genetic factor, which has been hard to see because it's only in that 20% of the population, not 50% of the population, let's say, for LDL. Lifestyle, nothing. The agents we have, nothing. We need new agents that are potent, and therefore we need new agents where people will take the drug, so it's got to be safe and duration of action. RNA modalities will give us that. I guess we're on to Giles. Thank you. Well, thank you very much, Henry. It's a tremendous privilege to follow on from such distinguished scientists as Henry and Tom, who spent a lifetime understanding the biology either of hepcidin or Lp(a), and then be able to use our technology to translate those discoveries into meaningful therapeutics. I think SLN360 really is a great example of that. In many ways, as you heard from what Henry said, siRNA really is a fantastic technology to apply to this condition, and I'll take you through that shortly. As you've heard, this is a major public health issue. You can see a little bit of epidemiological history here that the original gene originated in Africa and then spread throughout the world. You have a prevalence ranging from 50% in Africa to about 10% in Asia, and with North America and Europe, about 20% of the population are at risk from elevated Lp(a), giving a global prevalence of about 1.43 billion people. Sitting here in a biotech company and having wholly owned control of an asset like this is a real privilege. As you heard, from a development perspective, Lp(a) is really an ideal target for GalNAc siRNA. You've heard from Henry that it's a genetic disorder, so approaching it by genetic methodology or gene silencing makes absolute sense. You can use the exquisite specificity of Watson-Crick-based pairing to make sure that you hit the target accurately. You've heard that there's a very high confidence in the target based not only on epidemiological and cohort data, but also from genetic analysis such as Mendelian randomization, that shows that the association is causal. Finally, we can use the specificity of GalNAc targeting to hit the gene which is almost exclusively placed in the liver. Sometimes with pharmacology, you're worried about having too much effect, but as you saw in the distribution curve, although 20% have raised levels, 80% have low levels, and some people have very low levels, so the risk of exaggerated pharmacology is minimized. Some of these features here indicate why siRNA is particularly relevant from this disease. One, as you've heard, Lp(a) levels are genetically determined, so nothing you can do from a lifestyle perspective can potentially help. Pharmacology is required. It's recognized as a major untreated risk factor in cardiovascular disease. Lp(a) levels, as I said, are not significantly modified by other approaches. You saw from the large population worldwide, with up to 10% with having a high level greater than 90 mg per deciliter, which is associated with two to three times increased heart attack risk. What you really want is exactly the profile of an siRNA. This is shown in the data that we've generated, the preclinical data in the non-human primate. Unfortunately, we couldn't find hedgehogs. This does pretty well. You can see that there's a nice dose-related reduction in Lp(a) after a single-dose administration. Either single dose or three times 3mg per kg. A rapid reduction in Lp(a), serum Lp(a), and then consistent reduction all through the level of the experiment, up to 63 days. This is what you want in a primary prevention or secondary prevention therapy. You want strong intensity of treatment, with long duration of action. Of course, the other component is you want something that's very safe. One, you want to be able to show that there's no demonstrable effect on off-target genes in vitro, which we've been able to show. No effect on the plasminogen gene that Henry talked about at doses up to 200 mg per kilogram. Through the GalNAc targeting, you would expect drug to be pretty much restricted to the hepatocyte, which it is, and also to the kidney, which is the route of excretion. The GLP safety observations in the cynomolgus monkey is just restricted to reversible non-adverse microscopic findings and a very high safety margin for entry into the clinic. The no-effect level is greater than 60-fold the pharmacologically active dose, which was the highest dose that we tested in monkeys. You have all three components of a really nice profile for treating cardiovascular risk, high intensity of action, long duration of action, and very promising safety profile. With that preclinical data, we have initiated a phase I program in patients who are otherwise normal but have an elevated Lp(a). This is a single-ascending dose study with a multiple-ascending dose phase following that. Eight subjects per cohort in the single ascending dose, six active, two placebo, and then 12 subjects per cohort, nine active, three placebo in up to four cohorts. Dosing, as indicated there, involving up to 88 subjects with elevated Lp(a) over 60 mg per deciliter. To review the current status of this program, we announced earlier that the single ascending dose component is fully complete, and that puts us confident of results being expected in the first quarter of 2000 of next year. More recently, independent safety review committee has recommended that we are okay to go ahead into the multiple ascending dose component. More interestingly, have suggested that we extend the follow-up of singular dosing cohorts from 150 to 365 days, indicating, as we saw in the primate, a very long duration of action. Where we go from here? Well, the single ascending dose data we believe will drive the phase II study in atherosclerotic cardiovascular disease. It's not due to start in the second half of next year, obviously subject to conversation with regulators. The dose and interval can be predicted from our single ascending dose data, and the multiple ascending dose provides earlier safety assessment in our phase II ASCVD population. To pull that all together, having worked in cardiovascular development both in companies such as SmithKline Beecham and Novartis, I would be very proud to have a drug like this. I think it's a company-making asset. We saw that SLN360 is a GalNAc siRNA with potential to address a major unmet need in cardiovascular disease, not only in terms of the severity of the consequences of the risk factor, but also the prevalence in the population. I've demonstrated, I hope for you, a very promising preclinical safety and efficacy profile. The phase I single ascending dose study is well advanced in healthy volunteers with Lp(a), and we are preparing for multiple ascending dose study in patients with high Lp(a) and stable atherosclerotic cardiovascular disease. Really looking forward to being able to share with you the single ascending dose data, the first quarter of next year, which will help us design the phase II study. Thank you. Now I should like to hand over to Mark for some concluding remarks. Thank you very much, Giles, and thank you to all the speakers for all those excellent talks. I'd just like to spend a couple of moments concluding, if you like, from today at a company-wide level. My first focus is the two lead assets, SLN124 and SLN360. I think we really are very fortunate to have two, I think, very high potential programs leading the charge as a company. Firstly, as I think you will have heard, we really think there's a chance to build a hematology franchise with SLN124, addressing a whole range of potential indications using endogenous hepcidin modulation. Initially, we're focusing on thalassemia, myelodysplastic syndrome, and polycythemia vera, but we have the opportunity to add potentially other indications beyond that. You can see a sort of staging and sequencing, if you like, of launches in the future into multiple indications with the same asset. I think what's also very interesting about SLN124 is with these three indications now, we really can reach a very large number of patients. They're all actually orphan or rare disease indications, but actually you can see from PV, it's at the higher end of the spectrum of that definition. The addition of PV represents a substantial opportunity with around 3.5 million people in the world suffering from PV. We believe that from a commercialization perspective, we're thinking that this is in the region of a GBP 3 billion-GBP 5 billion peak sale opportunity, these three indications. A very substantial program that we have in our pipeline. The other feature of being in this area is that we're talking about hematologists and hem oncs as the primary prescribers and sort of relative to, say, cardiovascular, this is a relatively concentrated prescriber base. as such, this is the kind of program we could consider taking all the way to commercialization. Not only because it doesn't require a particularly large commercialization team, but also we're talking about high-value, unmet need indications. Now turning to SLN360, I just want to echo what's already been said. This is clearly a major problem, and it affects a very substantial number of patients, people living with elevated Lp(a) around the world. If you look just at the U.S. and the top five European markets, there are 136 million people being treated for high total cholesterol. that's actually very similar to the number of people estimated to be living with elevated Lp(a). it's a statin-like size market that we're looking to address with our SLN360 program. today, we are third in line behind Novartis with their antisense oligonucleotide program, and Amgen with an siRNA. for various reasons I won't go into, we do think the siRNA class has better prospects for treating these patients. to summarize the news from today's meeting, the breaking news, because we only heard it last night, is that the FDA have just accepted our IND in the United States for the SLN124 study in MDS, which I think is a great step forward as we think of expanding the SLN124 program. As we've said, we're on track for the thalassemia MDS phase I data in Q3 next year. We see a large potential opportunity for SLN124 in various hematological indications, we've announced today the initiation of a PV phase I study in the 2nd half of next year. As Giles mentioned, we'll be providing additional data from the healthy volunteer study at ASH in December. For the SLN360 program, we're on track for Q1, but also we were encouraged by the response or the recommendations coming from the independent safety review committee, meaning that we didn't need to go and do the optional 5th cohort that we had the option to do. We're also extending follow-up of those patients that have already been treated in the single ascending dose portion of the study. We're excited to add a third clinical stage program to our portfolio. As Marie said, we're on track to deliver two - three INDs per year by 2023. Really there's a lot of, I think, exciting milestones ahead of us in the weeks ahead, the months ahead, the years ahead to look forward to. Really that comes back to the value-creating opportunity of our company. We're now on the global stage. We're up against, if you like, our peers like Arrowhead, Alnylam, and we think the path to value creation is very clear. It's expanding the pipeline, which we're doing. It's advancing the pipeline, which we're also doing. I think we're also uniquely placed in having two extremely valuable assets leading the charge with SLN360 and SLN124. With that, I'd like to conclude today from a presentation point of view and invite our panelists to come up to the front for some Q&A. While we're doing that, we're also going to move this lectern so that you can all see the panel. Please. I'll come and sit in between. Thank you. I think for the Q&A, I know that there are questions that are coming in through the outside world for those who are on Webex, and I think I'm going to be able to see those questions in a minute. We can also take live questions here in the meeting room. I'll ask the team here to show me the first questions that are coming in. There's a question. Excuse me. Is it okay if I just- Of course. I'll repeat the question. Really on the SLN360 front, how important is it going to be to have a big outcomes trial for Lp(a) reduction? Do you think an accelerated pathway is going to be halted based on Lp(a) reduction, or is somebody going to have to do a big trial before the world accepts? Right. There is a big trial underway, as you all know, I think Novartis with the antisense. They own Ionis Antisense. That actually is not the largest trial that we've seen in a long time in our field. It's only about eight to nine thousand individuals, but they've taken extremely high-risk individuals. They'll end up with narrowing their indication. That's probably two years away from reporting out. I would imagine, but there are people here who know more about the regulatory side than I do, but I would imagine that since it's a new agent and the siRNAs will need to do something like that. If you think about the PCSK9s, they had a fast track for reducing LDL cholesterol. As I said a number of times, that was written in stone. They did not have an indication to prevent cardiovascular disease until each company did their one large study. I would imagine. thank you very much for that. just for those who hadn't heard the question online- It's all set. The question was whether we're going to need to do a large outcome study or is there a sort of a shorter route to be able to getting an approval, for example, demonstrating lowering Lp(a). Thank you, Professor Ginsberg, for your views. Maybe I could invite Giles also to add any commentary around that, assuming you can hear okay. Yeah. I think from the development strategy perspective, we assume that an outcome study will be needed. Can you hear me? Can you hear me, Steve? Yes, we can hear you. I think there's some concurrence that it's quite likely that that's going to be a requirement. Another question from the room. For Dr. Ganz. In these diseases where you're lowering iron in people that are already low iron. How much warning are you going to get for on-target tox? Is there an acute readout or are you going to have to wait for some sort of CNS effect if iron is going too low? The question is, how safe do you think it's going to be? How much warning are you going to get if maybe you've lowered iron too much? Can you repeat the question? Yes. The question was, what kind of warning are we going to get when we lower iron too much? Generally, the way that things happen is that the body prioritizes erythropoiesis for shutdown when iron goes down. As iron is going down, the first thing that shuts down is erythropoiesis. The first warning you're going to get is that you completely stop making red cells. Erythropoiesis count goes to zero. That is the first warning you're going to get. The iron depletion of organs takes much longer, and it is likely that hepcidin is to some extent protective. Why do I say that? It's protective of organs other than erythropoiesis. Why do I say that? I say that because the children who have iron refractory, iron deficiency anemia, who have transferrin saturations of as low as 1%- 2%, 10 times lower than a lower limit of normal. Those children are normal in every respect except that they're anemic. Even taking the iron to zero acutely will not, in mice, cause any effect. I think it's the progressive depletion of iron over a long period of time, which you get through phlebotomy for polycythemia vera. That's what you get. That is what's causing symptoms. That is what's causing things like restless leg, itching, extreme fatigue. That is the depletion of tissues of iron that happens over a long period of time. Now, I expect if the way we understand the physiology, I expect that a drug that raises hepcidin will protect against that total iron body depletion. I'm going to read a question now from the screen and then come back to the question here in the room. The question I think is for Giles. How do you see the way forward to a phase II study in ASCVD? Do you need to wait for the multiple ascending dose phase I study results? Yep. Well, thanks for the question. I think our feeling is that we will get adequate information from the single ascending dose to be able to design the phase II study. I think the safety that we see will be also informative. There is precedence for this, in that Amgen went from their single ascending dose straight into a phase II. We feel reasonably confident pending discussions with the regulators that we'll be able to do the same. Next question I think is for you, Marie. It is, do you have the discovery capacity for partner and proprietary programs to hit two to three INDs per year? The short answer to that is yes. The longer answer is that we have expanded our drug discovery capacity over the last few years at the same time as we have streamlined processes, and we have also gotten really good at resource forecasting. We are definitely confident that we will have enough resources to cover that. Also, to remind you, we are not starting all of these programs at the same time. They are staggered, and we are not using all the resources for every step. Yeah, we are confident that we will be able to manage this. Thank you, Marie. The next one is for Dr. Ganz. Will increasing hepcidin levels via suppressing TMPRSS6, will you impact on iron levels in tissues? Will iron be pulled out of the organs? It is a similar answer to the previous question, which is that the only way for cells to release iron is through ferroportin. When hepcidin is high, that pathway is actually made less and less effective the higher the hepcidin goes. Cells will lose less iron in the presence of high hepcidin. The difficulty in true iron deficiency that happens when people are phlebotomized is that hepcidin is low. What happens in those patients is that cells will start leaking more and more iron. Hepcidin protects cells against iron loss, but restricts iron flow to erythropoiesis. It's kind of a paradoxical but very beneficial, in this case, combination that most tissues are protected, but erythropoiesis is restricted. Thank you very much. The next question, I think, is Professor Ginsberg's. Is there an expectation on what benefit you would see in a CVOT trial that would be demonstrated by Lp(a)-lowering agents such as ASOs and siRNA? I think, obviously, anything we think about in that sense is an extrapolation from the epidemiology, the Mendelian randomization trials, and what we think Lp(a) does. I would say, though, I am confident that lowering LPA, on top of any other therapy, will be as effective and independently as effective as lowering LDL. With the drugs, if you had a 70%-80% reduction in LPA levels, I would think you'd be in the 20% range of reduction. I also think that there is a likelihood that you might be up in the 30%-40% range. That's the upper limit of what I understand is possible from my own reading and work in the field. While we have you, we have another question, I think that is in your direction, which is, "How should we correctly measure Lp(a) levels? It seems like assays differ, and going by weight may be a bit misleading compared to concentration. This would take an hour. Let me just say that we're a lot better than we were 20 years ago. We're better than we were 10 years ago. There are still many different assays out there, but now that there's interest, now that there's pharmaceutical company involvement, we expect that there will be a single unified assay soon. The units are a bit of a charade in one sense, but measuring the nanomolar measures should be at looking at Apo(a) directly and not being dependent on the kringles, and I can't go beyond that. Right now, the assays are good enough to know who's very high and who's in the normal range. It'll become an issue if, for instance, there is a study which you have to have 150 animals to get into, and they measure you at 140, and you're out. You might have been 160. It'll be an issue if the insurance companies won't pay for somebody if they're 140, and they really are 160. I would say within the next three-five years, when all the trials will come to fruition, we will have a unified assay that will be as good as any other assay we use in our field. Thank you very much. The next question is from myself and Giles. The question is SLN124. "What will drive the decision to expand to further indications? Are the indications on slide 43 the likely ones to be pursued over time?" Maybe I can start off by saying that, from our perspective, clearly, we want to be able to see preclinical data as one of the steps towards making that decision. We also would want to reassure ourselves that the level of unmet need and sort of the importance of bringing therapy to patients is something that we have a very good view of, too. Clearly, I think there's a lot of opportunities here as outlined by Professor Ganz, and I think that we'll evaluate all of those, I think, very carefully. Taken the first step today to do the PV study next year. I don't know if, Giles, you wanted to add anything to that? No, I think that obviously is the fundamental basis. I think the other thing to add, of course, is developmental complexity and registration endpoint ease of getting those. I think those are all factored into how we think about further indications. Clearly, getting nice, robust data as we've been able to show for the current indications is primary. Giles, this one perhaps invite you to answer this one. It's about the C3 program, SLN501. Why C3 rather than C5 or C1q? Is the data for the positive effects of C3 robust in our minds? Remember, of course, this is a partnered program with Mallinckrodt. If you look at the complement pathway, it's complicated, but the final complement pathway goes through C3. We think that this is a very good target and in fact, we're joined by other people that also think it's a good target. The potential value of targeting the complement system to treat complement-mediated conditions has been clearly demonstrated by Alexion with SOLIRIS, and we think that it's potentially very valuable. There are a lot of diseases in which C3 is proposed to play a key role in the pathogenesis. For all those reasons, we think it's a good target. We're looking forward to starting our clinical studies as Mark indicated next year. Giles, I think this one is also one for you. It's about the SLN-124 dosing in PV, and the question is, "How do you think about SLN-124 dosing in PV versus what you have disclosed in beta thalassemia and MDS? I think as you've heard from Tom, the therapeutic hypothesis is slightly different in that indication in that what you're trying to do is to use hepcidin to restrict erythropoietic drive and r educe red cell mass. I think from the healthy volunteer study, we know that our drug successfully knocks down the target, increases hepcidin and iron, and is safe, and it has a long duration of action. I think that will figure into how we consider the design for polycythemia vera. The next question is for Professor Ganz. Can we view clinical data generated in thalassemia or MDS and read that data through to other iron overload disorders? Good question. I think that when you talk about iron overload disorders, you're thinking about hereditary hemochromatosis or other iron loading on one hand, and other iron loading anemias that are not beta thalassemia or MDS on the other. I think I'm quite confident that the other iron loading anemias, the effects will be predicted by the effects we see in beta thalassemia. They're very similar in their pathogenesis. I expect that part is simple. I think hereditary hemochromatosis actually may be an even easier target, in that we know that if we replace hepcidin or raise hepcidin in that condition, and we know we can do that because in the mouse model of Hereditary Hemochromatosis due to HFE mutations, TMPRSS6 ablation will fix the problem completely. I think that Hereditary Hemochromatosis is, in principle, a very strongly validated target for treatment with the drug. To summarize, I think that the other iron loading anemias will follow the same pattern as beta thalassemia. Thank you very much. The next question is, two-three INDs per year from 2023. Please remind us, are these internal or would these also include our partners? The answer is, it does include our partners. I think the whole point here is expanding our pipeline through the combination of both our internal proprietary pipeline growth and our partnered pipeline growth. We're leveraging both levers to be able to deliver two-three INDs per year by 2023. For Dr. Ganz, do you think targeting liver-specific hepcidin upregulation with SLN124 is a better strategy than systemic replacement with rusfertide? A very good question. I think you're talking about two drugs with a very different profile. One of them is an injectable that may have to be injected at least once a week. That has acknowledged risks of local reactions and potentially other local complications around the injection site. Versus a long-acting drug that has a smooth profile of action, a long duration. I think we are talking about two different drugs. It may even be possible that at some point, there will be diseases that will be treated with one drug versus another drug. They're not directly comparable in my view. I think that the difference in the way this pharmacodynamic profile of the two drug is so large that they're not directly comparable. There are arguments to be made that in certain diseases, perhaps one might be easier to use than the other. But convenience is a big factor. This is a drug that has to be given over many, many, many years. I think things like how easy the drug is to administer will play out as an important factor. Thank you very much. This is a question for Dr. Ginsberg. Does SLN360 have at least to demonstrate safety and efficacy on par with olpasiran? Is there room in this market for two siRNAs? It's not my area of expertise, but it's pretty, I think, obvious that the efficacy and safety would have to be on par with competitors in the same class. That's really out of my area of expertise. Maybe I can take that one primary interest. I would just say- Yeah There are seven statins, I believe. 12. Okay. Every time one came along, it was going to take over the field and more people were treated. This is a huge population of people. I think there are many reasons doctors end up choosing one drug over another. They may try one, the patient complains, and they go to the other. I'll move that along to Mark. No, I think you answered it perfectly well. You're right. 12 statins in a similar size market, we're third in line, and our view would be that there's room for at least three, probably more in this marketplace because there's a lot of patients that need treating. It's a very large market. I do think the siRNA class, I believe, has advantages over antisense oligonucleotides. Professor Ginsberg, CVOT is in secondary prevention. Do you think Lp(a) lowering has a role in primary prevention? Absolutely, as LDL lowering has a role in primary prevention. It's the logistics, it's the cost, it's the regulatory factors that take control of what trials are done first. You need events in a trial. You need people who are going to have events in a reasonable amount of time. You can't afford to do 50,000 people for 15 years. You take people who've had events because that doubles their rate over the next five years. I think that's the quite reasonable approach. Once you show that secondary prevention works, I think it is very important to do a primary prevention trial. We've had those in the statins after the secondary prevention trials. I think without a doubt, despite the fact that you would need more people and maybe make sure it's five-six years rather than two-three years, that it will work, because the epidemiology, the genetics all says it will. Thank you very much. The next question is in relation to IP. I'm glad that we have Barbara Ruskin, our Chief Patent Officer, with us today. The question is, "Can you update us on composition of matter IP for SLN360? How does this navigate around olpasiran specifically?" I'll give you the easy question. Thanks. We have two patent families currently pending on SLN360 composition of matter. The first was filed, I believe, in 2017. It would give patent protection out to 2038 unextended. That has started being examined by international offices. It seems that our sequence is novel. Now we're working through why we've made an invention because the sequence is already known. Selecting a 19-mer to say, "I should have an invention by selecting this one 19-mer to knock down Lp(a)" is something that you have to overcome with the patent offices. It's novel, which addresses the second part of the question, I believe, which is how does that compare to olpasiran. What we know is that we're not using the same sequence. Remember, we're all picking short sequences and there are many short sequences across a 1,000 length mRNA. I'm making that up. We don't have any head-to-head comparisons. We're waiting for our clinical data, but it looks like we're going to be able to get patent protection even on our earliest family. Our second patent family was filed a year later, and that was after the lead optimization with all of the special chemistries. That hasn't started being looked at yet by the patent offices, but I expect that that's going to be easier because we're going to be able to show, hopefully, we'll be able to show unexpected and surprising effect of the chemistries in combination with that sequence. That patent family will go out to 2039 unextended. Thank you very much. I think this next question is for you, Marie. The question is, "Does the effectiveness of an RNAi depend on the overall mRNA structure? Is that structure generally conserved between rodents and humans? That is a lovely question. Thanks for asking that. We hypothesize that the secondary structure will have an effect on local accessibility of the target transcript. This is actually one of the many factors that we are including in silico predictions, in order to find the most potent molecules. I think I mentioned that one of the parameters that we are looking at is whether the target is preserved across species. We do find it rather practical if we can screen the same molecules in mice, in primates and, of course, eventually, if it can work in human beings. The structure of the mRNA, at least the secondary structure, will be a consequence of the sequence. The sequences that we therefore are looking at hitting or have a preference for are preserved. Yes, it's definitely so, or at least a popular hypothesis in the field that the secondary structures of the mRNA will have an effect on Well, you can talk about it as a determinant to find hotspots, and this is something we are tracking, and if we do find them, they do tend to be conserved across species. Thank you, Marie. I think the next question is for Giles, and it's around the SLN360 program. Was there a preset range for Lp(a) lowering or expectation by dose in the single ascending dose portion of the phase I study? How should we think about there being no need for cohort 5? Hopefully, both of those came through, Giles. Yeah. No, absolutely. Very good question. When designing a phase I study, obviously you have to go on what you've seen preclinically, but you're never quite sure how the data in the preclinical species will translate into human, whether the human target's going to be more or less sensitive to the primate. You always build some flexibility in your program. In terms of level of reduction, I think you heard from Dr. Ginsberg what sort of level are people looking for. 70% would be seen as a reasonable reduction. You saw in our nonhuman primate studies that we really got very nice reduction there, and at the higher doses for long durational action. Where we are with our current study, I think the consensus of the SRC was that we needed to follow up for longer, I presume because we're seeing a longer duration of action than we may have anticipated. Therefore, we don't need a further cohort. Thank you very much, Giles. I think the final question for today is for Professor Ginsberg. LDL-C is widely accepted as having a deleterious impact on cardiovascular health. Is there also broad agreement on Lp(a) amongst cardiologists? The second part of that question, the answer is unfortunately no. I would say the majority of cardiologists probably aren't even aware of Lp(a). That's a pretty sad statement for me to make. It's changing rapidly. To put that in context, Framingham came out with data in the late 1960s showing that LDL cholesterol was a risk factor for cardiovascular disease. It took several clinical trials that began in the 1980s into the 1990s to get the cardiology community on board, including the fact that they had a drug. There are multiple steps. Things move very slowly. I believe that when the Novartis trial is published and is positive, that things move much more rapidly now, we saw that with the PCSK9 uptake, and that the cardiology community will come around very quickly. That, and universal screening of patients being supported by the American Heart Association and the ACC, which I hope will be in the next guidelines. With that, I just wanted to close and say a big thank you to our guest speakers, Professor Ginsberg, Professor Ganz, all those who joined us, either in person here in New York or by Webex around the world, and look forward to following up. Bye-bye.