All right. Good morning, everyone. I'm Mike Ulz from Morgan Stanley. But just before we get started for our next session here, we're gonna pause for a moment of silence to remember those lost in the September 11 attacks. Okay, thanks, thanks, everyone. Thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here, and it's my pleasure to introduce the team from Silence, including Craig Tooman, Chief Executive Officer, Steven Romano, Head of R&D and Chief Medical Officer. Just a reminder, the format for today is a fireside chat. If anyone has a question, please feel free to raise your hand, and we'll try and address it during our discussion. But before we get started, I just need to read a quick 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." With that, I'll turn it over to Craig, who will just give us some introductory comments before we jump into the Q&A. Thank you, Mike, and thank you all for joining. Silence is really about silencing genes, and we'll talk a little bit about that today. We're in a great space and really enjoy the evolution of the company as we gravitate a little bit more toward the United States here and funds as ownership here in the U.S. The company has had an outstanding execution year thus far. One of the big items for us was the SLN360 phase II program. We kicked that off at the beginning of the year, and with anticipation that we would fully enroll that trial by year-end this year, and we fully enrolled that trial in four months, in April. So, something I've not seen, eight-month acceleration of a schedule like that. We also kicked off SLN124 in the PV study. Our other proprietary program, that is gaining good traction now. We like very much the way that trial is designed. We'll talk a little bit about that because the first portion of the phase I is open-label, so we're able to look at that data ourselves as we move forward, and then it'll convert to a typical phase II. So very pleased about that trial initiation. And finally, the partnerships which we have, and we'll talk about the hybrid model that we have that combines our own programs and those that are partnered. Great relationship with AstraZeneca, and we announced a $10 million milestone in the first candidate selection with AstraZeneca this year. And that really sets up a track, if you will, of further milestones, we believe, further down the road. So while we identify other targets in that 10-target program with them, we actually have locked now into one. So very pleased about the progress on all three of those fronts. Yeah. Great. So thanks for that introduction, and congratulations on all the progress so far this year. Maybe just for people that are not familiar with the platform, maybe you can just describe the platform a little bit, you know, in the context of the RNAi field and sort of how it's evolved over the past few years, and then what are some of the advantages there? So, we're an siRNA, mRNAi GOLD platform, as we call it. It's really an outstanding platform, both for the durability, the activity, the knockdown, which we'll talk about in our phase I, that we've seen was just outstanding. But again, it is genetic, and, what we've seen historically is that the likelihood of success in moving from phase I to phase II and phase II to phase III, is meaningfully different for, for this area, and so we know a lot of companies are now very interested in siRNA and its adaptability. Most importantly, it's also a reversible technology, so we are not permanently altering genes. It's completely reversible. It is durable, but all you need to do is stop taking the treatment, and, you will revert. So very pleased about that in general. Also, I think if you look at the natural progression from the ASOs into siRNA, you've certainly seen the knockdown and the durability be an enhancement factor. So obviously, we're hunting in a space where we like to be, and I think others are discovering. Steve, anything you want to add on that? Yeah, only to say that, you know, we've got great proprietary, you know, a portfolio of proprietary technologies that include the sequences that we target for the purpose of intervention, the linkers that we have, as well as the GalNAc, with GalNAc focus, which means we focus on hepatic genes, and hepatic expressed genes are over 14,000, so we've got a huge opportunity targeting the liver. So as long as we understand the biology, and we've got a target protein, we can actually intervene very confidently. Gotcha. Maybe you can talk a little bit about your approach to partnering. Craig, you mentioned it a little bit earlier in your introductory comments, but, for a fairly early-stage company with several partnerships, to us, that's validating, but maybe you can talk a little bit more about those. Feel very blessed to have those partnerships and from those. What's great about that is, for a company our size in biotech, we have this hybrid model, as we refer to it, where we're able to earn non-dilutive money from partners who are very skilled in their own areas. And it allows us, with our technology platform, to expand in areas we otherwise might not expand. So, AstraZeneca, as we mentioned AstraZeneca, a 10-target deal. We've just announced our first. Again, the combined expertise of the two companies really allows 1 + 1 = 3 in that synergy notion, and it's really a thrill to watch it happen. We also have Hansoh deal, and two of those have done very well, moved forward, progressed very quickly and early in the development. We have received $4 million in milestones for those, $10 million for AstraZeneca. So, again, these are sometimes an area where targets otherwise Silence itself, as a pure biotech company, wouldn't have the chance to explore. And the third is Mallinckrodt. I hired Steve from Mallinckrodt, who's a CSO there. Very pleased to be able to have hired Steve, who is on our board. And, there, again, complement space with Silence ourselves have entered, complement space first, maybe not, but the combined expertise with Mallinckrodt really made sense for us. So, you know, we were able to go in and see again some of the preclinical work on two of those compounds and bring them in-house. It was a great opportunity for us because, of course, Steve already knew all of the background of us as a partner to us on the other side, now joining us. But also the complement space is very exciting, right? And so getting to see that in the preclinical phase was great. The third program there, which is in phase I, continues with Mallinckrodt. We knew Mallinckrodt was gonna be focused on the later stage commercial opportunities for them. That's where they are in their arena, so it was a complete win-win for Silence and for Mallinckrodt. Got it. Maybe we can just shift gears a little bit to zerlasiran, formerly SLN360, you know, clinical development for Lp(a). So maybe just talk about that target a little bit. You know, how validated is it, you know, in case people just aren't that familiar with it? Well validated, certainly in the literature, for as an independent risk factor for cardiovascular disease. And you do see the, you know, two- three times higher risk in, heart attack, you know, stroke, et cetera. Many of these are impacted by Lp(a). And Lp(a), not so long ago, was not something, you know, colloquially described. Certainly in the medical community, they knew about it. But in the last two - three years, it has really blossomed as something that the medical community is paying a lot more attention to. And, Steve, I think even the medical societies are- Yeah, absolutely. So, you know, it's clearly acknowledged now as an independent risk factor contributing to cardiovascular outcomes and disease. But it's not modifiable the way, for instance, LDL and cholesterol is by exercise, diet, et cetera. And of course, there's some very good medicines to reduce LDL, as we know. But this is really a genetic condition, so you are accumulating risk from birth, essentially, but from age two onwards. So very, very different. So very excited about being able to target the residual risk of patients who are at higher risk for cardiovascular disease. For those patients, I guess, are they tested today for Lp(a)? And then if they are, have a high level, what do you do with those patients right now? Yeah. Most of them are not tested today, but the tests are available. Specialist centers, you can actually see it, and actually, the booths are now doing it at the medical conferences, so you can actually get tested. But we fully expect that, with the growing evolvement of this target, you're gonna see widespread. I mean, medical societies are already acknowledging that it's a risk factor, whether it's Europe, Canada, United States, and I think the guidelines are actually gonna mature as the treatments mature. You know, when the outcomes trials come out, we already have very good data about the influence of Lp(a) risk through epidemiological studies, through genetic analysis, Mendelian analysis, et cetera. So I think there's gonna only be, as Craig suggests, growing interest in that. Good. How would you characterize the current awareness among physicians? Are most aware at this point? I think the majority are aware. Yeah. I mean, it was a steep curve, but you're seeing it, it increased tremendously. And the bottom line is, even if you don't have an intervention right now, Mike, the bottom line is it identifies a potential sort of additional risk factor that would allow physicians to be even more aggressive about managing those risk factors that they can either treat pharmacologically or through modification, you know, behaviors, et cetera. So very important. Do any current treatments, you know, to reduce cardiovascular risk, have any impact on Lp(a)? PCSK9s have- Yeah. They're not specific to the treatment- Yeah. But we do know that what practitioners are looking for is something very specific- That's right. ... and higher end in terms of the knockdown, which we see in our class, right? The siRNAs are, you know, in that 90% arena, and we've seen that in our phase I. Can you maybe talk about what percentage of patients, I guess, what's the cutoff for what's considered high Lp(a), and what does that patient population look like? It's approximately, you know, when you get into high, it's 30 mg per deciliter, which equates to 75 to 125 nanomoles. The literature obviously is evolving as you look at those cutoffs- Yeah. Yep Yep ... and it's now seen as more linear at risk, as opposed to stairstep or threshold, in its orientation. But, you're talking about 10%-20% of the world's population, so this is a huge issue globally. It is not a U.S. problem. It is a global issue that we see across many countries in the world. So, huge on that medical need. Yep. Makes sense. Maybe we can shift to your phase I sort of APOLLO study. You showed some early data, very promising. Maybe just walk us through that and why that's important. 2021, April ACC, we depicted that data. 96% to 98% knockdown in the two highest doses, 300 and 600 mg, respectively. But you know, at half of the dose, right, at 300 mg, 96%, pretty incredible knockdown. And again, this was single dose. So, we're working on the multiple-dose, which maybe Steve can tell you a little bit more about in a minute. That readout comes here by year-end, but the single dose was just incredible. And of course, it was safe and 150 days out, we still saw 80% knockdown, time average. So really incredible and durable response and safe. Yep. Did you, could you hit, maybe remind us what doses, did you go higher than 600? 600 was the highest dose. Right. Could you have gone higher? I guess, do you need to go higher with nine- Really no need to when you see reductions to that extent. Yep. Got it. Somewhere between 98% and 100%. All right. I guess another question, obviously, you have an extremely high level of knockdown. Is there a consensus around, you know, how much you have to knock down to start to have an effect on cardiovascular risk that you can actually test for? You said it was linear, but- Yeah. Well, I mean, the accumulating view of the field is that you really have to get to 70% or more knockdown. Got it. Now, that is, as I said, is accumulating, you know, sort of alignment. But we have seen in the PCSK9 trials and even published data that was presented, that even modest effects are having an impact independently. So the bottom line is, I think for a specifically designed compound that's going to target Lp(a), we're really looking for 70% +. And as you can see, it looks very achievable. Yep. Sure. You mentioned giving an update sort of on APOLLO study Q4 this year. Can you just remind us what doses you're testing, what frequency, and kind of what we should be looking for, what you're looking for specifically? Yeah. So, we haven't really shared the doses specifically, but the bottom line is between the phase I single ascending- dose and the multiple-dose data, as well as the phase I data that's phase II data that's ongoing, we'll have a range of doses and a range of regimens that will allow us to pick the optimal dose for durability and efficacy going into phase III. So we've got multiple-doses and multiple regimens that we'll soon be able to review in the multiple-dose data. Can you maybe talk? I know you don't want to talk too specifically- Yeah ... but can you talk about maybe frequency, if you can? And is there any overlap in the APOLLO versus the phase II, or did you design both those studies to really test a range of doses and frequencies to kind of get the best answer? It's the latter way. Okay. So, we have a number of regimens with, including the doses and the difference in timing. All that will feed into a model, as obviously in the data as well, to predict the best optimal dose taking it, that will go into phase III, which, of course, will be a much larger study. Yep. So we get an update at the end of this year from APOLLO. What, you know, how many patients, how many doses? Yeah. Will that be kind of the end, or will we get another update later? You know what I'm saying? Yeah. No, this will be- Yeah. So, in the phase I, we have a total of 68 patients. There were 32 in the single ascending- dose, which we presented, as Craig mentioned, and another 36 in the current multiple-dose portion of that. And that will then go... The phase II has about 160 patients. So we'll have plenty of information, good PK data, obviously good pharmacodynamic data on the outcome of interest, that we can then select the best dose going forward into phase III. Yep. Fortunately, the phase I was very telling in terms of the dose response, so our starting point was excellent. Yep. How should we think about the ALPACAR, the phase II? You, you completed enrollment earlier this year. You have data mid-next year. I guess versus what we see in Four Q, will it just be supportive? Will it give us more information? How do we think about those? So we see those two trials together informing, obviously, the Phase III. That trial, as I mentioned, completed much more quickly than we thought. So we'll actually have two, almost timing-wise, two very good indicators following up for the Phase III design, which we've spent a lot of time doing already. So it'll be confirmatory in many respects to what we have assumed in planning some of that Phase III design. If you get the answers you're looking for off the APOLLO, could you potentially start the pivotal sooner, or would you still wait till you have sort of the phase II ALPACAR data? We'd want to see the Phase II- Yeah ... data. Yeah, of course. Gotcha. Um- But just to add, we're not waiting, so there's a lot of preparation- Yeah. Right ... as you can imagine, when you go into a phase III program. A lot of preparation. We know we have to differentiate, as any product would in a phase III program. Differentiation translates into your label. The bottom line is we're doing a lot of thinking internally, but also with a great deal of interactions with key opinion leaders. So- Yeah. ... feeling confident about our preparations- Yeah. ... going forward. Makes sense. Yeah. You mentioned differentiation. Where do you see potential opportunities for that? I know we're still waiting for the data, but could it be, I don't know, safety or... Any thoughts? I think all of these compounds- Yeah. ... appear to be pretty safe. Okay. So it's not really an issue of safety, although you want to optimize the dose and duration, and you want to balance your likelihood of efficacy and outcomes with a convenient regimen for both for patients and physicians. So I have a good idea. So you can differentiate on your regimen. Yeah. You can also differentiate on the population. Cardiovascular populations are broad. There's, you know, so we can also look very carefully at that. We know what the others are doing because some of that is published, so we can take advantage of some of that information. Yep. As we sign that. Being second might come in handy. Yeah. And we actually have a great, KOL network and larger- Oh, absolutely ... community that's also advising us. So I have to say that the larger body around this trial has really been terrific. Yep, maybe since we're on differentiation, you can talk about some of the competitors in the landscape. And there's been some updates from each of those, so maybe you can just share your thoughts on some of that development. We've seen the data, nothing surprising at all to us and the readouts that we've seen. Obviously, the ASOs have an association with a certain efficacy profile and knockdown and durability. The siRNAs as well, of which we are one, as I mentioned, have tended to see the knockdown in that 90% arena. So really, if you boil down to what you've seen historically from the other competitors, that kind of falls in those two buckets. And some of the competitive, I think, movements have been around either the knockdown or durability enhancements that they'd like to see. Yep. I mean, we certainly like to see the safety play out, and it's nice that there are other companies doing work in this population and demonstrating the safety of the class. And, in general, it gives you greater confidence in your own program. Yep. Makes sense. Maybe we can pivot to SLN124. You're in development for multiple rare hematological diseases. Maybe you can just talk about the strategy there and the current status of that program. You know, the great thing about this is it's seen in a broad range of hematological disorders. So we have spent our time here studying, which makes the most sense corporately. And we've made some, you know, moves in that in the last couple of years. And one, starting the PV trial, as I mentioned, this year. And these are smaller areas, if you will, but certainly interesting areas and high unmet medical need. And PV, in particular, we're getting a lot of interest from the investment community because of some of the perceived safety issues of some of the competitors. And for us, leaning into this with this Phase I, that's open-label, so we get a peek at safety here a little bit in addition to other things, but particularly safety in a Phase I. We've designed the study that way to kind of make it, you know, competitively interesting for us. Beyond that, we have seen some very good preclinical areas that we're not in today that we'll, you know, think about a little longer term as we evaluate which is the best area to go in here clinically. Yep. And maybe I'll just add for folks that might not be familiar with SLN124, it's targeting TMPRSS6, and TMPRSS6 sort of puts the brake on the body's ability to produce hepcidin. So you block TMPRSS6, you increase hepcidin. Hepcidin is a moderator of iron. It's a sort of a gold standard moderator in the body. And so there are a number of conditions that are associated with you know, the potential benefit from manipulating that system, and that's why we're very excited about that. We've got beta thalassemia data, the multiple-dose data coming out very soon. And as Craig said, in polycythemia vera, another condition we're intervening on with a mechanism against TMPRSS6 could be helpful. That, of course, is very exciting as well. You mentioned the beta thal data, sort of 4Q, I think is what you're sort of- That's right. Guiding to. Maybe just talk about what we should expect there, patient numbers, you know, what's the key endpoint? And can we get a sense of efficacy, or is the focus there really more safety initially? I think we can get certainly safety as well as a signal of efficacy. Absolutely. Because you could look in these patients for an elevation in hemoglobin. So we would be looking at, among other things, an elevation of hemoglobin that's clinically relevant in these patients. Yep. And maybe PV, you said there's a lot of interest in that- Yes. ... program. When might we see that data? And similar question like, We've not given a timetable for that just because it is a little tougher to enroll that leading into with that expectation, but it. We're doing very well now. We will look at that Phase I, which is open-label, and then determine whether we share some of that before we move into Phase II, which is, you know, the double-blind, placebo-controlled trial. So there's a point between those two where we'll highlight to the marketplace what we see. Yeah. And we've designed it, I think Craig mentioned this earlier, we've designed it so that we can accelerate if we need to. So that open-label portion, we can evaluate patients. We don't necessarily have to fill each of the cohorts, depending on the progression of those patients and the data we're getting. And then we can consider moving forward seamlessly into the phase II portion of the trial because it's a phase I-II combination trial. So we're very excited about that. Okay. Maybe I could just ask a more broader strategic question. Just given the platform and the broad potential across a number of different indications, maybe just talk about why you selected the indication you've selected so far, and then in the future, you know, what-- how could you expand that, or what other directions could you go in, and how do you think about that? Yeah, well, just to start, so the bottom line is you look at conditions where you think manipulation of hepcidin, you know, are associated with reductions in hepcidin, and you think that elevation of hepcidin could have an impact. So although the pathophysiology of some of the programs we've chosen are very different, we still know that hepcidin plays a, plays a role. Very different in beta thalassemia, for instance, than polycythemia vera. But there are other opportunities. We haven't discussed those, but there's a range of them, and I think we will build upon the data that we see both in beta thalassemia and polycythemia vera to depend to determine next steps. But back to the hybrid model, we do have, you can imagine, potential partners who reach out to us frequently, and actually more on SLN124 recently as well, with areas that they'd like to pursue with us. So we'll look at those as well as we evaluate the complexity of this map for ourselves. Maybe just even broader with the platform beyond that area, in terms of deciding to go with Lp(a) first versus something else initially, and, you know, what sort of drove that? Well, it's a portfolio approach for sure, as you can imagine. You know, we're not a huge company, so resource-wise, we look at what makes sense for us. Lp is a large opportunity, unmet medical need in huge markets, as we mentioned. And then, you know, it's great because SLN124 tends to be in kind of smaller areas. So the combination is a very different resource equation. The partnerships have allowed us to look at things, as I mentioned, we otherwise might not, and some of those are large, and some of those are medium in size, and some are small. So, for us, we're managing all of that, if you will, in kind of a portfolio sense. Yep, makes sense. How do you think about partnering for the Lp program? Is that something you will consider in the future at some point? What are the triggers there? We've made clear, I think, historically, that we're open to partnership on Lp(a) if it makes sense for us and makes sense for the partner. People frequently ask us, you know, what's the right timing for that? And my response is, well, when it makes sense for both parties. I've seen early-stage programs be partnered and later stage. It just depends. As you know, the big pharma companies tend to like the, you know, phase II results, if you will, and the certainty of having those. But it doesn't mean that they wait for that because they sometimes want to have an impact. So to me, it's time and place for both parties and ultimately, what makes sense for both. But we are open, and we've made clear we are open to that. Gotcha. I guess for the Lp program, you'll have the phase II data mid-next year. Assuming that's positive and you have some differentiation, can you just walk us through the next steps, maybe, maybe a little bit of the trial design, endpoints, duration of the study? So I think we mentioned earlier, both Steve and I, this—you can imagine the phase III design is something that is potentially complex- Yeah. And we want to make sure we really plan it out well. So we have been planning for quite some time. And, you know, we would move into that phase III as soon as practicable, whether it's ourselves or with a partner. And we've kind of given you our preference, but it just depends on how that all plays out. But certainly, we've spent a lot of time with KOLs, with our teams, with experts trying to figure out what is the best trial design for differentiation, you know, for the molecule that we see today, and then we'll wait for those other readouts to confirm that. Yeah. We're way down the road on the planning, I'd say, Steve. Oh, absolutely. Yeah. The primary endpoint would be sort of the cardiovascular outcomes. Is there anything you can- Yeah, so we're- Shorten that? ... keeping that kind of close- Okay. ... because we're really considering... again, differentiation is so important, but obviously, it's going to have cardiovascular- Yeah. ... um, outcomes. Yeah, fair enough. Yeah. Okay. I guess, maybe just talk about your current cash position, runway, how you manage that going forward. You talked a little bit about partnerships, but just- It's been very helpful in this hybrid model, again, versus straight biotech, to have that non-dilutive opportunity. And we can often see it. People ask us, and, you know, we can't always comment on the timing of that. We try to do our best to kind of forecast a year ahead of what we see. We did forecast ahead this year that we'd get the $10 million from AstraZeneca and the $4 million from Hansoh, and look, that is all in the bank today. So we're at $77 million in cash pro forma end of Q2. That includes the $14 million of milestones, which we've achieved and now received. And so, you know, we're feeling like we're in a good cash position, currently. Yep. Got you. And is there anything else we should be looking for? Maybe just the last question, just, you know, remind us what the catalysts are from here over the next year or so. So it's a rich year for us. So as I mentioned, so happy we've been able to execute on the things we've been able to execute on, particularly that phase II trial on SLN360. That set up a lot of things, and for us to get behind that data, you know, with our cash balances before, you know, that readout comes. I think also we've got the MAD data, SLN124 for thalassemia coming by year-end. We also have the SLN360 MAD data coming by year-end. And then mid-year, as we mentioned, will be the phase II readout. So you have kind of several things coming here in the next six months. Yeah. Okay, great. So a lot to look forward to. Thanks, Craig and Steve, for sharing your time today. We really appreciate it. Thank you for having us and for covering us. Thank you.