phase II SANRECO top line data expected in August 2026 alongside zerlasiran, a phase III-ready siRNA targeting Lp(a) for cardiovascular disease. Earlier programs also include in dyslipidemia SLN312 and obesity SLN098. It's my pleasure to introduce you to Curtis Rambaran, Chief Medical Officer, who's representing Silence today. Thanks for joining us. Maybe first, if you could just provide us with a brief overview of Silence Therapeutics today, including the mRNAi GOLD Platform, the core clinical pipeline, and the most important value drivers as you see them over the next year. Yeah. Thank you, and it's great to be back. Thank you for having us again. Silence is a clinical stage biotechnology company, and we are focused on developing precision-type medicines based on our siRNA technology, and we have a platform called mRNAi GOLD Platform. The GOLD Platform is designed to deliver medicines that are targeted, long duration of effect, and very potent. We have a pipeline that is a combination of cardiometabolic and hematological assets presently. I'll start with the divesiran that's of siRNA that's targeting TMPRSS6. This is for patients with polycythemia vera. We have an siRNA targeting Lp(a) gene silencing. This is the zerlasiran. We have completed our phase I, phase II. This is a phase III-ready asset. We have another clinical stage asset, SLN312. That's an siRNA that's targeting ANGPTL3, and that's in development for dyslipidemia, and we will be presenting data at the end of this month at the EAS, the European Atherosclerosis Society meeting, data from the phase I trial. That's the clinical stage assets. In terms of the key drivers, I think firstly, divesiran, we have completed the phase I. We have presented previously very compelling phase I data. The phase II trial is expected to read out in August. That will be a significant milestone for the company and a significant catalyst. We are very much looking forward to that. For the zerlasiran, for the Lp(a), we are anticipating the first readout from the cardiovascular outcome trial, which will certainly show the translation of the biology into the clinic, and that's phase III-ready, so we are very well poised to move into a phase III trial. For SLN312, as I mentioned, we are presenting the phase I data, so this essentially will be a phase II-ready asset that again we are looking at different options for development. Beyond the clinical stage assets, we do have some preclinical assets under the cardiometabolic realm that we are developing, and we're also again investing in our extrahepatic efforts. For those who are newer to RNAi, what do you view as the key advantages more broadly, you know, for RNAi within genetic medicines, particularly around potency, durability, reversibility, and dosing frequency? Maybe I just say a bit about RNA interferons itself. RNA interferons refers to a preexisting cellular machinery that is optimized evolutionarily to degrade viral RNA. siRNAs are short, specific sequences of RNA, and they sort of co-opt this machinery in a very, very nice fashion. They're able then to silence specific targets by associating with specific target messenger RNAs and degrading them so that they don't actually get to the protein-making machinery within the cell. That leads to effective gene silencing, and several things make the siRNA very appealing. Historically, we are now able to go after targets that are previously considered to be undruggable, not targeted by, say, small molecules or biologics. And the excitement about it partly was because of the potency. We have seen that, one, it works on a preexisting cellular machinery, as I mentioned, and two, very small concentrations of siRNA can lead to substantial knockdown of a target gene. Very potent. It also has a very long duration of action universally across programs in development, and this is driven by two factors really. One being that it has a long duration of effect because the catalytic activity within the RISC of the multiprotein complex allows a single siRNA molecule to target multiple messenger RNA transcripts. We look at duration of action. We have seen in the clinic that even with our phase I and phase II data that this technology clinically can be dosed very infrequently, three monthly, sometimes even longer. Therefore for patients, we are now entering a different realm. We are now entering the true realm of precision-type medicines that are very targeted, long duration of effect, very potent. It's very attractive to patients because from a convenience perspective and from an option perspective. As RNAi expands beyond this first major wave of liver-targeted medicine, where do you think Silence is most differentiated? Is it chemistry, target selection, clinical execution, partnering strategy, or some combination? Silence has had a long history in oligonucleotide development. We do have proprietary siRNA molecules and linkers, as a first step. We have learned chemical modifications over time, and this has led to enhanced stability and improved activity. That's two very key things. Certainly we have been very open to partnerships. We have developed some programs certainly on our own. We have been very open to looking at different partnership that could work to take the assets further in development. Just moving on to divesiran and polycythemia vera, can you reintroduce us to this program, its mechanism targeting TMPRSS6 and the rationale for developing it in PV? Divesiran is a very unique molecule. It targets TMPRSS6 gene. TMPRSS6 is a negative regulator of hepcidin. When you suppress TMPRSS6, you get increased hepcidin levels. Hepcidin is the master regulator of iron flux in the systemic circulation. When you increase hepcidin, three main things happen. You reduce iron absorption from the gut, you regulate iron recycling in the macrophages, and you suppress the release of iron from storage. Those three things result in a reduction in iron availability to the bone marrow. In polycythemia vera, these patients have an exacerbated excessive production of red blood cells. With divesiran, what we are doing, we are physiologically shunting iron away from the bone marrow, so it is not available for red blood cell production. That results in a reduction in hematocrit because a hematocrit is an index of red blood cell formation. Therefore, you get, as we have shown in phase I, a progressive and sustained durable control of hematocrit to levels below 45%, which is the guideline recommended target that you should go for. In addition, we have showed that phase I, we have divesiran is very safe and very tolerable up to 9 mgs per kilogram. The phase II SANRECO trial is fully enrolled. Top-line data are expected August 2026. That's, you know, just a few months from now. Maybe you can walk us through the trial design, including the every 6-week and every 12-week dosing arms and the primary endpoint of hematocrit control without phlebotomy. Sure. The phase II is in two parts. The first part is a placebo-controlled, randomized, double-blind period for 36 weeks. This will be data collected on the longest treatment period. The treatment period in phase I was up to 24 weeks. This will be 36. After the 36 weeks, all subjects go on drug, enter an extension phase that's double blind and then open label. As you mentioned, we have recruited 48 PV phlebotomy-dependent PV patients. We have three different cohorts. We have placebo, we have divesiran 6 mgs per kg every 6 weeks, and divesiran 6 mgs per kg every 12 weeks. We have roughly 2/3 of the population on active and 1/3 on a placebo. The primary endpoint is the proportion of responders between divesiran and placebo versus placebo between weeks 18 to 36. That's our key period because we felt that that's a time point where the physiological effect of the drug has been dosed enough to be able to take place. We'll be looking at the response rate and a responder would be any patient that has the hematocrit that remains controlled, meaning less than 45 in the absence of phlebotomies. We are looking at control of hematocrit, removing phlebotomies during that 18-36 week period. We'll also importantly for some of the other regulatory agencies be looking at the mean change in phlebotomies from baseline to week 36. The EHA 2026 poster is going to highlight the phase I data, I believe, on reduced phlebotomies, improved iron stores, and symptom improvement. What should investors focus on from that presentation as they think about the August phase II readout? What would constitute a clear win in SANRECO? We have already presented very compelling phase I data in terms of efficacy and safety. Two new things will be presented at EHA in June. One is the quality of life data. We haven't presented that yet. I can tell you it shows that most of the subjects actually show symptom improvement, so we're looking forward to showing that. Secondly, we wanted to really get further insights on the duration of action, the durability of the drug. We think it's quite long, and that's why we have gone to 12 weeks in the phase II as a second cohort. We looked at the patients who had the last dose in phase I when their next went on to have a phlebotomy that period. I can tell you it looks very, very exciting. We're looking forward to presenting those, two things at EHA. How important is the 12-week dosing arm to divesiran's differentiation? You know, would a strong six-week profile alone be commercially compelling? I think from our market research and our interaction with the key opinion leaders and the global thought leaders, they do believe that the six weeks actually is going to be commercially very exciting. Because remember, even at six weeks, that still will be the least frequently administered drug in development. divesiran is first in class, potentially best in class. Certainly, the 12 weeks will be a great advantage, and that's why we have checked it in phase II. I think when you see the data from the poster at EHA, I think, you know, it does look very, very promising in terms of durability. How do you see divesiran fitting into the PV treatment landscape relative to phlebotomy, cytoreductive therapy, JAK inhibitors interference, and hepcidin mimetics such as rusfertide? As I mentioned, this is first-in-class siRNA, potentially best-in-class. We will be targeting our phlebotomy-dependent patients. That includes low-risk patients who need phlebotomies to control hematocrit, high-risk patients who could receive amenable or eligible for cytoreductives, but are cytoreductive naive either because of choice or because of intolerance, and thirdly, patients who are on cytoreductives but do not have optimal control. It's across that spectrum of the breadth. Certainly, we're looking at the first-line options, particularly in the lower risk patients. Assuming SANRECO is positive, what are the next steps from a regulatory and development perspective? How should we think about the phase III path and timing? We are doing a lot of groundwork in parallel. We are looking for the leanest, phase III design. We're looking at the fastest route to filing. We certainly were planning to leverage our Fast Track Orphan Designation. We are resubmitting for breakthrough, and we are anticipating to engage the FDA end of this year or the next year. There's a lot of work ongoing, particularly around the CRO level operationally, to position us to be able to start the phase III, we would say in H2 of next year. Just moving on to zerlasiran and Lp(a), shifting here to cardiovascular disease. Can you reintroduce zerlasiran and explain why Lp(a) remains such an important, untreated cardiovascular risk factor? As a cardiovascular physician, I'm really excited about Lp(a) because this is a genetic risk factor which we have no treatment for. It's accumulating evidence that it increases the risk of cardiovascular disease, MIs, strokes, peripheral disease, aortic valve disease. Unlike LDL, there's no effect from fasting or from exercise or diet. one in five of the global population, so one in five of us potentially in this room, have high Lp(a) levels and no treatment. This is a huge potential, and we developed zerlasiran as our first entry into the clinic because it's an siRNA designed to specifically lower Lp(a) by targeting the Lp(a) gene. As we have published very compelling Phase I and Phase II data that we need frequent dosing, we can substantially lower Lp in a very controlled manner and with very robust in terms of a duration of effect and potency. Zerlasiran is phase III-ready. Just in terms of the work that's been completed, including manufacturing scale-up, regulatory alignment with the FDA and EMA, what still needs to happen before a, you know, a cardiovascular outcomes trial could begin? When we say phase III-ready, we have already met the big regulatory agencies. We have got approval on the study design and approval on the endpoints. We have done a lot of groundwork also with the CROs. In addition, we have scaled up manufacturing of phase III-ready material. We did two also very important things. We did a pre-screening study in over 2,500 subjects looking at our phase III enrollment, our phase III entry criteria. I don't think many of you will know, last week, available online is we published our Japan phase I study. We actually have a footprint in Japan. We have developed some experience, and I think that's gonna be very useful. The Lp(a) HORIZON CVOT for pelacarsen is expected to read out later this year. How are you thinking about the potential upside for the read-through to zerlasiran if that trial validates Lp(a) lowering as a cardiovascular risk reduction strategy? We're certainly sharing the feel on, if it's positive and it likely will be, I think it's certainly going to bolster the interest in the field. It will maybe cause a clamor for increased products and options for patients. It will certainly, again, reinforce the commercial potential because we see this, and certainly the experts see this as a statin-like opportunity. And one thing I should mention is that, you know, there's one advantage of us not being first. We were able to craft a differentiated phase III design, and we think we can play to the strengths of the siRNA in terms of potency, duration of action, and safety. We think we are well-positioned once that reads out to very quickly move into a Phase III or to seek an adequate partnership. Just moving on to SLN312. This program has been re-returned to Silence from AstraZeneca. Maybe you can talk a little bit about the program, ANGPTL3 biology, why it remains attractive in dyslipidemia, and what we have to look forward to for the upcoming, EAS late-breaking presentation. ANGPTL3 remains attractive because it's a LDL-independent mechanism that when suppressed leads to a reduction in the atherogenic lipoproteins, so LDL, ApoB, triglycerides. If you look at contemporary studies that are ongoing, data looks very, very promising. For SLN312, we are looking forward to seeing the phase I data. This was a study in dyslipidemic subjects, including diabetic subjects. We're looking at the potency, the safety, and the potential insights on durability. Then just on the emerging pipeline, so beyond the clinical stage program, can you talk to us about the next wave of pipeline assets, particularly SLN365 targeting GPR146 for hypercholesterolemia and SLN098 targeting INHBE for obesity? Yeah, we are equally excited about these novel targets. The GPR146, again, is an LDL-independent mechanism. We are currently looking at options that may include a combination therapy with other assets in the pipeline or externally. The reason I say that is if you look at, for example, homozygous FH, where ANGPTL3 has been marketed already, these diseases invariably needs combination therapy. We're definitely looking at the potential for combination. For INHBE, again, strategically and commercially and in terms of the field, this is another very exciting asset along obesity and cardiometabolic disease. We have a, what we think is a very good asset. We are completing some in vivo efficacy studies internally. Again, we are looking at options that will include potential novel partnerships. Sorry, novel combinations. Also, these are the sort of assets that after generating internal data, we'll be very open to looking at available partnerships. How do you think about extrahepatic siRNA delivery as the next frontier of RNAi of the mRNAi GOLD Platform, and what investment is the company making in that direction? I think we have established a pretty good track record in the GalNAc conjugated, as others have. We have certainly generated some data in-house on different sub- cell types. We are continuing to do some experiments on those, so we'll be generating more data this year. Again, you know, these are the sort of things where we are looking at external potential partnerships to leverage the data that we have generated and potentially, you know, sitting on different aspects of our pipeline. As a last question, as you look across the pipeline to divesiran or zerlasiran, SLN312, SLN365, SLN098, and extrahepatic delivery, what do you think is most underappreciated about Silence today, and what would define success over the next year? It's a great question. I would say Silence, I think, we have done extremely well. It's been a bit under the radar in our clinical delivery. If you look at zerlasiran for Lp(a) and divesiran for PV in both phase II trials, we recruited ahead of time. We recruited actually more numbers than we targeted and within our budget. Remember, these are two programs where we are competing with the big boys, the big pharma. I would say that we can get stuff done, particularly when it comes to the clinical execution. In terms of, you know, the big headlines, I would say divesiran, that phase II data will be certainly transformational for the company. We have an asset that's potentially best in class. It's the first in class siRNA. I think for Lp(a), we are well-positioned when the data reads out from the CVOT to move very quickly with the groundwork that we have done. This is tremendous market opportunity, statin-like. There will be a clamor from patients for many, many different options. I think SLN312 certainly you'll see the phase I data that'll be presented at EAS. That's a phase II-ready asset. We'll have three clinical assets, phase II and beyond. It really adds another dimension to the cardiometabolic aspect. In combination with those three, as I mentioned, we are generating, you know, early data in some novel targets, SLN365 and INHBE. I think the next year it should be very exciting. It'll be data, data, and, you know, we're really looking forward to it, so hopefully we'll come back and share some of that with you. Right. Terrific. Well, Curtis Rambaran, thank you so much, and thanks to Silence for attending the conference. Thanks, everyone, for being with us. Have a great rest of your day and conference. Thank you.