Great. Welcome everybody to the Leerink Partners Healthcare Conference. My name is Roanna Ruiz. I'm one of the Senior Biotech Analysts here at Leerink. It's my pleasure to introduce Silence Therapeutics and members of the team. With me today, I have Craig Tooman, CEO and Steve Romano, Chief R&D Officer. Thanks for joining us. Thank you very much. Thank you to the Leerink team. I'll start with the forward-looking statements. Safe harbor. We will probably be making some forward-looking statements, either in the presentation or in Q&A, so please make note of that. Silence is aptly named because we block genes. We silence diseases through precision-engineered medicines created with our own proprietary special sauce, our siRNA technology, plus the linkers, so that we are a reversible technology and all done through chemistry. We're very well positioned today because we have a very productive GOLD platform, which we'll talk about. It's GalNAc, oligonucleotide delivery. We're delivering very positive results in multiple areas of unmet medical need. We also have multiple clinical programs, including phase III-ready CV asset by the first half. That's an Lp(a) and we'll talk more about that. Also, very exciting phase II, first-in-class siRNA in polycythemia vera. We also have a partnership, as you know, probably, with AstraZeneca. That's in a phase I program, undisclosed, but that's going very well too. If we look at a little longer term, we're looking at extrahepatic programs with some really early promising data in multiple cell types. We have a strong financial position with cash runway into 2027 now. A nice mix of very good data sets, data readouts, things to come in the pipeline, and a great balance sheet. Silence delivered great clinical results last year. If you look at zerlasiran, for example, and the ALPACAR- 360 phase II study, very positive results and high Lp(a). That's a very large market opportunity, as you know, up to 20% of the world's population, so very underserved. We also finalized the phase III CVOT design t hat program will require a CVOT. We spent a lot of time making sure that design is prepared in the best way possible. We've had really great global regulatory feedback on the phase III CVOT design, again, global, so not just the FDA. Zerlasiran is in good shape from a preparedness standpoint. Divesiran SANRECO phase I study delivered very positive results in polycythemia vera. That's part of SLN 124, which has some other opportunities preclinically around it that we're looking at. The lead program is polycythemia vera, and we'll spend most of the time on that today. We were also granted orphan drug designation for PV in Europe. The SANRECO phase II study has dosed already its first patients, so that's off and running. The GOLD platform, more broadly, as I mentioned, also we entered the clinic with that program with AstraZeneca. We actually hope that moves into phase II and we would get associated milestones. We're supporting that program very well. We've also progressed several undisclosed preclinical programs. As we move them forward, particularly into phase I, we'll talk more about those, but it's a pretty rich background. This is our pipeline. Zerlasiran (SLN 360) again, for Lp(a). We're getting that phase III ready. As we've suggested, we are in partnership dialogues, and we'll continue those dialogues to try to fund that study, if you will, for full phase III and a CVOT. Divesiran is SLN 124, lead program, polycythemia vera, started phase II. We'll talk about the timing of that soon. We also are looking at other multiple heme conditions with SLN 124. SLN 312, as I mentioned, is a program we've developed and licensed to AstraZeneca. SLN 548 is complement-mediated disease. That's coming forward in our pipeline most recently. We have multiple programs that are undisclosed. Anticipated 2025 milestones for divesiran for PV. As you know, we had a very good open label phase I. We're following up completion of that, which is in now. We'll be actually sharing that phase I data at medical meetings throughout the year. We'll highlight the continuation and the finalization of that study. SANRECO phase II study, full enrollment, we hope to achieve by year-end, so by the fourth quarter. That is enrolling. As I mentioned, SLN 548 is a complement-mediated disease target in phase I. We're going to start phase I, sorry, by the second half of 2025. That is next to come. Talking a little bit more about divesiran and the heme disorders, you probably know polycythemia vera, it's a rare blood cancer, has significant unmet medical needs. It's a myeloproliferative neoplasm. It really is characterized by excessive red blood cell production. That elevated hematocrit really is what we'll spend some time talking about today. We're really looking at controlling that hematocrit level through our treatment. It's a serious chronic disease. It's associated with thrombosis, so you get a viscous blood through that overproduction of RBCs. Of course, that brings with it cardiovascular risks and stroke. It is a rare disease with 150,000 subjects in the U.S. and 3.5 million worldwide. It's actually diagnosed later in life, often 50 to 70 years old when individuals first get that diagnosis. The median survival is about 20 years. For us in the study, as you'll see, the treatment goal is to try and control hematocrit at less than 45%. That's really the association to reduce the cardiovascular and thrombotic events. Forty-five percent is the target. People living with PV have very significant unmet needs. They've got very inconsistent hematocrit control. It's interesting, as we talked about 45 being the control arena, if you're in the 45%-50% elevated hematocrit, you're four times more likely to die from CV causes or major thrombotic events than those that are actually in the control, or less than 45%. Seventy-eight percent of patients have uncontrolled hematocrit with tests greater than or equal to 45%. Again, very inconsistent hematocrit control. Patients also have iron deficiency. Most patients are iron deficient due to depleted bone marrow iron levels. It's interesting that some of the treatments actually exacerbate that iron deficiency. It's a bit of a cycle. The disease burden, we've talked a little bit about it. Patients have this elevated hematocrit. They often require very frequent, in some cases, phlebotomies to manage the condition. What we're really trying to go in and do is to offer a treatment that offsets that frequent requirement for phlebotomies. Thirty to 40% of patients who receive cytoreductive therapy have a suboptimal response and toxicity issues. The symptoms can be burdensome. It's fatigue, concentration problems, and in the worst case, thrombosis. A patient here has suggested, you know, the PV aspect means that you have to have phlebotomies regularly, which we'll see. I think the most crippling thing about that is the fatigue. What does divesiran do? It's a first-in-class siRNA. We're very pleased by that for polycythemia vera. It specifically silences TMPRSS6 in the liver, where hepcidin is produced. Silencing TMPRSS6 leads to the increase in hepcidin. With increased hepcidin, you've got change in iron delivery. That effectively lowers the RBC production. divesiran, first in class here with an siRNA, has fast-track and orphan drug designations in PV. The phase I study for divesiran evaluated PV patients with a larger range of baseline hematocrit levels prior to dosing. This was an open label trial, phase I, 21 patients, three doses, and administered subcu every six weeks for four doses. A 16-week follow-up period followed the date of the last administered dose. The total duration of the study is 34 weeks, which we've just completed and we'll be talking more about. The key inclusion criteria, of course, is a PV diagnosis, at least three phlebotomies in the last six months or five in the last year prior to screening t hat is a WHO designation. Also, the stable dose of cytoreductive agents are allowed in this study. There is no hematocrit threshold. We brought in patients with high hematocrit and those that were controlled. We will talk about that differentiation with a phase II trial in a minute. This is the outcome of the phase I trial. On the left side in orange, you can see the three cohorts. You can see for each one of those red dots, that represents a phlebotomy. You can see the screening period and the dosing. The dosing occurs in the dotted lines and t hen the follow-up period. You can see in all three cohorts a real significant reduction in the number of phlebotomies. In fact, 79 phlebotomies occurred prior to dosing in this group, and only five in the treatment period and two in the follow-up period. All of those five that were in the treatment period came in with high hematocrit. These were not controlled patients coming in. They were at high hematocrit. So a very, very effective treatment so far in phase I. No well-controlled patients, importantly. In other words, hematocrit at 45%, no well-controlled patients required a phlebotomy in this trial. A very significant finding. If you look at the hematocrit in all the PV patients, you look at the cohorts, the three here, and you look at the 169 days, which you can see is quite a nice change from baseline, again, across all cohorts. If you actually looked at hepcidin, you'll see that significant increases from baseline, again, in all three cohorts. If you look out to day 169, again, you can see that pretty clearly. Divesiran demonstrated a very favorable safety profile as well. There were no dose-limiting toxicities at all and no treatment-related serious adverse events or TEAEs leading to any discontinuation in the trial. You're seeing durability, you're seeing very strong efficacy, and you're seeing really strong safety. Really, to summarize in this divesiran first-in-class siRNA program for PV, as I mentioned, efficacy really great, and we're looking to replicate that in phase II. Durability, which is a real hallmark of siRNA technology, was very good a nd safety and convenient dosing. Of course, the convenient dosing was administered subcu every six weeks, again, four times with a follow-up period. We'll continue to look at this in a little more detail in the phase II. How does the phase II look? Again, the phase I had a little bit more optionality in the high hematocrit patients and the controlled patients. This is only controlling, so less than 45% baseline hematocrit prior to dosing. This is looking at only that controlled group. You still need for inclusion criteria a PV diagnosis and again, the WHO designation of three phlebotomies in the last six months or five in the last year prior to screening. That's the same. Again, the cytoreductive agents in a stable dose form can be allowed. The hematocrit level at 45%, that's what's key. The dosing and follow-up, we are going to look at two dosing regimens, two regimens, and primary endpoint at 36 weeks. The primary objective is the percent of patients with hematocrit at or below 45%, so that control group, and not needing or requiring phlebotomies. That is what we saw in the phase I. The effect of divesiran in improving PV-related symptoms is also crucial. We will also be looking at symptoms. Remember, fatigue and other things are associated with the disease. Full enrollment is expected in the phase II trial by year-end. Turning just a little bit to SLN 548 for complement-mediated diseases, this is something that we have in the portfolio and we are bringing forward. We think it is a very attractive opportunity because it is a clinically validated mechanism. Obviously, that has been demonstrated, and we feel like applying our siRNA technology that has a very precise and potent and durable effect in many situations could give us a real opportunity here. Again, convenient dosing is a hallmark of our technology, and we'll be looking for that. We think SLN 548 has the potential to address multiple alternative pathway-driven diseases and has a very attractive TPP. We will talk about that more as we roll the program out in the back half. It selectively targets complement factor B to inhibit the alternative pathway. It targets CFB. It's really inhibiting the downstream production of C3 convertase and the alternative pathway in its amplification loop. As we mentioned, it's clinically validated. We're starting with that. We think it has the ability and potential to address renal diseases and other conditions associated with overactivation of the alternative pathway. We haven't defined exactly which target and how we're going to pursue this, but we will be getting started in the second half with a phase I healthy volunteer study, which will be a randomized double-blind placebo-controlled single ascending dose study, approximately 32 healthy volunteers. All patients will be vaccinated and receive prophylactic antibiotics if needed, if appropriate. The study is four cohorts, eight subjects per cohort, single dose administered subcu with a 12-week study, including the follow-up. It is a relatively short study, we believe, for us to get to some early answers. Our primary objectives here are to assess safety, tolerability, PK and PD effects. That is on track to initiate enrollment in the second half of this year. In summary for Silence, we feel like we have a very productive GOLD platform on multiple fronts, delivering really great clinical results in areas of high unmet medical need. The clinical programs and Lp(a) in that phase III ready by mid-year, great cardiovascular asset, outstanding data that we've seen so far, very durable and safe and high knockdown. The phase II first-in-class siRNA for PV, which we're very excited is now in phase II. The extrahepatic program is a little bit earlier for us, but some very promising early data. We look forward to exploring that more and telling you more about that. As I mentioned, we're in a strong financial position with a projected cash runway into 2027 now. Nice balance sheet. With that, Steve and I are here for Q&A if you have any questions at all. Yeah, that sounds good. Maybe while the audience warms up, I can kick it off with some questions. I noticed in the beginning you were talking about zerlasiran and probably needing a CV outcome study and getting some regulatory feedback there. I guess what can you share about the feedback you've gotten so far and your thoughts on that trial design? We feel very, very good about the trial design. Some great people have spent a lot of time figuring out how to be differentiated. I will not go into too much detail on how it is differentiated for competitive reasons, but some real industry veterans have also worked with our team to do that. The feedback from the agencies has really been great. I mean, very little that you actually have to either alter or deliberate with the agencies as you get to completing that trial design and getting it signed off on. Very, very pleased by that. Steve, anything that you want to add? I think that's exactly right. I mean, when you're starting a large phase III program that's going to be globally executed, you really do need to have the input of all the different major regulators. Oftentimes I see things a little differently, but in this case, we got very positive feedback, very, very little need to make any changes to our design. I think, as Craig said, and it's worth underscoring, we've worked very hard with external folks to come up with what we believe is a differentiated phase III because we know this is a competitive space, but it's a large space. We feel we have opportunities to differentiate in the phase III and those that, if positive, could read through into the label and obviously into the market. Yep. I'm also very, very proud of our team for the preparedness, including manufacturing. It's not something that small companies have on their radar for a program of this size, 20% of the world's population potentially in terms of the market. To scale up and get yourself prepared when you're Silence has been quite a feat. I'm very proud of our team. It's the same with intellectual property, et cetera. Very broad-based support for the phase III program. Yep, got it. I know in the Lp(a) lowering space, there are other CV outcomes trials ongoing as we speak. There's been a lot of debate about Novartis's HORIZON trial and some of the other ones coming after it. I am curious, have you drawn some learnings from some of those trials or what are you taking away from those and could they read through to your program? We are looking forward to the outcome, obviously, of HORIZON. Of course, there is no data yet that we can look at and learn from. Given that that first program is an ASO and ours is an siRNA, we feel well positioned to see the readout of that and learn from it. We would not necessarily hold up our program for the learnings now that that has been pushed out a year. I do think the industry will get learnings from that, and particularly those of us in the Lp(a) space. Yep. I was curious, what are your thoughts on thinking about Lp(a) lowering and the debates about dosing frequency, convenience versus potency, et cetera? Where does your mind stand in thinking about zerlasiran and positioning it in the future? Being an siRNA, we're very, very pleased that we're getting the knockdown in the 90% percentile, as we like to say. Very, very safe, very, very durable. Steve, do you want to comment a little bit? Yeah, I think when you're making decisions about dosing and dosing interval, you look at all your data. Obviously, the siRNAs are very potent, so we can achieve maximum suppression of well beyond 98-99%. It is a matter of, do you need to maintain patients with that level of suppression? What level are you comfortable with, and to what extent do you feel confident that's going to translate in an outcomes trial to a benefit? I think we generally feel pretty comfortable that we can reach a very competitive profile with our product where we have durable, potent reduction in Lp(a) that will translate into a benefit in moderating the risk of patients with cardiovascular disease, particularly high-risk vascular patients. Yep, yep. It's very interesting how the world wasn't talking about Lp(a) openly three, four years ago. Certainly now you see it in popular press, Apple News, NBC, things like this. They're carrying articles about Lp(a). The awareness has really changed since our early foray in this target. Yeah, I'd agree with that. Sort of a zoom-out, bigger picture question. What's your estimate or thoughts on how big the Lp(a) lowering market could be? I mean, does it have enough room for multiple players and things like that? Again, 20% of the world's population. You've got epidemiology that's very similar to the statin market. We all know there were many, many entrants in that market all selling multiple billion dollars in annual revenue. We feel like it's a great market opportunity. Look forward to hopefully securing a partner and moving into phase III. Yep. I'll switch gears to divesiran for a bit. I just wanted to check in. How is enrollment going for the phase II so far, and what are you hoping to see in the results? Enrollment is going well. Obviously, we moved from the phase I to the phase II. We took a lot of our learnings as we prepared for the phase II. We have now committed to this year completing the enrollment of that trial. Hopefully that gives you some sense of our confidence in getting that enrolled. Steve, you want to add? Yeah, and as far as what we're looking for, as Craig mentioned earlier, we're now going to only enroll patients who are well controlled. These are patients that are 45 or actually below 45 hematocrit. What we will look to is sustaining patients' hematocrit at that level below 45% while removing or reducing the need for phlebotomy. That really is the outcome. That's not so different from, for instance, you might have heard on the press releases about respiratory, et cetera. That's really the target, to keep these patients below 45%, but remove or grossly reduce the need for phlebotomies to get them there. Yep, got it. Just thinking about divesiran and competition, et cetera, could you just level set for investors who are newer to the program? What are its main differentiators versus competition, and what has physician or KOL feedback been from the trials, et cetera? I'll start with the latter part because the feedback has been great. The bottom line is there's a lot of enthusiasm in this space. There's a lot of excitement about targeting hepcidin in general. There are other products, obviously, that are doing that. Our data in particular was seen as very positive. I mean, the infrequency, the need for infrequent dosing in the case of our study, we provided the drug on a Q6 week basis. Everybody who was under 45%, as Craig said, maintained the control. We followed them for an additional 16 weeks and saw persistence of the elevated hepcidin, which is really driving the effect here. That's the mechanism. A reduction in phlebotomies all the way out to the last day of observation. We see a real opportunity to have a best-in-class profile if our phase II and III obviously share our peer to be as effective as we've seen in phase I. I think that that interval is very important, the convenience of dosing infrequently. We're going to explore in the phase II an even less frequent dosing frequency. I think the important interval, I think the importance of that is some of the other compounds are targeting their monoclonal antibodies or their ASOs, and they typically can't reach that degree of infrequency. We feel that that might be a very important differentiator. Again, we'll have to wait till we generate that data and see. Yep, sounds good. You know, one of the greatest things to me is hearing from the patients. And it's very, very interesting when we completed the phase I, what the patients had to say about really wanting this to continue in the phase II. I mean, they told us, right? And the KOLs who were actually treating those patients. So that to me is really the bottom line. I agree. I thought your phase I data was really interesting. Maybe to help investors as well, just talk through some of the major learnings from that and any changes or adaptations that you thought about going into the phase II. Like what's the sequence of thoughts that went into the phase II design? Steve, I'll let you take it. Yeah, so obviously in the phase I, we had the opportunity to explore the effect of the drug across a range of patients, regardless of hematocrit at baseline. What we have learned is that the drug is very effective in lowering hematocrit and raising hepcidin in that broad range of patients. As we move into phase II, we're going to reduce that variability and only bring patients in who are well controlled. We feel very confident based on the effect in our well-controlled subpopulation in phase I that we can replicate that to a great degree. We're very excited about that. The bottom line is we just really need to move forward as quickly as possible and confirm the great effect we saw. The effect size is quite dramatic, and we want to be able to establish that in a phase II. This will be a placebo-controlled trial. The first trial in the phase I was open label. So it's important to establish that efficacy against placebo, all in the background of standard of care therapy. The nice part of that, looking at those two groups, the higher hematocrit and the controlled group is in a phase I of that nature, you can explore and look at the effect. We saw great effect in that group, right? There was a high hematocrit moving down toward more normal levels. That was the benefit of that phase I and learning from it to roll into phase II. I noticed earlier you were alluding to manufacturing prep, possible scale-up, getting ready for a larger phase III, et cetera. Maybe could you just elaborate on that and what have you been working on these days? The only thing I can say there is in earlier research, a company not so long ago, Silence, manufacturing is just not something that day-to-day is something that researchers think about. It is really an evolution. I'm very, very proud of the company because very quickly they started seeing development results. With development results means you need to be prepared, right? A lot of people spent a lot of time kind of strategizing and figuring out where to go, how to scale up what we needed. They have to work in tandem with the size of the study, right? This is unusual in terms of its magnitude. For a company like Silence to go from not too long ago being early research to really getting prepared for a phase II trial, this size is commendable. Yep, sounds great. Tagging on a bigger picture question to that, could you just remind us your thoughts on cash runway outlook and balancing different investments with seeking a partner potentially for phase III and then the PV program, pushing that along as speedily as you can, but efficiently? Like how are you thinking about that? We tried to be very, very clear at the year-end call recently. We have $147 million in cash at year-end and cash equivalents. That takes us now into 2027. We have a nice runway. What we've effectively done with that is we look at the portfolio to your point and you try to fund those assets, all of which are working for us right now. We have taken the Lp(a) trial and set the large expenses of that aside, pending partnership. In the meantime, saved really the allocation of funding for the PV trial to make sure that we get this phase II done and funded. That's our prioritization and a lso, when you look at the partnership, the AstraZeneca relationship is one where it's incoming in terms of milestones to us. As that moves and progresses from phase I into phase II, we would likely get a nice milestone. We are looking at the entire set of opportunities all the time. We are very open to partnering some, and we would like to keep some for ourselves. I hear you. I know in our last minute here, just want to ask another question that will help investors doing work on the story. Is there anything that you think is currently most underappreciated or areas where you think investors should do more work on the Silence story? We like very much this opportunity, first in class in siRNA. Again, for Silence to become first in class against so many companies was really a great accomplishment. We like this PV opportunity. The partnering we have purposely set aside on the Lp(a) so that we can continue to do what we're doing in the pipeline, but still have that as an opportunity and really hope that we can have that happen. Okay, great. I think with that, we're at time. Craig and Steve, thank you very much for joining us and look forward to more updates. Thank you for having us very much. Thank you.