Good morning. I would like to welcome you to the Silence Therapeutics conference call to discuss top-line results from the phase II SANRECO study. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question- and- answer session where you will have the opportunity to ask questions. Thank you. I would now like to turn the call over to Gem Hopkins, Vice President and Head of Investor Relations and Corporate Communications. Thank you, Heidi, and thanks everyone for joining us. With me today are Iain Ross, our Chairman and Interim Principal Executive Officer, who will provide some opening comments, and Steven Romano, our Chief R&D Officer, who will review the SANRECO study and top-line results. We will then open the call to your questions. Rhonda Hellums, our Chief Financial Officer, is also joining us on the line and available for questions. Today's press release and presentation are available on our corporate website at silence-therapeutics.com/events. Before we begin, I would like to remind you that this call will contain remarks concerning Silence's future expectations, clinical development plans and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Our actual results may differ from those contemplated by these forward-looking statements. Factors that could cause these results to differ materially are described in today's press release, as well as our filings with the SEC. Any forward-looking statements that we make on this call are based on assumptions as of today, and we undertake no obligation to update these statements as a result of new information or future events. With that, I'd like to turn the call over to Iain. Iain? Thank you, Gem, and good morning and good afternoon, everyone. Earlier this morning, we issued a press release announcing positive top-line results for our phase II SANRECO trial evaluating divesiran, a first-in-class siRNA therapy in patients with polycythemia vera or PV. Let me be clear, this is the big win scenario. We are absolutely thrilled with these results and what they could mean for patients, physicians, families, and the broader PV community. This is also an important milestone for Silence. Turning to slide four, Silence is a platform company that has pioneered siRNA research for over two decades. The PV results we are sharing today highlight the key strengths of the siRNA approach, high potency, durable effect, specificity, favorable tolerability, and the potential for infrequent dosing. We now have completed clinical data across multiple programs in hundreds of patients with rare and cardiometabolic diseases, reinforcing the strength and productivity of our GOLD platform. We see a significant franchise opportunity for divesiran, our first-in-class siRNA therapy for PV, a rare hematologic disease with substantial unmet need. Of the roughly 150,000 patients in the U.S. and an estimated 3.5 million globally, most still rely on regular phlebotomy. Based on its emerging profile, we believe divesiran could offer a differentiated, best-in-class treatment option for PV patients. Beyond PV, encouraging preclinical data in several other hematologic conditions support the potential for divesiran to become a broader hematology franchise asset. Slide five. This shows why PV is our first indication and why it represents a compelling commercial opportunity. First, the unmet need remains significant. Many patients still rely on phlebotomy, underscoring inadequate durable disease control and a large addressable market. Today's treatments have meaningful limitations. Physicians continue to navigate trade-offs in efficacy, safety, and tolerability, and the treatment burden. At the same time, Jakavi's approximately GBP 1 billion in annual PV sales demonstrates the strong commercial potential. We believe divesiran has the potential to raise the bar with a differentiated profile that combines the robust efficacy results, favorable safety profile, infrequent dosing, and an improved patient experience. Overall, we see a large underserved population, a validated market, and an opportunity for a best-in-class therapy with significant long-term value. Turning to slide six. Today, I'm very pleased to say the SANRECO top-line results delivered on all fronts. Let me repeat that. It delivered on all fronts. The study met its primary endpoint with strong response rates observed at both the every six-week and every 12-week dosing intervals. Divesiran was well-tolerated with no major safety concerns. The results Steve is about to walk you through clearly support infrequent dosing and a potentially best-in-class product for the treatment of PV. With that, I will turn the call over to Steve to discuss the SANRECO program and the divesiran PV data in greater detail. Steve? Thank you, Iain. We're very excited to share the top-line results of our SANRECO phase II trial. Let's jump right in. As a reminder, PV is a rare myeloproliferative neoplasm. It's associated with a JAK mutation in nearly all patients and leads to a clonal expansion of red blood cells. This presents in patients as elevations in hematocrit levels. The primary objective of treatment is to reduce hematocrit and maintain it less than 45%. This is most often achieved through periodic therapeutic phlebotomy, the removal of blood from the patient. Today, we will be reporting on the SANRECO phase II results in 48 patients. As a reminder, we previously conducted a healthy volunteer study in 24 patients, and of course, the phase I portion of the ongoing SANRECO study in 21 patients. You're likely very familiar with the terrific results reported from that portion of the trial. This slide highlights the global phase II trial locations. We conducted the trial in nine countries across four continents, the U.S., Europe, Southeast Asia, and Australia. The phase II trial has three components. The first is a 36-week double-blind randomized portion leading to the primary outcomes we will discuss shortly. The second component is a blinded extension period where those patients randomized to placebo in the previous period have been blindly randomized in a one-to-one fashion to six mg per kg, either Q6 weeks or Q12 weeks. All other patients remained on their initially randomized dose interval. The plan is to transition all patients to the dose interval chosen for phase III and follow patients out to 144 weeks for further safety and efficacy evaluation. I'd like to briefly go over a bit more detail on the phase II design prior to delivering the top-line results. All patients met the World Health Organization criteria for PV and were considered phlebotomy-dependent. This was defined as having a minimum of three phlebotomies in the previous six months or five in the previous year. This is very similar to other trials ongoing in this condition. We allowed patients to be maintained on other standard of care cytoreductive treatment if their regimens were stable for a minimum of 12 weeks. Importantly, all patients entered with hematocrit well controlled, meaning less than 45%. Patients were randomized to drug or placebo in a one-to-one-to-one manner, with all patients receiving divesiran 6 mg per kg, but either on a Q6 or Q12 week interval. The primary endpoint was the proportion of patients maintaining hematocrit less than 45% without the need for phlebotomy during weeks 18- 36. There were a number of secondary outcomes, which included safety, tolerability, PK, and quality-of-life measures. Now we can turn to the results, which are quite exciting. As you can see, 88% of divesiran-treated patients met the criteria for response, versus 18% of those patients on placebo. This gives us a nearly 70% placebo-adjusted difference between divesiran and placebo. We were delighted to see this robust effect that we knew based on our phase I results that we had a potent compound. This was very highly significant with a p-value of less than 0.0001. Remember that the study was a phase II in an orphan condition, so the power was actually based on the combined arms, active arms, versus placebo. I just reviewed that data. We can also, of course, evaluate the effect of each active dose arm. Here we see, once again, a very robust effect in both the Q12 week and the Q6 week arm, with response rates over 80% and 90% in the respective arms. These can essentially be considered similarly large response rates, over 60% and 70% placebo-adjusted differences. We will plan to move forward into phase III with the less frequent quarterly dosed interval. You may recall that the SANRECO trial was designed as a combined phase I, II trial, and that patients from phase I were eligible to enroll in phase II. Our assumption was that the timeframe between completion of the phase I trial, which was 16 weeks beyond a patient's last dose, and the initiation of phase II, would greatly minimize any potential carryover effects of earlier treatment exposure. To be more confident in that assumption, we conducted a sensitivity analysis on those patients entering phase II who met the same stringent criteria of phase I. In particular, the need to have had a minimum of three phlebotomies in the previous six months or five in the previous year. As you can see, that included 40 patients, and the response rate in this population of patients was nearly 90%, with a very low placebo response rate. As a reminder, the study was powered actually based on 10 patients per arm, and we in fact enrolled 48 overall. A key secondary endpoint was the phlebotomy rate. This is of interest as it is an outcome of greatest concern to the EMA. As shown here, the mean number of phlebotomies over week 0- 36 was 0.2 in the divesiran combined arm versus 2.1 in the placebo arm, with again, a highly statistical p-value. The difference is perhaps more clearly captured in the bar graph, showing the percent of patients who did not require any phlebotomies over the same timeframe. Over 90% of just divesiran-treated patients versus just 12.5% of placebo-treated patients. divesiran groups also showed improvements in a number of other secondary outcomes, including hematocrit control, markers of iron metabolism, including ferritin, and patient-reported quality-of-life outcome. More detailed presentations of this and other data will be shared at upcoming research conferences. Summarizing safety and tolerability, as previously seen in phase I, divesiran was well-tolerated, and no new safety issues were observed. ISRs were relatively infrequent and all self-limiting. As is expected, many PV patients will have laboratory results that are reflective of anemia, given these patients are receiving frequent phlebotomies, often in addition to other cytoreductives. Given that background, there were only two investigator-reported adverse events of anemia, both grade 1. With regards to next steps, we have submitted an abstract to ASH, which will be held in New Orleans in December, we will plan on having an end-of-phase II meeting with the FDA by year- end. Given the robust top-line data I have shared with you, we will work to initiate the phase III registration trial in the first half of 2027. Summarizing, we feel the emerging data represent a potentially best-in-class profile for a first-in-class siRNA in phlebotomy-dependent PV patients. I hope you will agree we demonstrate terrific efficacy with a nearly 90% response rate in divesiran-treated patients, generally well-tolerated safety profile, and now have the opportunity to pursue a quarterly dose in our phase III trial. With that, I will pass it back to Iain. Thank you, Steve. We hope you share our enthusiasm for these impressive data today and the potential that divesiran represents. We are now happy to take your questions. Thank you. We will now begin the question- and- answer session. If you wish to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. We will take our first question. The question comes from the line of Andrew Tsai from Jefferies. Please go ahead. Your line is open. Hi. Good morning, and congratulations on these stellar results. With this data set on hand, can you give us a teaser at what your phase III design could look like at this juncture with the quarterly dosing interval? How big of a study are you thinking? How quickly could it enroll, and how quickly could we generate the data? Then secondly, can we expect you to file a Breakthrough Designation over the coming weeks? Thank you. Yep. Thank you for the question. Yes, we are going to be planning our phase III study. I cannot really talk to the details of that trial. I will say it is very likely, obviously, to be a one-to-one randomization in a parallel group study design, not different from many of the other studies that have been done in the space. With regards to numbers, we certainly feel very confident that we have a very robust effect size, and that would suggest that we do not necessarily need large numbers of patients to confirm that. But keep in mind, we have to have discussions with the FDA regarding the minimum requirements for a safety database. So that will be critical. But I can assure you, we will look to manage the most efficiently designed trial and execute that as efficiently as possible as well. I also can't really comment to the length of the trial, but typically, as you can imagine, it's got to be a study of 32- 36 weeks in duration. If it's 200, 250 patients like the others, as I mentioned, we'll look to see if we can't make that a bit more efficient. The bottom line, we would assume a timeframe of enrollment of somewhere in the 12- 18 month range. I should leave it at that. Yes, we'll pursue the quarterly dosing. With regards to Breakthrough, that's something we're considering very carefully right now. Thanks. As a quick follow-up, bigger picture, there are several PV treatments available or soon to be available. Can you remind us the ultimate market positioning of divesiran and how its addressable market might be different actually? Maybe said another way, what would be the hypothetical use case if this were to make it to the market? Thank you. Well, just remember, it's going to be based on the population of patients that we'll study. As you know, we are studying a broader group of patients with PV, but they all need to be or have been in the trials, considered phlebotomy-dependent. Now, they could have been on other cytoreductive therapy, so that expands the opportunity as long as those medicines are stable. We're showing that there doesn't appear to be any difference between those patients who are only on phlebotomy and those patients that are treated with cytoreductives as backgrounds as well. The population would be really anybody who requires phlebotomy at a minimum level to maintain their hematocrit regardless of their background therapy and regardless of their status, for instance, low or high risk profile. Thanks. Congrats again. Yeah, thank you. Thank you. We will take our next question. Your next question comes from the line of Mike Ulz from Morgan Stanley. Please go ahead. Your line is open. Good morning. Thanks for the question, and congratulations on the very robust data as well. Maybe just to follow- up quickly on the phase III, just your decision to move forward with the Q12-week dose versus maybe moving both doses forward, if you can give us a little color there. Thanks. Yeah, Mike. Well, typically, obviously, in an orphan condition, you want to minimize the active treatment arms based on the size of the study to keep the size of the study reasonable and be able to execute it in a reasonable timeframe. We will carefully look at all the data. Of course, as we've suggested, it looks as though the Q12-week dose will be the right dose to move forward with. It would be much more sensible to keep that on a one-to-one randomization with placebo. More to come when we have discussions with the agency and confirm the design of the trial. Thank you. Congrats again. Thanks, Mike. Thank you. We will take our next question. The next question comes from Rich Law from Goldman Sachs. Please go ahead. Your line is open. Rich Law, your line is open. Please ask your question. Rich Law, are you able to check your line is not muted, please? If you're happy, I will proceed with the next question. Please stand by. Your next question comes from the line of Prakhar Agrawal from Cantor. Please go ahead. Your line is open. Hi. Thank you so much for taking my questions. Congrats on the strong data. Maybe just first, I had a couple. First question on the baselines, if you can compare and contrast the baseline in this population versus maybe what has been seen with rusfertide in phase II and phase III. Then I had a follow-up. The phase I. Again, as I mentioned, these are patients that are phlebotomy-dependent. They could be on background therapy. They could be only maintained on phlebotomies, and they could either be high or low risk with regards to their profile. Of course, that depends on age and the history of thromboembolic events. I would suggest it's a rather typical population, as have been enrolled in other trials, including the rusfertide trial. The bottom line is we'll reveal those details in an upcoming research meeting. I will tell you, as is typical, you have a predominance of males and the age of the patients roughly are in the 50s on average. A very typical population of patients with polycythemia vera. Got it. Thank you so much. Maybe on the safety profile, you said two cases of grade 1 anemia. If you can elaborate on what doses were these patients on and maybe the nature of the anemia events, and if you can just elaborate on the broader safety profile as well, because that's something that we have gotten a lot of questions on. Injection reactions, the rate versus phase I, as well as thrombocytosis or platelet count increase versus phase I. Even qualitative comments will be very helpful. Thank you. Yeah. I'll give some general comments on this, and we're going to share more of those details, as we mentioned in a research presentation. The bottom line is we did see a modest elevation in platelets, as would be expected. Remember, that is typical of a hepcidin-directed therapy where you're restricting iron to the bone marrow. You'll have a reactive thrombocytosis. It's not unlike what we reported in phase I, and I believe it's similar to what has been reported in other studies. That's very typical. That was not considered a concern. With regards to WBCs, which is another thing you keep a good eye on, there was no change there. Again, that was very similar to our phase I data. With regards to ISRs, a low rate of ISRs. We haven't shared the exact figure, but low rate, all of them self-limiting and grade 1. Very manageable and again, very similar to what we experienced in phase I. With regards to the anemias, keep in mind, physicians who are treating patients with polycythemia vera, particularly those patients who are phlebotomy-dependent, are used to seeing out-of-range values at baseline. Very frequently, these patients come in already with out-of-range values with regards to hemoglobin, for instance. The physicians are very comfortable managing that, and I think that might contribute to the fact that we only had two cases. Neither of them were symptomatic, and both were grade 1. They happened to be in the Q6 arm. I think that's what I can generally say is the safety and tolerability, very similar to what we've highlighted and shared from the phase I study. We'll share more of that data, as I mentioned in research presentations coming up. Thank you. Thank you. We will take our next question. The question comes from the line of Patrick Trucchio from H.C. Wainwright & Co. Please go ahead. Your line is open. Thanks. Good morning, and congrats on the data. My first question is just in terms of the onset. I was wondering how quickly divesiran separated from placebo. As it relates to the secondary endpoints, specifically on symptoms, can you give us a little bit more detail on the improvement in symptoms and just the importance of improvement on symptoms in this indication? Yeah. Well, I'll start with the latter excuse me, question, Patrick. We haven't shared, again, those details. We're still going over that. We're going to be looking at those results from both the MPN but also from the PROMIS that focuses largely on fatigue. We'll be looking at all the individual items as well. Bottom line is everything seems to be moving in the right direction. Remember, this is a phase II study. This isn't a confirmatory phase III. We'll look at the effect that we have on symptoms from the phase II study, and we'll consider that for powering assumptions moving into phase III. I can say we are seeing very nice improvement, as we would have hoped, based on the overall clinical improvement of these patients. It's not dissimilar to the exploratory data we shared at EHA back in June from the phase I. I think that's a good indication that we will be able to demonstrate an effect on symptoms more robustly in a phase III trial that is well-powered. Very excited about that. To your point about whether that's important, that's very important. Obviously, you want to maintain patients below 45. We know the benefit there with regards to cardiovascular outcomes. Your first question, excuse me, was did you have a time to effect that you could tease out on drug or placebo? We'll share more of that information because remember, in this case, we're treating everybody for 18 weeks before we even evaluate the response, and that response is really dichotomized, whether you are a responder or not, based on the ability to maintain hematocrit below 45 without the need for phlebotomy. We do know from phase I, the open label study, that you get a very rapid elevation of hepcidin and a reduction in hematocrit that actually occurs in the first several weeks of exposure to the drug. You can imagine that the effect on drug will likely have a very early onset, and then there's the persistence and durability of that effect. For the phase II results I shared, we really just talked about the outcome, which was the response criteria between weeks 18 and 36. Terrific. Thanks so much. Yep. Thank you. We will take our next question. Your next question comes from the line of Rich Law from Goldman Sachs. Please go ahead. Your line is open. Hi. Can you guys hear me now? Hello? Yes, you can be heard. Please proceed. Okay. Fantastic. Yeah, sorry for the technical difficulties. Looking at both the Q12W and the Q6W doses, it seems like the Q6W is more potent, given the small sample size compared to Protagonist's phase III study, what is giving you guys confidence that the trial results are reliable enough to advance the less potent Q12W into phase III? Just kind of following up on that, can you comment on the standard deviation between the Q12W and the Q6W? I'm sorry, that last point was, what difference between the two? I'm sorry. The standard deviation. Oh. Well, we'll share more details on the stats at a later time. I'll go back to your first question, which is important. Again, the study was powered as for the combined arms, but clearly when you look at both arms, if it were just a matter of one or two patients shifting arms, it would be almost exactly the same. Bottom line is both are looking very robustly effective. The next thing we'll do, obviously, is look at all the individual level data on the patients exposed to both arms so we can obviously build our confidence. Right now it's very clear that either dose demonstrated robust effects with a 60%-70% improvement over placebo. I think you could essentially see that in a small study that wasn't powered for each of the arms compared to placebo. You can see that in fact, both arms look relatively similar in effect. I think got it. Then just following up, how will you compare the patient baseline to rusfertide phase III, in terms of patients, regarding the average number of phlebotomies and then also patients on CRT? Look, I can't say a direct comparison to rusfertide right now, but again, remember this is phase II. In general, we seem to be enrolling the same types of patients, phlebotomy-dependent patients, whether or not they're on background therapy of cytoreductives or not, and regardless of their profile with regards to whether they are characterized as high risk or low risk. Of course the predominance of males versus females, et cetera. I would say rather similar at this point, but we'll share more details so that you can look directly at the comparisons when we present the full data set. Great. Thank you, congrats again. Thank you. Thank you. We will take our next question, the question comes from the line of Keay Nakae. Sorry, Keay Nakae from Chardan. Please go ahead. Your line is open. Yes. Thank you. Yeah, again, congrats on the data. I know the phase III details are yet to be worked out, but should we anticipate something similar to the phase III for rusfertide in terms of design? Yea h. Again, yes, that's an important point. Obviously, again, we'll need to do a confirmatory trial. That's our expectation. We need to do a confirmatory trial. We want to keep that as lean as is possible, but you still need to meet a minimum requirement with regards to safety database. We'll have that discussion with the agency at the end of phase II. We put in a plug, if you will, for a 250-patient study, as has been done for rusfertide and as is planned for the Ono compound, sapablursen. Again, we have very robust and consistent effect from our drug, a huge effect size when you look at the placebo-subtracted difference, and we will argue for what we believe is the most reasonably sized study to meet the regulatory requirements and still demonstrate in a confirmatory standpoint our trial, the effect of the drug for purposes of labeling. All right. Great. Thank you. Thank you. Once again, if you wish to ask a question, please press star one one on your telephone. We will take our next question. The question comes from the line of Myles Minter from William Blair. Please go ahead. Your line is open. Hey. Thanks for taking the questions. Congrats on the great data. Looks amazing from my seat. I had a question actually given the end-of-phase II meeting coming up and you just mentioned that you'd put a boilerplate in there for a 250-patient phase III study. What did you say the primary endpoint was there? You do differ a little bit from the VERIFY study. They have a little added clause in their response rate that they don't want to see patients that have greater than a 3% move in hematocrit. Have you done that analysis on the phase II? Is that going to be incorporated in the primary endpoint that you're putting forward for the phase III? That's the first one. The second one's just on moving the Q12 weekly forward over the Q6. I think I get that. I just wanted to know how much of that is based on the risk-benefit analysis that you're seeing out of the data versus the emerging competitive landscape where you've got one earlier stage player that's trying to do Q6 monthly, but you haven't necessarily seen any data to suggest that. Just your thoughts there would be great. Thanks very much. Yeah, sure. On the latter, yes, of course, we will make a decision based on benefit risk for each of those arms. Of course, right now, based on the confidence we have from the consistency of the effect in both arms, we feel that a 12-week or quarterly dosing is a very nice and competitive profile based on the fact that these patients are seen on a regular basis. They need to be checked in on a regular basis. That is still a very infrequent dosing interval for these patients. We do see an upside to the quarterly dosing fitting well into the pattern of management of these patients. Your first question was? I'm so sorry. Yeah. I can say it again. It was just based on the fact that VERIFY its primary endpoint analysis- Oh, yes for its responder criteria had that greater than 3% movement hematocrit added in there, and whether or not you see that as a requirement in phase II or you propose that to discuss it in the end of phase II meeting. Thanks. Yeah. I'm sorry, Myles. Yes, of course. Yeah, we had a pretty clean cutoff for our phase II, which is either if you hit 45 or you had a phlebotomy, then you were a non-responder. As you can see, we had such an effective response here in both of the arms and certainly in the combined arms that I'm not sure it really makes a difference. We will consider that because I think the other company did that for good reason, is that some patients come in close to the margin and you want to feel confident that you're categorizing them accurately as a responder or non-responder and give yourself a little bit of room there, which makes perfect sense. We'll consider that. We have not done the analysis on the phase II with that in mind. Again, a very clean cutoff of 45 or above or a phlebotomy regardless of your background rate of phlebotomy, actually allowed us to make a very clear evaluation of effect. Makes sense. Congrats on the data. We'll see you at ASH. Thanks, Myles. Thank you. There seems to be no further questions. I would like to hand back for closing remarks. Well, thank you very much, everybody, for your questions. I think the data speaks for itself, and we're very excited about it. I'd like to also thank the Silence team for their hard work in delivering a very well-executed and timely clinical trial. Thank you all again, and if you have any follow-up questions individually, you can reach out to Gem. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.