Oh, my gosh, you see your hands going? All right, good afternoon, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Goldstein, the biotech analyst here, and it's my pleasure to introduce the team from Silence Therapeutics, including Craig Tooman, CEO, and Steven Romano, head of R&D. Just a quick reminder, the format for today is a fireside chat, so if anyone in the audience has a question, you know, please feel free to raise your hand and we'll address it in our discussion. But before we get started, I just need to read a disclaimer. "For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative." And with that, Craig and Steve, thanks again for joining us today. And I thought maybe we'd start with a couple of just background questions on the platform. If you can maybe just talk about, you know, RNA, RNAi GOLD, and kind of, you know, how it works and what are some of the advantages there. So we call it the GOLD Platform, GalNAc oligonucleotide delivery system. It's siRNA. It has a genetic basis, so we're looking for areas, particularly in the liver, with a gene disease issue and trying to solve that. So that's where we spend our time. We find that it's very, very specific and very durable, and as you can see in our studies, very, very efficacious. So, we like very much that we're able to apply this in a variety of fronts. We have now two proprietary programs, I know we'll talk more about those, but, one is in a very large cardiovascular arena and one is in a orphan disease area. So very broad bookends, if you will, with a lot of treatment opportunities in between. Yeah. Given just the broad opportunity set, you know, maybe talk a little bit about how you decided to, you know, sort of pick your two lead indications. So again, we are currently more focused on the liver, although we're looking outside the liver as well, like, many in the industry are. And, when we look at those opportunities, more broadly within the liver, one that really came forward was Lp(a). So this is a large unmet medical need in the cardiovascular space, and it was one that we really thought we would focus our efforts on first, and that is now bearing fruit in clinical studies. Yep, makes sense, and may we stick with zerlasiran, you know, before we dig into the data, maybe talk a little bit about what's currently known about Lp(a), you know, how it affects the heart, and the risks there. Yeah. So, so Lp(a) is a known risk factor for cardiovascular outcomes. It's an independent risk factor, and it's genetically determined or largely genetically determined. 90% or so is genetically determined. So it's the type of risk that you have really from pretty much after birth onwards, so very different from LDL or other risk factors that tend to sort of progress through adulthood and then have to be managed. So this is a risk you're carrying for a long period of time, and it's probably an important contributor to residual risk in patients who are already at risk for cardiovascular outcomes because of elevated cholesterol, hypertension, obesity, et cetera. So a very important, yet to be managed, risk factor for patients at high risk of cardiovascular outcomes. Yep. I guess how validated is Lp(a) and then also, you know- Yep T he level of awareness in testing, and- Yeah and how's that sort of currently? Yeah, so it is. It's a validated endpoint with regards to the genetics, the GWAS, GWAS data, the epidemiological data, and the Mendelian analyses that have been performed, so in large databases like the UK Biobank and other databases. So there's a lot of confidence in the association of elevated Lp(a) to cardiovascular outcomes. Now, what we need to do is demonstrate that by targeting that biomarker and lowering it substantially, as our product does, that that translates into benefiting patients with elevated Lp(a). And those are the outcome trials that are running and that we will run ourselves as well for zerlasiran. Yep. So today, there is no specific treatment available for this very large unmet medical need, and that's why we're so keen really to do the research in this area. Yep. Can you talk a little bit about just the screening for patients, or patients currently screened or not, because there's really no treatments or... And how do you- Yeah Sort of advance that or accelerate that? It is not part of the lipid panel today, right? So you actually have to go in and request it. It is available if you go in and ask, and the academic centers are taking the lead, as you would expect, and making this more available than others. But as this becomes better known, Lp(a) in general, and the testing becomes better known, people are going in to ask, "You know, what is my Lp(a) level? Mm-hmm. As Steve mentioned, there actually is no, no treatment, so what you have is this quagmire of going in and knowing what your Lp is, but actually not being able to get treated, which is why we're, again, keen to do this. Yeah. I might just add that the awareness is growing. So if you look at the cardiology societies, whether they're European-based, Canadian, US, even Southeast Asia, they are now recommending, or at least, suggesting, that if you are come from a family with a high risk of cardiovascular disease or family history, or you have a history yourself, you should be tested as an adult at least once. So I think even though the awareness is still on the lower end, it's growing rapidly, and as soon as one of these trials actually demonstrates the effect of lowering Lp(a), you're gonna see essentially a hockey stick, where the guidance is gonna be taken advantage of. Yep. Makes sense. I guess, what's sort of considered a high level of Lp(a)? Is that sort of well understood? And the threshold in terms of reducing it, you know, to have a benefit, is that sort of well understood yet or, or what's- It's not well known broadly, colloquially, but the 75 nanomoles per liter is an area where you look for a normal base, and from there to 125 is a bit of a gray zone. Beyond and above 125 is an area where concern grows for cardiovascular events. So that is something that is continually being updated as people are more familiar and studies come forward, and people are increasingly looking at even lower levels. Maybe you mentioned a very large market opportunity or a lot of patients. You know, can you maybe put some numbers around that or how to think about what that could look like? So it's estimated to be 20% of the world's population, so it's a huge market, huge unmet medical need. We see it across the globe. Of course, some regions are more impacted than others, but 20%, again, just a huge market and no treatment available today, specific for Lp(a). Are cholesterol-lowering agents tried for Lp(a), and have they had any effect? No, no. I mean, the cholesterol-lowering agents, the LDL-focused agents, are pretty specific for lowering LDL. And, you know, even though there has been some, you know, modest impact on lowering of Lp(a), for instance, with the PCSK9s, maybe 20%-25%, it's not the robust level of reduction that you will likely need if you're going to develop a compound that's specifically targeted for patients with very elevated Lp(a). Gotcha, then maybe we can dig into some of your clinical data now. You've shared some very promising Phase 2 data for zerlasiran, and maybe you can walk us through some of the key findings there. Yeah, sure. No, I'm happy to. So, you know, and by the way, we just had published in April in JAMA our multi-dose portion of our Phase 1 as well, which showed a very robust effect. We looked at doses of four and eight weeks, Q4 and Q8 weeks, in the dose ranges we studied. We showed a reduction in those higher dose ranges, 300-450, of up to 98%-99% at 60 days, and that persisted at 90% level out to 201 days. So that was a really nice framing of the potency of our compound and the durability. Then in the Phase 2 study, that is ongoing, but just getting ready to complete it, we looked at 16- and 24-week intervals, and we showed, again, very robust effects. Similarly, we show maximum reductions in excess of 90%, and we've shown benefit at our primary outcome measure at 36 weeks on the primary outcome assessment, which is a time average analysis, which we'll present later in the year. We've also presented the 48-week data, which is the end of the treatment period, and again demonstrated the consistency of that effect, the robustness and the durability of that effect. Now we're following patients out to 60 weeks just to demonstrate that tail end of the durability, but also to assess tolerability and safety out to the 60 weeks, and we'll present all of that data later this year. With, I guess, 90% reduction, is the. Do you need to get below a certain threshold, or is a certain range of lowering, is that enough, or is it the combination of the two, or just- The field is generally consensus around 70% or greater being a reasonable range- Yep W hen you're targeting Lp with a specific and robust intervention. You know, the ASOs, antisense oligonucleotide that Novartis is developing, probably gets to the 70%-75%, maybe a little bit more. The siRNAs, like ours and others, can maximally get, as I mentioned, 90% +, and we demonstrated that in our trial. At maximum suppression, you can get to 98% or 99%. Now, your question, is there a threshold? There's no biological rationale for a specific threshold, but again, just if you're looking to design a trial, you're gonna look at patients with elevated Lp - Yeah A nd hope to apply a compound that will robustly reduce that, both in absolute value as well as% reduction. So, more reduction, generally better? Robust reduction that's generally maintained over time. Okay I s really what you're aiming for. Yep, yep. It's a balance between the, you know, the reduction and the convenience to the patient- Yep And to the physician with regards to the treatment interval. Yep. Can you maybe just talk a little bit more about the treatment intervals you've tested, you know, how you're thinking about dosing? You know- Yep How you sort of mentioned, I think, three hundred milligrams is your selected dose, but maybe just talk a little bit more about how you ended up there and- Mm-hmm Your considerations now for the frequency. Yeah. So the three hundred milligram dose, you know, we studied doses up to six hundred milligrams across the single ascending and the multiple dosing, and now currently in the Phase 2. So it looks as though, you know, three hundred is probably as good as four hundred and fifty. I mean, the data that I mentioned- Mm-hmm In JAMA in April showed that really the three hundred and four hundred and fifty, pretty much those lines were right on- Mm-hmm T op of each other. So it doesn't look like there's a reason to go beyond three hundred. Three hundred is great as well because it allows for a single injection based on volume and the concentration of the formulation. So then the question is, you know, what, what's the best interval or optimal- Yep I nterval to take into Phase 3? And as I mentioned earlier, we've looked now across the program at Q4, Q8, Q16, Q24. We'll put all that into our updated PK/PD modeling. Mm-hmm A nd we'll choose a dose that we think is optimally, you know, is optimal to take into Phase 3. It's likely to be a quarterly dose, or longer. Longer, okay. Very competitive. A very competitive- Yeah P rofile. Maybe just talk about the update we're gonna get to sixty weeks. Kind of where should our focus be, or what are we trying to learn from that sort of longer-term data? Yeah. Yeah, so the bottom line is that sixty-week data is just essentially completing the trial. So you're gonna see the consistency of the effect and the persistence of the effect to some degree. There'll be some attenuation out to sixty weeks, 'cause that's quite a long period of time after the last couple doses, and of course, safety and tolerability. So one thing we know about our technology, and specifically this compound, is it's very safe, very well tolerated. We saw some, you know, mild cases of injection site reactions, which is not unusual in an injectable subcutaneous product. But so that's really what you'll see, is the consistency of the effect and the competitiveness of the profile. Can you talk about the variability of the knockdown, maybe across different patients? Is it wide ranging? Is it pretty tight? We haven't revealed those details. Yes. We will share that information in a future manuscript and research presentation. Yeah. But, yes, you do look to see... And that's part of the art of choosing the right dose to go- Yeah I nto Phase 3, is that you're choosing a dose and an interval? Mm That captures a majority of the patients into the range that you would hope is Yeah Is going to translate into a benefit. Yep, got it, and you know, post that sixty-week data, maybe talk about next steps for the program and sort of how you're thinking about advancing it, and trial design, et cetera. So we've been thinking about trial design for over a year and a half, and, advised by a great group of advisors as well. So we think we have a very good design. It's differentiated, and so we're looking forward to kicking that off by the first half of next year. Yep. I think you're also planning to meet with the FDA. Is that still the case? And I guess, what are some of the key questions you might have for the FDA, or is it more sort of straightforward and checking the box on a few things, or? Yeah, I mean, you always wanna have alignment on- Yep your design, particularly on your analysis. Because when you do your Phase 3, obviously, you're thinking through to your label and how the drug is gonna be used once approved. So we really believe there's an opportunity to differentiate our compound from the compounds that are currently in development in Phase 3, in the CVOTs. And so we want to get the agency's agreement on our approach. So those are typical sort of end-of-Phase 2 questions. Yep. Then, is it fair to assume there'll be some type of outcome, and maybe just how long could the study be? Is it- A CVOT. It will be a CVOT. Okay. Oh, yes, I'm sorry. Yep. Yep. Yeah, it's a single CVOT trial, and those trials are event driven. So you know, typically, you think about a year to a year and a half to enroll a large trial like that. And then usually, there's a minimum amount of time you need to follow those patients up. Mm-hmm. So typically, what you're thinking about is sort of a four- to five-year- Mm-hmm range for a study like this. Yep. And can you talk about the competitive landscape? You sort of mentioned a few times some points of differentiation. Maybe just talk a little bit about those, you know, key differentiators for you. Yeah. So you know, as I mentioned, the lead compounds now with regards to the Phase 3 programs that are ongoing is the Novartis compound. So that, of course, is an antisense compound. That's given on a monthly basis, and you know, it has you know, good efficacy, of course. You know, it has an effect of in the 70%-80% range. The siRNAs are more potent at their maximum suppression, so like zerlasiran. You know, Amgen has a compound, and clearly, they're also in that upper range, as we are. So that's why we're very confident we've got a very competitive profile, and that's why it's important to. By the way, the Novartis trial is gonna read out next year, midyear, and the Amgen trial is likely to read out in 2026. That's why it's very important for us to really distinguish ourselves in the design of our Phase 3. Yeah. The types of high-risk patients we put in the trial, certain important, sort of inclusion and exclusion criteria, you know, for instance, you know, thinking through, the level of Lp that you would allow in, those kinds of things. Yep. But those are very competitive issues, as you can imagine. With the Novartis study reading out, is there something you could maybe learn in that study that makes you sort of rethink how you wanna design the Phase 3, or, or? So we will already have initiated- Yeah Our trial by the time we get that answer. Will we learn from that? We will all learn from that, and we're hoping for its success. We can make some adjustments, of course, along the way, but minimally, once our trial is underway. Gotcha. And how are you thinking about, you know, sort of the future of this asset in terms of commercialization? And is that something you do on your own? Do you partner it? When's the optimal time to do that? What does an optimal partner look like? It is a large asset for us, a large potential asset. There aren't too many assets, if you look at the forecast, going forward, over the next decade. In cardiovascular arena, there are probably single-digit number of assets that are multi-billion dollar sellers. We're very pleased that we're in that league, potentially. It does, however, require the resources and the commitment to get there and the promotional activity. We will and have been talking to, you know, potential partners for resourcing more broadly, whether that's promotional activity, development, R&D sharing, or just more broadly. Is a preference, you know, global partner, I assume, is that, or not? Just depends on the resource they bring- Yeah To be honest. Gotcha. Could be regional, could be global. Yep. Any way to think about timing, optimal timing for that to happen, or is it hard to sort of- Excuse me. No real optimal timing. I would say it's a continuum, I think- Yeah Of de-risking and what the value potential could be as you de-risk. We've done a great job of de-risking. Yep M oving through the clinical trials. The data has been outstanding, as we've alluded to. So, I think the partners that we've talked to have been very encouraged as we've moved through those phases and had such great readouts. Yep, makes sense. Maybe we can shift to just divisiran. Polycythemia vera, maybe just give us a brief background there on the disease and kind of the unmet need currently. So it is a myeloproliferative neoplasm associated with extra red blood cell production. So it is one of those conditions that is a challenge to treat. We're very pleased that, again, we're in this arena with siRNA, and we've just now shared the data that I know we'll go over. It's just outstanding data for us, because for a control group that comes in at a hematocrit at 45%, we were able to continue that with treatment at 100% efficacy. So it's a very unusual in pharmaceuticals to have 100% efficacy, but it's just an outstanding result. So, the condition is one where patients have phlebotomies or take blood on multiple occasions, three in the last six months, or one or five in the last year, leading up to the treatment. And after the treatment, we've had this incredible effect. So we will continue this as quickly as we can into a Phase 2, 'cause that was an open label, Phase 1. Yep. Can you maybe talk a little bit more about the endpoints? You touched on some of them, reduction in phlebotomies. Maybe just expand on that a little. Yeah. No, absolutely. So as Craig was saying, these are all phlebotomy-dependent patients, so they have a minimum requirement to come into the trial. We allowed patients who had any, a range of hematocrits at baseline. Yeah. So we didn't restrict it to those who were well-controlled. You know, this is a Phase 1, so we had the opportunity to explore a range, the effect across a range of patients. We also didn't, you know... We also, I should say, allowed patients on any background therapy, so we allowed standard of care therapy beyond phlebotomies, as long as it was stabilized for the previous twelve weeks prior to entry into the study. So the outcomes that we were really looking at are, you know, twofold. So we're looking clearly at a reduction in phlebotomy. So you want to, for those patients who are well-controlled, you wanna keep them well-controlled, but remove the need for phlebotomy, and you wanna maintain or reduce hematocrit. In those higher hematocrit patients, you wanna see a reduction in hematocrit and a reduction in the need for phlebotomies, and in the patients who come in well-controlled, you wanna maintain that low level of hematocrit below 45 without the need for a phlebotomy, and that's essentially what we showed. As Craig said, for the patients who came in well-controlled, every one of them in the limited data set that we presented, and we'll present more later. Yeah This year at ASH. Each one of those patients maintained their hematocrit below forty-five without the need for a phlebotomy. So in the group that had high hematocrit at baseline, we had two patients, each of whom had a single phlebotomy requirement, but that was a significant reduction from their historic- Yeah R ate of phlebotomy. So really very, very excited about the data. We also showed good target engagement, so you're elevating hepcidin, and that appears to be associated- Yeah W ith benefit. Everything lines up nicely. Everything lines up, yes. Yep. You know, the RBCs are associated with viscous blood, right? So one of the real concerns for patients is that, they have potential blood clotting, and you know where that leads. Mm-hmm. It's a very severe outcome, so... Yeah. The results were pretty impressive, and you mentioned, you know, sharing, you know, sort of a longer term update, you know, later this year at ASH. You know, what, what should we be looking for? Is it just more of the same, or you want more, more reductions in hematocrit or anything? We'll have completed the enrollment and the, you know, the completion of most of the patients in the three cohorts. We studied three mgs per kg- Yeah S ix mgs per kg, and nine mgs per kg. When we released the data, that was a cutoff of late March, when we released that in late June, so we'll have completion of more of those patients. But we'll also show some of the other biomarkers, so many of the blood-related indices, as well as the indices of iron metabolism. So you'll get a much fuller picture of the effect of the drug over time. Can you talk about next steps from here? I think it's advancing into a Phase 2 study, and maybe what that design could look like, and is there anything notably different in terms of maybe baseline characteristics or patients you might enroll? We are the first with an siRNA and PV, and we'd like to remain in that position. Our goal really is to initiate the Phase 2 by year-end. It's a lofty goal, but we would like to get there. Yeah, and I think what's important is the patients that we'll put into Phase 2 and three now, or into our full development program, whatever that ends up looking like, and I'll talk a little bit about that in a second- Sure A re gonna be well-controlled patients. So, you know, you'll remove the variance that you have by starting patients at all levels of hematocrit. Yeah. So everybody will be well-controlled, and then you'll look to see if you can maintain control as well as, obviously, without the need for phlebotomies. But we have, you know, we have a couple. We're an orphan designated product. We have fast track designation with the agency. So that all gives you a good, you know, opportunity to have, you know, robust discussions with the agency about the most efficient program design. So not just the Phase 2- Mm-hmm B ut what would it take to get the product to the market as efficiently as possible? so that's one of the things we'll be talking about. So are you referring to maybe, like, accelerated approval or some other type of endpoint? Yeah. Is that what- Not necessarily accelerated approval- Okay B ut an efficient development plan. Okay. You know, we have no safety issues that have been- Yeah I dentified, nothing in the preclinical space that would be of concern, and we've now exposed healthy volunteers, patients with certain iron loading conditions like beta thalassemia, and now the patients with polycythemia vera, and the safety and tolerability look really nice. So I think there's an opportunity to say to the agency, "What's the best..." You know, and a very robust effect size in the Phase 1. Yeah. Yeah. Yeah. So what is the most- Right E fficient development program to get this to? A nd durability will also be a real differentiator. Yeah, durability is huge, you know, because right now we've tested Q six weeks. So in our Phase 1 trial, we gave the drug four doses every six weeks and then followed them out at an additional sixteen weeks. So we'll have a good sense of the durability of the effect and whether or not we could even extend that in- Yeah Phase 2 and 3. Yeah. You mentioned focusing on well-controlled patients in the Phase 2, and how does that look as you sort of continue to move forward, you know, with a registration path? Like, even if you study in these smaller subset, do you get a broad label, or do you get a more narrower label, or? Yeah, and, it's not a smaller subset- Okay B ecause you can still bring in patients who might have elevated hematocrits, but before they get randomized- I see what you're saying, yeah. Y ou get them to a level, and then you challenge them with, Yeah Y our agent or placebo and see if you can maintain them. So it's still going after the broadest group of patients who are phlebotomy-dependent. Yep, makes sense. Can you talk a little bit about dosing frequency? I think you said you've tested every six weeks- Right But I think there's opportunity. You've mentioned in the past the dose may be even less frequent. You know, what- Yeah. How do you test that? Where do you test that? You know, how less frequent- Yeah Is less frequent? Yeah, so, you know, you want an efficient program because this is a rare, relatively rare orphan condition, so you have to be careful. Yeah. But you know, in our healthy volunteer study, we gave a single dose and looked out, you know, two months and saw a very, you know, sort of, robust effect at four weeks. That was attenuated a bit, but was maintained through to two months, and that's how we decided to choose a Q six-week dosing strategy for the current study. Now, we'll look across the three dose cohorts that we have, three, six, and nine mg per kg, you know, in the study that we're completing, and we'll choose the dose that we think is, is optimal. Then, we have the option to take that dose and look at it at six weeks. We can repeat exactly what we did- Mm-hmm B ut we can also consider whether we wanna look at a longer term interval, say, for instance, quarterly. So those are the things we're gonna consider as we move forward. Okay. Makes sense, and there's a competitor out there. Maybe you can just talk about some of the differentiation you've seen so far. Yeah. So with. Well, the competitor, rusfertide, is, of course, the lead compound there, and that's a synthetic peptide, so it's a little different than ours. Ours were sort of targeting TMPRSS6 and silencing TMPRSS6, which has an impact on the elevation of hepcidin, et cetera. They're giving exogenous hormone. They're giving it on a weekly basis, so it's a sub-Q injection, but on a weekly basis. Ours will be less frequently, obviously, because the technology allows us to do that. Yeah. And there are other products in development, but we wanna be the first siRNA. We're the lead siRNA right now. We think that is a terrific technology to apply to this condition, and we just wanna, you know, accelerate our program. Yeah A s quickly as possible, and as Craig said, we're gonna start a Phase 2 by year-end. Yep, makes sense. Maybe we can just shift. You have some partnerships. Maybe just talk a little bit about those and, you know, what that tells us about your platform. Again, we explore with partners in areas we may not ourselves necessarily explore, and it's great because we receive non-dilutive funds for that: one with AstraZeneca, one with Hansoh, China. The AstraZeneca relationship covers up to 10 targets in kinda broad categories. Fortunately, we're in a Phase 1 clinical program that seems to be going very well. Again, we're working on kind of the next set of opportunities with AstraZeneca. We also have this relationship with Hansoh, with three targets, and we tend to do the earlier work before we transfer over and receive funds for that. Both of those are going quite well, and combined, we can earn up to $5 billion in income from those two relationships. So again, it's a great way in biotech to actually have the ability to achieve non-dilutive funds. Can you talk a bit more about the rest of your pipeline? I think you have some complement inhibitors and some other sort of unannounced targets. Maybe just talk a little bit about that and how does that fit into your priorities. Is it, you know, advancing those near term or partnering them, or how do you think about that? So the two proprietary programs keep us very busy- Yep Z erlasiran and SLN360, SLN124 and the PV program, but fortunately, we didn't stop work on the other programs in the last couple of years and funded them, and so now actually, we're spending time prioritizing those and looking to see which one of those we move forward or which of those we partner, so we actually have the flexibility to do that. In terms of the complement space, as you probably know, we had the Mallinckrodt relationship. We were able to bring back two of the preclinical assets that we saw data on that was very good, and that is up to us now to determine whether we move those forward or partner. It is a hot space. Yep S o we're glad we have the opportunity to do that. We have other programs- Yep L arge and small. So again, this technology is diverse, and so we have some that are in the larger areas, some that are more in the orphan area. But the technology, we think, is very, very good to, you know, move forward with some of these programs. Okay. Maybe just one last question, if you can remind us the current cash position and sort of the runway. We are in a good cash position, $189 million at the end of Q2 in cash and cash equivalents. So, that will fund us into twenty twenty-six. And so we have factored in these other programs that we wanna move forward, the proprietary programs first. And so we'll look at those two, and then beyond that, the rest of the funding. So we're feeling like we're in a very nice position. Okay P articularly given this very, very tough external environment- Yep W e've lived through. Definitely. Okay, great. Looks like we're just about out of time, so why don't we end it there? Thanks, Craig. Thank you very much. Steve, appreciate it. Thank you very much. Appreciate it.