Great. Welcome, everyone, to the Piper Sandler Healthcare Conference. My name is Biren Amin. I'm one of the managing directors here at Piper Sandler. I'd like to welcome our next company, Silence Therapeutics. We have President and CEO Craig Tooman and their Chief R&D Officer, Steven Romano. So welcome, gentlemen. Thank you. Maybe start off, provide us with an overview of the pipeline at Silence Therapeutics and some of the key catalysts to look forward to. So Silence has been around for 20 years plus, not new. Reverse mergers into a UK company with Atugen many years ago. So our roots are in Germany, in Berlin, Germany, and still are there. And we've actually opened a US office in Hoboken as well. So we are in the UK, in London, as a headquarters in the US and still in Germany. So pretty global company, about 125 employees. We've been doing siRNA for, as I mentioned, a couple of decades. So a lot of expertise, a lot of intellectual property built over that time period. Very excited that we've moved with two proprietary programs that I know we'll talk a lot more about, siRNA programs, move those forward into the clinic. And we're really getting incredible data out of those two programs. We also have partnerships with AstraZeneca and other companies. So we are a hybrid model of working on programs with other great partners and bringing in some non-dilutive funding at the same time that we're doing our own work. So very exciting time for us. We have an upcoming presentation at ASH this weekend on one of our programs, and really looking forward to that. Great. So I guess, as our last round, is the siRNA program that targets Lp(a)? Tell us a little bit about Lp(a) as a target. I mean, clearly, the cardiovascular field has been focused on LDL, HDL, Lp(a). I mean, you're starting to see a lot of progress there with your company as well as other companies targeting this. What's the relevance of Lp(a) in terms of driving cardiovascular disease? So Lp(a) is gaining a lot of attention. It has not been well understood. More recently, a lot more coverage and understanding. Companies starting to study it and talk about it. A lot of pre-marketing occurring. It is a highly associated risk factor for cardiovascular events. And there is now a trial ongoing that should read out next year to show that causal effect with pharmacotherapy for the first time and events. So, we're very interested to see that, and we'll follow behind on that study. Lp(a) has two to three times higher risk cardiovascular events if you have high levels. And the high levels are really 75 nanomoles per liter. That's kind of the designation or more. So that is the kind of relevant group you're looking for. It is a huge opportunity because it impacts 20% of the world's population. And it is genetic. The issue here is, unlike cholesterol, you can't influence that with diet or exercise. You're just born with that. That's why the medical communities have suggested, get a test once in your life at least. That number that you're given for your Lp(a) will probably stick with you. We're looking forward to being able to move into the realm of offering treatments for that. I guess our patients broadly tested for Lp(a). I guess, and you mentioned, Craig, 20% of the world's population have elevated levels. I guess in the U.S., is that a similar figure in terms of? Very similar. It's a global phenomenon. It's not a U.S. phenomenon. And so it's very interesting because with this increase in attention to the field, people do want to get tested, and they're starting to understand. In fact, I even had locally recently a flyer come through the mail saying, "We're going to test for Lp(a) if you want to participate in that." So it's growing kind of on a national scale. But today, it's not included in your typical lipid panels. I'm sure at some point it will be. But again, there's no pharmacotherapy available today. But you can go and ask and have that included in your panel. It's part of the blood panels that you can get. So I think you're going to hear a lot more about this marketplace. I guess with your zerlasiran, so this is a siRNA that targets Lp(a). You're seeing significant knockdown. Maybe describe the level of knockdown on Lp(a) that you're seeing in the profile that's been generated so far. I know Steve will tell you a little bit more about the studies. But what we're seeing here with the siRNA approach is 90% plus in terms of maximum knockdown in the studies we've seen phase one and phase two. So just incredible knockdown when you have a specific target with siRNA that we're studying here. That is better than the previous class that's under review that tends to show 70 percentile or so. So it really, I think, is going to be a great advance. And I guess, how frequently is it dosed? And what's the data? How's the data look so far? Infrequent dosing. And maybe Steven, you want to talk a little bit more? Yeah, no, absolutely infrequent dosing. So the technology itself lends itself to infrequent dosing. We studied a range of doses in our phase one, both in the single ascending dose as well as the multiple dose portion of the phase two, excuse me, of the phase one, and of course, in our phase two. So across the program, we've looked at Q4, Q8, and then more recently in the phase two study, Q16 and Q24. So we wanted to get a good understanding of the range of the effect across a broad dosing interval and doses. We're confident that we will go forward with a 300 milligram dose that allows for a single injection. And to date, we're updating our PK/PD modeling because we're going to base our decision with regards to the choice going into phase three, not the dose, but the interval on updated PK/PD modeling. And what we see is a very durable, very competitive profile replicated in the phase two as we saw in phase one, maximum suppression beyond 90%. As you know, we saw as much as 98% or 99% in the multiple dose portion of the phase one, which was published in JAMA in April. And we're seeing those maximum degrees of suppression in our phase two as well. And we know we probably have at least a quarterly or longer dosing schedule, which really puts it in frame of a very, very competitive compound and infrequent dosing. So at a minimum quarterly schedule, and potentially beyond that, you could even look at, let's just say, a Q24. Would that be a? So we're looking, as I said, quarterly or longer. And we're still evaluating that. Got it. And then I guess at AHA, you had presented at the late breaking session. So congratulations on that, on the phase 2 ALPACAR-360 study. What were the data that were presented at the AHA meeting? Yeah, so the program, the phase 2 program, was a 60-week program. The primary outcome measure was at week 36. The end of treatment period was a week 48, and then we followed them out. Because of the durability of the effect, you really want to look at the long term, both tolerability, safety, as well as the attenuation of the effect over a long period of time. We looked out to 60 weeks, so all that data was shared there. The primary outcome measure was a little different from the other studies. We looked at what's referred to as a time- averaged analysis, and a time -averaged analysis, rather than just looking at a change from baseline to a single point, really takes into account the peaks and troughs over the course of that period of time. So it takes more information in and suggests the general level of suppression that any individual is experiencing. So we saw, again, in these longer intervals going out to 16 and 24 weeks, levels of 81% to 85% or 86% in that time average, and still saw maximum suppression over 90%. So very, very confident because we've replicated the data that we showed in phase 1. The time -averaged analysis, is that a standardized approach as it compares to how your competitors look at Lp(a) reduction? I think you'll see more of this being applied to future studies because it does have a more fulsome view of the level of suppression over time versus simply looking at baseline to a single point in time where things could go in a range or there'd be some variability on the response in between. What are the views of FDA, for example, on time -averaged analysis? Oh, I think this would be a perfectly acceptable analysis. And I guess and then so phase three. Talk about your plans there. I mean, you've mentioned that those saying you would evaluate a minimum of Q12 weeks and beyond. What type of a trial would that entail in terms of patient numbers? I know you haven't disclosed much on that, but what's like a typical phase three trial design? Yeah, well, I think you can see what Novartis is doing with their antisense and what Amgen is currently doing with their siRNA as well as Lilly based on the ClinicalTrials.gov information and other manuscripts that have shared some of the design components. So it is a cardiovascular outcome trial. So in these trials, they're usually in the range of 6,000 to 8,000 patients, depending on the type of patients you would focus on, largely focusing on secondary prevention. So you can imagine that that's the range of the size of the study. And it will take one dose forward into phase three compared to placebo. And you follow those patients for a number of years, typically up to about four or five years in the course of the study. Got it. And then I guess you mentioned Novartis is running a cardiovascular outcomes trial. They've got a co-primary endpoint looking at greater than 70 and greater than 90 subgroups. Talk about that approach and how you think about that as it relates to what your plans? I can only say what I've read and what I've seen based on their discussions in the public domain. Yeah, they're looking at a co-primary. First of all, that 70 and 90 is in milligrams per deciliter. If you translate that into nanomoles per liter, which is considered sort of a better way to evaluate the Lp(a) levels, and it's pretty standard now, you're talking about 175 and 225. These are very high levels of Lp(a). A very small population of patients, perhaps the top decile or so. I think they did a clever thing in that they could declare a positive study, whether they hit it at 70 and above in their entire population or whether it is 90 or above. I think when these studies were planned, and I could only, this is conjecture, but when these studies were planned, it was believed that you really needed to have a very large absolute reduction in Lp(a). So it's no surprise to me that they would look at that higher level, which might at 80%, 70%-80% suppression demonstrate a very large absolute reduction. Now, the field has moved forward because there's additional data that suggests, in fact, much lower levels are likely to be associated. And that absolute reduction is probably well less than half that. But yeah, I think it was a clever design for them. And we're all looking for them to succeed because obviously that's going to lift all boats. It will be the first study, as Craig suggested, where you'll be able to demonstrate that, in fact, a potent intervention in lowering this particular biomarker is going to translate into benefit. So we're all excited about that. We understand the timing is first half next year. That is the latest. So, timing first half next year, how does that impact your phase three trial design, if at all? Would you potentially look for those data and then that would potentially inform on your phase three design and start of the trial? You can imagine our phase three has already been well thought through and designed with a great group of internal people and experts. So it won't necessarily impact how we move forward with that design. But it could actually inform us a bit. I mean, it's great to get key learnings from others and be sure there's going to be things that you can take from that trial. Absolutely. And I guess with zerlasiran, how does it compare to some of the other? We talked about the Novartis program. I think Amgen has Lp(a) program. And so how does zerlasiran compare to some of those other programs? So the one thing we can say is the ASOs, Antisense oligo, which we've talked about initially, probably has lesser duration and lesser knockdown. The siRNAs, which are the other three that you've referred to, that class, we're very pleased to be in that class. And the lead kind of independent compound, if you will, because we've not been partnered, and we can talk about that later. But that is our own in-house developed Lp(a) compound. So we're very pleased that we're in that league of long duration and excellent knockdown within the siRNA class. And then we move to trial design and differentiation, which we can talk a little bit more about. But we spent a lot of time trying to determine how we can best differentiate in the trial design itself. Yeah, and I think that's where you really have the opportunity to differentiate yourselves in a way that could read through to the label and therefore perhaps, almost certainly, to access reimbursement. And we've had some really nice conversations with HTA groups and U.S. payers as we prepared for the phase three. So we not only got the experts' input to the design of the trial, but of course, also considered the input from future payers. So look, we know we have an infrequently dosed product at quarterly or better. So we're very competitive in that way. But we really can look at a broader range potentially of at-risk patients in our phase three trial. So for instance, we know Lp(a) affects all of the vasculature in the body, whether it's cerebral, coronary, or peripheral. The other studies have largely focused on MACE and largely focused on cardiovascular. So we believe there's an opportunity to define a broader range of high-risk vascular patients. We also believe, based on sort of a comment I made earlier, that perhaps at lower ranges of Lp(a), for instance, in our phase 2 study, our inclusion criteria was 125 nanomoles per liter or above, that there is still an opportunity for patients with lower levels, but still in the elevated range, and still obviously with high-risk vascular disease, many of them secondary prevention, could benefit from an intervention like ours. So we're not giving away the details because it's such a competitive space, as you can imagine. But we feel very confident that we've designed a trial that would help differentiate us from the other programs ongoing. So it feels like broader patient population in terms of when you look at Lp(a) cutoff relative to others, as well as from the, I guess, symptomology standpoint, potentially broader patient population there as well in your phase three design. That's right. That's right. In 6,000 to 8,000 patients, I mean, it's a large study. I'm sure you're going to have sites across U.S. and ex-U.S. As a smaller biopharma entity, how do you think about taking this forward yourself versus partnering and the ability to complete the study? So for us, it's Silence portfolio approach. I'm very pleased to have lead programs that are working so incredibly well. But we do all the time look at where to put our funding first. And PV, for example, wasn't on radar two years ago for investors for us. That program is coming in with near 100% efficacy within the control group, which is incredible in this phase one trial. And you'll see more of that at ASH. So we're continually looking at the assets that we have from a proprietary standpoint, whether that's PV and also Lp(a). And again, great data with Lp(a). We've said that on our chassis, an asset like that is very large. And so we have and we will continue to be in dialogue with potential partners for that. But again, it's that portfolio approach. We'll determine where we want to put the asset and the funding. Great. And Craig, you mentioned the second asset, which I did want to get to, the divesiran. So you're going to have data at ASH. Tell us a little bit more about that and PV and the potential there. We depicted the first part of that phase one study in June in a webcast. Steve went through that data. Maybe, Steve, you want to update a little bit on what we'll see? Yeah, sure. So the PV trial that we did was a phase one trial, open label. And we looked at these patients, all of whom received four doses q6 weeks. And then we're followed. So for the first 18 weeks, week 0, 6, 12, and 18, they had their four doses. And then we follow them out to 34 weeks, so a full 16 weeks, to get a good sense of the benefit that could accrue to these patients and the persistence of that effect over a long period of time to contribute to the design of the full development program. So all these patients had polycythemia vera based on the WHO criteria. We enrolled 21 patients, 19 of whom we will speak to at this week's ASH presentation on Sunday. All of them were dependent on phlebotomies at baseline. So they had to have a minimum number of phlebotomies in the previous six or 12 months. We allowed for patients who were both well controlled, meaning their hematocrits at the time they entered were below 45, and those who were not well controlled so had hematocrits as high as 56. We also allowed for low-risk patients as well as high-risk patients. And we allowed for patients regardless of their background therapy. So we have patients who may not have been on cytoreductives or were on a stable cytoreductive regimen. And what we are going to share is more of what we saw in the June cutoff, the June presentation we made, which is persistence of the effect, particularly in the well-controlled patients. Not a single patient that was well controlled under 45, in fact, that extended to 50, under 50, required a phlebotomy during the course of the treatment period. We went from 79 phlebotomies in the previous six months in these 19 patients to just six phlebotomies up to the follow-up period that we've had. And all of those phlebotomies were in patients that came in with very high hematocrit who were also benefiting from the drug. It's just that it takes a little time to come from very high levels down. So we're very excited about this data because this is, first of all, we're first in class in the siRNA space, and we want to keep that. And we have a very, very attractive profile that we feel confident we'll be able to reproduce into phase two. And in fact, one more point, we're hoping to have our first patient enrolled in the phase two program by year-end. So very close. This month. This month. That's great. Congratulations on that. And I guess on the phase one, so you had announced data this summer, right? And so I guess at ASH, it'll be more patients in the cohort three. We'll have more patients in every cohort because what we were able to do in the course of the study is to move from cohort to cohort with fewer patients having achieved a certain minimum exposure. So we're filling out the cohort. So you'll see more of that. But more importantly, we'll have 14 patients who will have completed the entire treatment period. And we'll have an additional 8 who will have completed the entire follow-up period. So just more robust data. We'll share more of the specifics around both the iron indices as well as blood indices. And obviously, the hepcidin data, which is very important because obviously, we intervene in that pathway. So you want to take a good look at the elevations and the persistence of the elevation of hepcidin, which we believe is driving the iron restriction to the bone marrow and therefore the decrease in hematocrit and the outcomes that we have been seeing. We're very excited about PV as a lead indication, but also SLN124 is the molecule from which PV is derived, and we believe there are other possibilities with this as well, so longer term, stay tuned on that. We think from the blood regulation standpoint, a lot of opportunities. Great. And you had mentioned phase 2 start this month. That would be considered a pivotal? It's a phase 2 study right now. We'll have discussions with the agency around the overall program and what's required. Obviously, this is an orphan. We've got orphan designation. We have fast-track designation. We're looking at the guidelines for developing orphan and rare conditions. There's latitude. We'll have those discussions. We want to have as efficient a development program as we can. And how many patients? And what is the sentinel? Have you? So we haven't divulged all the details. But in ClinicalTrials.gov, which people can take a look at, our phase one, phase two was to include up to about 65 patients. And so you can get a sense of the size of the randomized control portion of the trial. That effect size is so robust that that should help us to have a very lean but informative phase two. And one of the things we're looking at, I'll just add, is we looked at q6 weeks. But given the durability and what we're seeing with regards to the follow-up on these patients, there may be an opportunity to extend that interval further. Got it. And I guess there are other approaches. I mean, you're clearly using siRNA to knock down TMPRSS6. But there are other approaches that target, such as monoclonal antibodies. That's right. How does this compare to some of those other approaches? Look, I mean, it's a rational sort of scientific approach to target TMPRSS6 in a different way. I mean, we're silencing the TMPRSS6 protein. But you can target it with a monoclonal antibody. I mean, the issue with monoclonal antibodies is typically, as you know, they may not have the durability. Now, there's ways of extending the half-life of monoclonal antibodies. So we can see. But I think we'll just really have to see to what extent they can do that. Obviously, the siRNA class is generally built for durability and safety. You don't have immunogenicity issues that you need to monitor with monoclonal antibodies. Obviously, Ionis is also out with an ASO. Again, I think there's benefits to siRNA over ASO with regards to the durability. But we want to be first in class siRNA. We want to maintain what we think is going to be a tremendously competitive profile. First in class, best in class profile. We'd love to see that best in class realized. First in class, first for silence, so we're very, very pleased about that. Great. Great. And Craig, you had mentioned you would potentially think about broadening it out. When do we start to hear more about it? Is that more of like a 2025 story? It's obviously, as we move into later phases, we'll be more open about that. Again, very competitive space. But what we've seen preclinically is very interesting. And we'll likely pursue some of those. Craig, so you've partnered some of your tech platform out to other companies such as AstraZeneca. They've nominated a candidate and moved that into the clinic earlier this year. But the target hasn't been disclosed. When do we start to hear more about those efforts from AZ and how that might benefit Silence? Yeah, really great relationship with AZ. Great to watch because really, we have a multi-target relationship as we have the opportunity to, together, the two companies determine what we're going to pursue and then do that. Watching the first one here that you see in the clinic, and by contract, it's up to them to disclose going forward. So we can't say more about it, but from our perspective, to watch two scientific teams from two great companies interact and create something different than either company would have created on its own, I find just fascinating, and I think both of our scientific teams have acknowledged that, right? So one plus one equals three. Very, very interested to see that continue to do well, and we're, of course, supporting that for AstraZeneca and then looking at additional targets that we can work with them on. In essence, those are deals that have an upfront and milestones and royalties. So for each one of those that we pursue all the way to the end, it's probably a $300-$400 million opportunity for us. So back to that non-dilutive opportunity for us to fund and look at things that otherwise we might not do ourselves. It's a great opportunity. That's great. And then I guess from a cash balance standpoint, you have a lot going on with Zerlasiran and Divesiran. Do you have the balance sheet to fund both programs and see them through to approval? Back to that portfolio approach, constantly looking at it. We have $172 million at the end of Q3. That gets us into 2026, assuming the funding of these trials that we've talked about continue. As I mentioned, in that portfolio, we'll continue to look at the assets and determine what we fund first and then lean on non-dilutive sources first, including partnership, before looking at alternative sources. Great. I want to thank you for your time. It sounds like exciting programs. And it's going to be an exciting ASH in a few days. It will. And thank you for having me. Thank you very much, Biren. Thank you. Appreciate it.