Good afternoon, everyone. Thank you for attending Jefferies London Healthcare Conference. My name is Kelly Shi, one of the biotech analysts here. In this fireside session, we are very pleased to have Mr. Craig Tooman, Chief Executive Officer, and Mr. Curtis Rambaran, Chief Medical Officer of Silence Therapeutics, join us today. Welcome both. Maybe to set the stage, first, let's chat about the company's achievement from the last 12 months and how do you see your technology platform as differentiated from other siRNA programs. Thank you. Thank you very much and thanks for coming, everyone so just really quick background on Silence. Many of you know we're approximately a 20-year-old company. We are a PLC, so we're U.K.-based, London office. We actually have labs in Berlin, Germany, through a reverse merger with Atugen some time ago. And we've opened now a U.S. office in Hoboken, New Jersey so we're about 125 employees. We've been working in siRNA for that period of time. So a very exciting time for us as we're moving clinical programs forward. In particular, I'm sure we'll talk about the two lead proprietary programs. So very enthused that we believe we've got a differentiated program. We are designed in siRNA with proprietary linkers, sequences, and chemistry. And that's the secret sauce that we believe leads to the intellectual property portfolio that we have today. Great, maybe we can also talk about the overall, what do you see the market potential targeting LPA as your leading program and also some of the key events in the space that have sparked the investor interest? Lp(a) is a huge marketplace estimates are 20% of the world's population it's not a U.S. phenomenon. It's a global phenomenon so you'll find it everywhere. Epidemiology is very similar to the statin market if you look at patient number. So as you'll recall in the statin market, multiple parties all selling up to $14 billion, I think Pfizer did when they went off patent. So many companies, large market potential. On medical need, there's nothing approved today specifically for the treatment of Lp(a) and Curtis, do you want to talk a little bit about the trials? So just a reminder, LPA is the next frontier in cardiovascular disease development of therapeutics it's a very unique molecule. It's got a structure of one molecule of an LDL-like particle and one molecule of a very polymorphic glycoprotein called APOE. So you have two potential detrimental insults onto the vasculature, the pro-inflammatory, pro-atherogenic for the LDL-like particle, the pro-atherogenic and potentially pro-thrombotic effects of the APOE, predisposing, therefore, to cardiovascular events, predominantly heart attacks and stroke. We know that this affects one in five of the global population of elevated levels. So this is a huge potential globally. It is predominantly genetically determined. So your levels peak early in childhood and remains constantly elevated unless you intervene. And as of now, we have no approved therapies. So we think great potential. Some of the key events you asked about are certainly the development of outcome trials. We have one will be hopefully early next year. We'll get some insights. But equally important, you've got to test for LPA levels, a simple blood test, and now the main cardiovascular societies, so the European Atherosclerosis Society, the Canadian Cardiovascular Society recommend that LPA tested at least once in an adult lifetime. I can tell you since we published our first data in 2022, we have seen a groundswell of increase in enthusiasm in the field. The key thing is really testing because we are confident as you continue testing, we'll find more patients with elevated levels. I'll also add the pre-marketing, as you can imagine, and some of the trials ongoing now are pretty intense. So even in our local communities, we're actually seeing outreach in terms of measuring Lp(a) in individuals. So it definitely is gaining ground. Okay. Great. And also one way to think about other cardiovascular risk reduction medicines such as statin and PCSK9, how do you see LPA targeting strategy differentiating in terms of maybe targeted population? And also maybe put a number on that. How should we think about the market potential if LPA programs succeed in the outcome trial? It's a good question. So we know for LDL, unlike the Lp(a), your levels sort of increase throughout life and it peaks around midlife. For Lp(a), you're born with either normal or high levels, and that remains constant throughout life. So you're carrying this additional burden on the vasculature from an early life. So we think intervening is very, very important. In terms of therapeutics, we know for LDL, to get significant lowering, you do need combination therapies. So a combination of statins or ezetimibe, bempedoic acid, PCSK9's do get you into the range of about 60%. What is unique about our target for Lp(a), we have already demonstrated in phase 2 that you could have profound lowering of Lp(a), more than 90% peak with a single targeted agent. So this is very exciting because when I entered drug development, we spoke about precision-type medicine. We are now getting into true targeted precision medicine, so I think great potential. Okay, great. And one investor look at RNAi program, you really focus on knocking down efficiency and durability of response and of knocking down. Curious for Lp(a) based on the maybe natural history studies and also human genetic studies, do you think is more knocking down the better or the sufficient once the Lp(a) level within the normal range? And how clinically meaningful is the difference, for example, 10% knocking down efficiency difference? We know from the Mendelian randomization studies that LPA is causative. We know there is a continuous relationship between LPA concentration and risk. The very high level is higher risk. Where exactly the inflection point is, there's been some debate. We do know, importantly to remember, that LPA is a risk amplifier. It does amplify risk in the presence of your conventional cardiovascular risk factors: hypertension, diabetes, blood pressure, smoking, increased weight. What is equally important for LPA is your baseline risk. In the presence of your baseline risk, it is amplified with LPA. In terms of what degree of lowering, certainly our first goal is to get patients to the normal range, which historically is 75 nanomoles. We have already studied in phase one and phase two levels, certainly above this. We need the outcome data. We are not sure yet what degree of lowering will absolutely convey benefit. But I can refer you to some data from the U.K. Biobank that suggests that 50 nanomoles elevation of Lp(a) is related to an 11% increased risk of a cardiovascular event. That is in a middle-aged population followed over time. So I think if we look at the genetics, we looked at the epidemiology, we looked at reports, we looked at some of the U.K. Biobank data, I think there's good reason to believe that its biology will translate into benefit. Okay. And any other biomarker could be predictive to the clinical outcome? I think what we really need is the hard outcome data, so the impact on major adverse cardiovascular events and important point to remember also is LPA does affect all vascular beds, so across the vasculature, not just the coronary vessels. I see. And next, when we look at a competitive landscape, you have presented the phase one data in healthy volunteer and the phase two data at ASCVD and also AHA very, very recently. If you take a comprehensive view, how do you think regarding the knocking down efficiency and the durability compared to the peers for the same LPA program? Yeah. So we did present our phase 2 data at AHA. That's a couple of days ago in Chicago. So I think in phase 1, just to summarize, we saw very good potency and insight on durability and safety looking at single doses up to 600 milligrams. And then we looked at multiple doses. We looked at dosing intervals every four and every eight weeks. We felt very confident to be able to predict our future regimens, including a minimum of a 12-week interval in our future studies. In the phase 2, we took the opportunity to look at other dosing regimens that could extend the dosing intervals, 16 weeks, 24 weeks, as you would normally do in a phase 2. We studied 178 patients with stable cardiovascular disease with LPA levels more than 125 nanomoles. Bear in mind your historical normal is around 75. So that is significantly above. Even though we used a cutoff of 125, the median across the group was 215. So very much into the region you'd want to target. We did show a very impressive knockdown, potency, and efficacy, and durability. We followed these subjects out to 60 weeks. I must mention that our primary endpoint was the change in Lp(a), the time average change in Lp(a) from baseline to week 36. Now, maybe I'll say a bit about this. The time average we believe is a very meaningful way to look at efficacy, particularly for therapies that are infrequently dosed. What this does, it averages the change at each potential time point. We measured Lp(a) at four weekly intervals from baseline down to week 36. In addition to getting a readout at week 36, we get a time average analysis from baseline to week 36. This factors in peaks and troughs of drug effects. It also gives you an indication of between dosing what your efficacy is, and we showed that the time average baseline to week 36 was more than 80% in the three dosing groups, which was delivered 300 q16, 300 milligrams q24, 450 q24. We also showed that if we took a snapshot at week 36, the median peak response was more than 90% in all the groups, so it was very consistent with the phase one. In addition, we followed these patients out to 60 weeks, and even at 60 weeks, which will be 36 weeks after your last dose in the 24-week group and 28 in your 16-week group, we still had a time average of more than 70% at week 60. In addition, we had no new safety signals drug was very well tolerated. No one in the trial defaulted or had missed doses it was very, very well tolerated. So we are very pleased to see that the phase one has translated very nicely into phase two and we are now starting to continue our preparations looking forward to the phase three. Okay. Great. What would be the ideal targeted LPA reduction level when we think about time average endpoint? So, good question. I think, again, we need our community to look at change versus meaningful effect on cardiovascular events. I can tell you that our global steering committee that's made up of the good and great in cardiovascular disease do feel that we need at least a 70% knockdown generally. But I think we do need a data to make that link. What I think the goal should be is to, at a minimum, get patients into the normal range below 75 and sustain that and I think if you look at our data in the phase 2, we can certainly do that during the dosing interval. Based on this new data set at AHA, what kind of implication into your phase 3 design? I think previously you guided 300 milligrams as the dose level. And in terms of treatment interval, do you think 16, 24 weeks, you have any preference at the moment? The 300-milligram dose has been shown to be safe, effective. It's a single injection. It's very well tolerated. The 450 did not show any additional efficacy in the phase 2. That's the dose we are going to take forward. We have always said that at a minimum, we'll be at a 12-week interval. We have developed a very nice model made of the nonhuman primate data, the phase 1, the phase 2. We're going to update that model and look at all the different various dosing regimens for the later development. One thing I should mention is that, as I mentioned earlier, we're in a very exciting time of precision-targeted medicines. All of the siRNAs to date have shown very good durability and also potency. But I think when we think of differentiation, it is we see it beyond the dose and the dosing regimen. I think a big factor will be the phase three design. We have spent a lot, most of the last two years, developing a differentiated design we feel very confident in. And I think Lp(a) is a perfect example. This is a large global population into the billions. We have a great opportunity to look at target population, Lp(a) levels, and to focus on a composite primary endpoint that will differentiate us, particularly when it relates to the label. Okay, and when we think about timeline for phase three, could you help us to set an expectation for the trial initiation? And do you think the first outcome data drop could actually have some implication in terms of the most appropriate trial design? Yeah, so we have not paused we continue development aggressively towards phase three. As you know, you've got a plan well in advance. We anticipate to start by the middle of next year. I should also mention we have had very good feedback from industry experts, from our steering committee, and from the regulators on our late development planning and programs. Certainly, the data that may read out next year, we're not sure of the actual timing, will certainly help the field. We are cheering everyone for success, certainly, and I think we are confident in our design. Certainly, it will help the field it will definitely help the field. What has been the physician community's feedback in terms of Lp(a) program? What do they care the most? If it is treatment interval, what kind of difference actually makes a difference? I think speaking to physicians and colleagues of mine, when we continue our cardiovascular medicine training, they want a therapy. Because the challenge we have now is when we try to encourage testing patients, why should I be tested? Because there is no therapy available. We're encouraging that you should be tested because we know that LPA is a risk amplifier. And if your levels are high, you should aggressively treat your other risk factors. So I think patients are looking forward, sorry, prescribers and physicians are looking forward to be able to offer a treatment option to these patients as a first step. As I mentioned, we have a great opportunity to differentiate. This is a huge population, very much like the statin market we anticipate a room for multiple players. I think if you look at the field for cardiovascular, this is the first time we have multiple siRNAs, so we're going to continue to learn about it and refine our ability to differentiate. Okay, and maybe about the treatment interval? I think having an infrequent, well, we are now into the realm of offering infrequent therapies. So when I was practicing in clinic, it's oral or the GLP-1s at week. Now we have the PCSK9s two weeks, every four weeks. And that has taken some time. It's taken some time to actually get people accustomed. Now we are going to get into a realm where we can offer three monthly, four, six, potentially, depending on the field. I think the ability to have something that dosed infrequently is attractive because these patients do like coming back to see their physicians. So we can't keep them away too long. Okay. And also at AHA, there was an oral regimen data drop. And how do you think about the impact to the rest of the LPA program? Again, it's just we are very keen to see that other therapies and other approaches can help. But I think we have to learn more. We have only had a few days for that data has arrived. So we certainly look more. But I think the SRN is a new paradigm. It's offering a great option for durability, potency, infrequent dosing, all in one. Another thing to mention in the SRN is we have not seen to date any significant drug-drug interactions. And that's a real advantage. We think dosing in a population already on numerous medications. Okay. Great, and also we want to move to another investor's highly focused program at Silence Therapeutics one targeting TMPRSS6 for treating polycythemia vera, PV, let's just call it. Can you let us know what is the discovery from your phase one data? Just as a reminder, this PV indication is the first indication in use that comes out of our SLN124 program. We're very excited about the program because we think it has a lot of legs in terms of other uses and indications. The data that we've seen, and I'll have Curtis walk you through that, in this program, it was near perfect. For the group that was controlled coming into this trial, 100% remained controlled. Those that were uncontrolled moved toward control. 100% efficacy, if you will, in being phlebotomy-free is really, really very exciting data. That was an open-label study. You'll see more of that at ASH. I'll let you, Curtis, tell you just a little bit more about that data. Thanks, so as Craig mentioned, we are very excited with this program, the ability to be the first SRN in the field leading the way. The phase one data is very exciting. At ASH, we are presenting additional data to what was presented in summer. It will be data on 16 patients that have completed this study and data in all 21 patients. The phlebotomy data continues to be very exciting, virtually eliminating the need for it. The effect on hematocrit, as Craig mentioned, in phase one, we included a range of patients with high and sort of lowish hematocrit levels, and in both groups, we saw sustained reduction in hematocrit. We'll present more of that data and also the biomarkers related to hepcidin and effect on different indices of the hematological cascade. For the knockdown efficiency and also hepcidin, maybe also on the phlebotomy, the procedure remove blood, what kind of reference point we can use when we look at this phase one data at ASH? So, I guess you look at how these patients were phlebotomy dependent, meaning that you needed to have three phlebotomies in the last six months or five in a year before coming into the trial. So now we are basically potentially going to afford a treatment where there's absolutely no need for phlebotomies, which would have positive influence on the patients, the quality of life. We know some patients don't often tolerate the phlebotomy procedure themselves. These patients at baseline tend to be iron deficient. So they do have a lot of symptoms. So I think we are looking to see if there's an opportunity to give a therapeutic that maybe potentially reduces the need for phlebotomies. So it could apply to patients who are phlebotomy dependent and potentially also patients who may be newly diagnosed and looking for therapeutic options. How sizable is the PV market? How do you think about this program next to the current available therapies? So again, a real unmet medical need. It is in the rare disease space. But we do know that other products that are second line are actually selling in the billion-dollar or so range. So revenues are real. But we do feel like we have a very unusual opportunity here and not to be niched and not to be second line. So we look forward to growing that. Okay. And lastly, maybe you could give us an overview of your partnership with AstraZeneca and Hansoh and share any recent update and maybe also future update? Yes, thank you. We do have a relationship with AstraZeneca, up to 10 targets. Very excited that we have a project in the clinic with AstraZeneca. So that is a confidential program that only they can describe. But we are supporting them and very excited about that. Up to 10 targets, and that's non-dilutive funding for us when that happens. In terms of Hansoh, three targets, those are progressing as well. We have rights outside of China on two. And Hansoh has a global opportunity for the third target so as we're paid in those non-dilutive funds, we like that in the hybrid model, a little less funding that we need to utilize the equity markets for. In terms of the future and what we're looking at the pipeline, even during the tough markets, we didn't turn those investments off we turned them down a little bit. But we do have complement and other programs, as you know, from our Mallinckrodt relationship initially and other proprietary programs that we look forward to telling you more about. So again, as we see this siRNA technology, you see it in rare disease utilization and large market opportunities like Lp(a) and programs in between so it's a great modality. Fantastic, we're going to wrap up here and.