Okay, let's get started with our next session with Silence Therapeutics. With me today is the Chief R&D Officer, Dr. Steve Romano. Steve, thank you so much for joining us today. Nice to be here. Thank you. Maybe to start, can you provide a couple minutes of overview to tell us about your platform and your key accomplishments to date? Yeah, no, absolutely. Silence Therapeutics is a global clinical stage biopharmaceutical company, and we have a proprietary silencing siRNA excuse me technology that we utilize to bring compounds to the market, or hopefully to the market soon. Bottom line is, we have technology that is based on our sequences, our ability to choose the right sequences, the linkers that we use, and the GalNAc ligand that we use. GOLD, our platform, stands for GalNAc Oligonucleotide Discovery Platform. GalNAc targets hepatocytes, so if you understand the biology of a condition and you know that it's associated with a disease-associated protein in the liver, you can target that fairly specifically, and with minimal ex... with minimal off-target effects, and hopefully have an effect in patients with particular conditions. So our sequences, we actually have a proprietary algorithm, like computational algorithm, that we use to choose the right sequences, and we have a list of different, what we call our toolbox of chemistries, that we apply to these sequences. That allows us to produce sequences that are stable, potent, and hopefully durable, and then we move forward with those. And we also have proprietary components of our linkers. The GalNAc itself is relatively commoditized, but helps focus, as I mentioned, to bring the payload, if you will, to the liver. 2024 has been a big year for us, and largely because we have been advancing compounds into development and through development stages. For many years, we were really a research-based company. Over the last several years, we've been able to progress compounds into the clinic. Our lead compound is zerlasiran, which is targeting Lp(a), a cardiovascular risk factor, and that has completed phase II, and we'll be moving into phase III in the first half of next year. Our next proprietary compound is divesiran. It targets TMPRSS6, and it's being developed for polycythemia vera, and we are completing phase I and hope to start phase II later this year. Then additionally, we had a third compound come to the clinic. This is within our AZ partnership, and that's an undisclosed target, but that has moved into phase I starting in February. Again, a very exciting year for us. Programs are progressing in the clinic and advancing into full stage development. Great! Let's dig a little deeper into your lead, zerlasiran. Yep ... targeting Lp(a). I think maybe folks understand that is an independent risk factor- Yes -for atherosclerotic cardiovascular disease. And tell us how it's designed and what it's intending to do, since it's a slightly different problem than LDL. Yeah. Well, maybe we should talk a little bit about Lp(a). So Lp(a) actually is an independent risk factor contributing to cardiovascular disease. It's about 90% of the variances is genetic, so it's genetically defined. You have it as an infant child, and then you develop this, you carry this risk, I should say, through your life. It's not affected by lifestyle. So unlike, for instance, cholesterol, where you can adapt your exercise habits, your diet, et cetera, and of course, there are therapies to intervene pretty robustly at lowering LDL, you can't. There's no effect on your Lp(a) level, so it's a pretty sturdy risk factor that persists. About 20%-25% of the population have elevated Lp(a), and all the data that we have to date shows that it really appears to be a causative factor with regards to negative outcomes in patients with cardiovascular disease. You have a two- to four-fold increase in certain outcomes, such as MI or stroke, as well as a contribution to calcific aortic stenosis. Very substantial contribution to risk, and probably a big component of residual risk in patients who otherwise have their risk factors, whether it's hypertension, cholesterol, diabetes, obesity under control. A big portion of that residual risk is likely to be contributed to by elevations in Lp(a). Very, very important. So I think even though people understand that it is a risk factor, it's still not widely screened for, and Lp(a) is not part of a standard lipid panel. So do you think part of that is due to the fact there isn't an approved therapeutic that directly targets it? Yeah, I think that's a big part. Obviously, researchers have been looking at Lp(a) essentially for decades, but it's really been the past five, ten years that I think the general awareness has increased. A big part of that is, in fact, that there are programs in the clinic. Whenever you're able to move from research into the clinic, and you demonstrate a robust effect on a biomarker that you believe is disease-associated, you're gonna garner more interest. Now, of course, we have good programs now, several programs that have demonstrated a very robust effect on Lp(a), our compound in particular. You can reduce Lp(a) by 98%-99%, maximally. So the bottom line is now it's gotta translate into the cardiovascular outcome trials to demonstrate that you can actually modify this risk and have an effect on your outcome. So I think that's gonna change. The first study that comes through and demonstrates that lowering Lp(a) is in fact associated with a reduction of certain outcomes, I think that's gonna be a huge inflection point with regards to the, you know, the desire to get your Lp(a) level measured and to do something about it. Now, what's nice is that over the past few years, some of the major and influential cardiology societies have actually made recommendations, at least suggested or made recommendations, that an adult should at least have their Lp(a) measured once in a lifetime, and that's because Lp(a) is a risk factor-... accelerator, risk amplifier, so even though you can't do anything about it as far as a robust, you know, specific intervention, it allows the physician to think very aggressively about managing all the other risk factors that are, in fact, modifiable by lifestyle or by drug intervention. and maybe just to further subdivide the opportunity here and why there's so much investor interest in Lp(a), you know, I think clinicians are now saying, you know, maybe once the level is, like, 50-70. Mm-hmm ... milligrams per deciliter, you know, maybe that's an appropriate time to start treating these patients. So what does that market look like for that patient population? Yeah, well, first, the market is going to be huge. I mean, the bottom line is, if 20% of the population has what has been conservatively considered elevated Lp(a), and that is, to your point, about 125 nanomoles or higher, that's already 20, 25% of the population. The bottom line is, over the last few years, there are data from population analyses, et cetera, that suggest lower levels are actually associated with elevated risk in patients who are at risk for cardiovascular disease. That could be 125 down to 90 or even 75. Still very elevated, above normal levels, and in high-risk patients, substantially contributing to risk. So I think you're going to see that change over time, but you're absolutely right. Generally speaking, the focus has been 125 and above. I think that guidepost is moving. Okay, great. So let's dive into your human clinical data. Yep. It started with the phase I APOLLO data. That showed some really nice results, starting in normal, healthy volunteers- Mm-hmm ... then moving into patients. More recently, this year, you presented data for your phase II study. Yeah. So maybe review some of the- Yep ... the key findings there. Yeah, so if we go back, we did a phase I that included a single ascending dose as well as a multiple dose. That single ascending dose looked at doses up to 600 milligrams, and demonstrated a very robust effect at the higher end of the dose range study. So we saw a 96%-98% suppression after a single dose, and we saw persistence out to 150 days, which was the period of observation, of 90% or greater, so, or 80%-90%, excuse me, so very robust effect. In the multiple dose portion, we looked at two doses, at zero and four weeks for the lower dose tested, and zero and eight weeks for the higher doses, 300 and 450, and then followed them out to 201 days. There again, we replicated that robust effect, about 96, 98, even 99% suppression, and showed again 90% persistence at the end of that observation period of 201 days. The phase II study... By the way, both of those were published, the single ascending dose in JAMA in April of 2022, and the multiple dose portion just this past April in JAMA as well. This phase II study looked at patients who had... By the way, that I should have mentioned, in the multiple dose portion of the phase I, they were targeting patients with high risk of ASCVD or risk of ASCVD at 150 nanomoles per liter or higher. In the phase II, we moved that down to 125 nanomoles per liter or higher and brought in patients again at risk for ASCVD events. And there, what we did is we designed a study that would go 60 weeks, the primary outcome being 36 weeks, with an end of treatment period at 48 weeks. Those two last time periods we've already reported, to your point, in press releases. We'll have more data coming out later, actually next, in November, very soon at AHA. But we looked at longer intervals. So we looked at higher doses, like 300 and 450, given at Q16 weeks, so essentially four months, as well as Q6 months, Q24 weeks, and we reported very significant effects at the primary outcome measure of 36 weeks, with again replicating the maximal suppression of over 90%. At 48 weeks, again, we showed a persistence of that effect, so again, replicating what we believe is a very competitive profile. And, at 60 weeks, we will demonstrate the durability of that effect, but more importantly, the safety, because obviously, these are durable compounds. They last long, and you need to make sure you evaluate the effect over a long period of time in phase II. So very excited about showing all of that data soon. Well, great. Well, a question I often get from investors is, you know, how much knockdown really matters, and how is that going to translate into outcomes benefit? We... You know, there's some data from some longevity studies using apheresis, which is really like a sledgehammer compared to the elegant way you guys are knocking it down. You know, and they, that would show that if you knock it down or reduce it by 70%, you're going to get an outcome benefit. So how do we think about, you know, knocking it down, you know, 90% or more? Mm-hmm. What might that mean for that top decile in terms of an outcome? Yeah, well, look, I think the field had aligned conservatively on a requirement of 70% or greater for a specific intervention. And I believe all the products that are currently in development, including Novartis' ASO, it's an antisense oligonucleotide, crosses that threshold. Obviously, the siRNAs can go a little deeper, as I mentioned, 90% plus. But the bottom line is, I think we're going to have to see this. And by the way, that threshold is based on the genetic data, the population analyses, the Mendelian analyses, continued, you know, additional population evaluations, as well as post-hoc analyses of the PCSK9 databases, which show even a modest reduction was contributing independently and statistically to the outcomes in those trials, with regards to risk reduction. So I think, you know, we've taken a conservative stand, that 70% plus is probably what's required. The bottom line is, until you actually have the outcomes data, it's hard to determine whether 80%, 90%, much above 70% is going to bring you additional benefit or not. But I think all the compounds that are currently in development, including ours, have a robust effect on that biomarker that should, in well-powered, you know, large outcome trials, such as those that are running right now, demonstrate a benefit. I think there's a strong level of confidence, you know, that the probability of success is high. Yeah, so, you know, really kind of, just a wild guess for people to say who's best in class, given the amount of knockdown that we've seen the various companies present to date? That's hard to say. That's really hard to say. Again, the siRNAs can maximally suppress above 90%. The ASO gets 70%-80%. I think all of those are in a range of demonstrating effect. Now, keep in mind, this is a large market, so you know, it's not too different in size, for instance, from the statin market, and the projections from a market standpoint are 16 billion and north of that. So there is plenty of room for multiple compounds. So, you know, best in class, we can look at the durability of these compounds, the convenience, you know, dosing intervals for these compounds. But I think it's really gonna come down to, you know, the effect you see in the cardiovascular outcome trials, and the manner in which that is captured in the labels, 'cause that will read through to, you know, reimbursement, access and reimbursement on the payer side. Great. So you mentioned the CVOT, the outcome trials. Novartis is already in their study. Maybe we'll see a readout middle of next year. Right. The Amgen, which is an siRNA similar to yours, maybe that's a little later. Mm-hmm. So they're further along. You'll start yours next year. Given that you're a little behind, but again, a huge market- Yep ... so the time difference really in the scheme of things is not that different. Mm-hmm. How might, though, you try to differentiate your study? Yeah, so that's a great point. Again, to your point, if we were to do exactly the same as the other compounds, you'd still have a large market to enter and a valuable asset. But I think it's very important actually to look at ways of differentiating. So we have had and we've already planned our phase III program. I can't give you all the details of that because it's a very competitive space. But we had great input from our steering committee, which includes some of the top lipidologists, cardiologists, trialists, and feel very confident that we have an opportunity to differentiate, largely by looking at a broader range of high-risk vascular patients. So we know Lp(a) affects all the vascular beds, so, whether it's coronary, cerebral, peripheral, there are ways of defining high-risk vascular patients that could potentially allow for a differentiated label. There's also an opportunity, as I kind of hinted at earlier, to look at lower levels, so, allowing patients that are high risk but at lower levels of Lp(a), because again, Lp(a) is a risk amplifier in patients who already are burdened by multiple risk factors for cardiovascular outcomes. So there's an opportunity to move the bar with regards to the threshold. Now, of course, the current studies have really focused on the very highest levels of Lp(a), 150, 175, 200. We think there's an opportunity to go lower. Now, that doesn't mean you niche yourself to those lower levels. You just allow patients with lower levels. In our phase II study, which allowed patients at 125 or above, the median was well above 200, 213, 215. So the population is really skewed to the right, so you are letting some patients in below that, but expanding the population that could be targeted by your drug. Now, we've had really good conversations with health technology assessors in Europe, as well as with payers in the US, as any company would do as you prepare for your phase III, because not only do you need to meet the regulatory requirements, you wanna be able to kind of give the market what they need, particularly the payers, who are gonna make the decisions about access and reimbursement. They've also suggested to us, in this new class of medicines, they're largely gonna target the access and reimbursement based on the details of the trial in each of the labels. So now, you can't hold payers to their, their viewpoint, but it suggests there's an opportunity to differentiate, and we're gonna take advantage of that. Okay. Well, the other question we get all the time is, you know, everybody knows the CVOTs are large, they're expensive. The other two companies we mentioned, they're large. You're smaller. Mm-hmm. So, you know, how are you thinking about, moving forward, conducting that study? At what point might you either partner with somebody- Mm-hmm ... or, you know, some other form of licensing? Yeah, well, I will say it's a big opportunity for us, right? For a small company. We are ready to pursue it, and we're ready to move into phase III, and we have the funding available to start that study, but we are a partnering company at heart. So we have a hybrid model, where we have a number of proprietary compounds, but we also have important partnerships, AZ, Hansoh, in the past with Mallinckrodt. So we definitely see this as an opportunity to partner. We've got the chops to do the development piece, with funding, but to be able to commercialize a product in the cardiovascular space is well beyond our means. So we have been talking with partners. There are many partners interested, but we don't wanna hold back on initiating because it's a very competitive, you know, space, so we wanna move forward with our phase III. So more to come, but we are continuing to have conversations with partners. Okay, great. You just mentioned your design capabilities. Yeah. Let's talk about your second candidate- Sure ... SLN-124. Knocking down a different target, you've presented some initial data for- Yeah polycythemia vera or PV. So maybe review both the preclinical data, the strength of that, and how that's translated thus far. Yeah -into the patients? Yeah, so we're very excited about this opportunity. You know, polycythemia vera is a condition. It's a myeloproliferative neoplasm. It's a blood disorder that causes an overproduction of red blood cells, causes the blood to get thick and viscous, and can lead to both ischemic and thrombotic events. So, very, you know, very important area with medical need, 'cause many patients with polycythemia vera are not well managed or not managed as continuously in levels that are considered safe with regards to hematocrits, achieved below 45. So we're targeting TMPRSS6. TMPRSS6 is a negative regulator of hepcidin. If we are able to elevate hepcidin, you can essentially restrict iron to the bone marrow and reduce the production of RBCs, and therefore have an impact on hematocrit. So our preclinical program, our preclinical data showed a very robust effect on reduction of that target, TMPRSS6, 90% or greater. We did, we had really nice in vivo models, preclinical in vivo models that demonstrated an effect in a number of conditions, including iron loading conditions and conditions of low hepcidin, the latter relevant to PV patients. And then we moved into the clinic with a healthy volunteer study that demonstrated, after a single dose, a substantial elevation of hepcidin, four or five-fold, and a reduction in iron of about 50%, so established proof of mechanism in healthy volunteers, and then moved into the phase I study. That study, which we reported some of the results of, 'cause we're just completing it, showed a very robust effect in patients who are phlebotomy dependent. This was a study where we looked at only active, actively treated patients, no placebo, but otherwise a typical phase I design, three cohorts, up to eight patients per cohort, starting with three mgs, moving to six and then to nine, and then gave everybody four doses at Q six-week intervals, so week zero, six, twelve, and eighteen, and then followed them out to thirty-four weeks. What we showed is that in that every patient who entered the trial, who was well-controlled or had hematocrits below forty-five, none of them required a phlebotomy over the course of the treatment period, so a very robust effect. We also showed that hematocrit came down and was maintained at those levels below forty-five. For patients who were higher than 45, and we had patients as high as 56, we also showed a decrease in hematocrit to levels below 45 over time, and we had two patients, each of whom required a phlebotomy in the period of time that we presented the data in late June. So really very excited about this data. I think it's potentially best-in-class data. Certainly will be we want to be first-in-class with an siRNA to the marketplace. So maybe tee up what you're going to report on next for that program. Yeah, we'll have all of our patients in each of the cohorts will have completed the treatment period. Nearly all will have completed the follow-up to thirty-four weeks. So we'll have a continued, what I'm hoping is a very robust set of data to share at ASH in December. We're waiting to hear, but we're feeling fairly confident that's where we'll present it. So you'll see all that data, but you'll also see additional indices of iron metabolism as well as blood indices. So you'll have a more thorough sort of presentation of the data. Okay, so all of that data will then inform the next study. That's right. And so at least from where you're standing today, what might that study design look like? Yeah, so we're looking at what likely will be a randomized controlled program. We're gonna talk to the FDA very soon, actually. We have a you know fast track designation, and it's an orphan drug. There's opportunities based on the most updated guidance from the FDA from December of 2023, regarding you know rare conditions in orphan development programs. We want to be able to do the most efficient trial moving forward. Now, in that trial, we will only take patients who are well-controlled, so we have a lot of confidence in the effect in that population, given what we saw in the phase I. So we feel very confident that moving into a full development program, whatever that looks like, we'll be able to replicate that data. It's a very, very strong effect size. Okay, and then maybe let's touch on some of your partnered programs. Yeah. So we have partnerships ongoing with AstraZeneca, as well as with Hansoh. The AstraZeneca I mentioned earlier, we had our first program move into the clinic. It's up to AZ to disclose that, but it is in phase I, which is great. We're working on other potential targets there as well. With Hansoh, we've got three programs, all of which, or I should say two of which, we have options for global rights. They retain the China region rights for the first two, and then they have a third opportunity where they retain global rights. All of those are moving forward nicely in discovery and non-clinical development, so very, very happy about that. These, of course, provide us with some, you know, non-dilutive capital as we progress our programs, which is very helpful. Okay, so maybe let's talk about that and maybe exclude the potential revenue that may come in- Yep From the partnerships. But based on the cash on hand, how far of a runway does that support? Yeah, so as of the end of June, we reported that we had approximately GBP 190 million, about GBP 189 million on the books. That does allow us to move forward with our phase II program, as well as to initiate the large CVOT trial with Lp into phase III, and that gets us into 2026. So we have the runway to move both of these very valuable programs forward. Okay, so maybe I'll squeeze in one final question. Yep. But what do you think, at this point, investors maybe are still missing about the Silence story? Well, I don't think they're missing, but what they're discovering is that we are a platform company. I think in the past, there was consideration that we were a Lp(a) company because that was our leading compound, and there was a lot of focus only on that. But I think the fact that we've been able to move forward our second wholly owned proprietary compound into phase I, now into phase II by end of year, and the fact that we've been able to validate our technology in with our collaborations, for instance, AZ, and move another compound into the clinic, I think that has raised the profile of the company. Clearly, people believe that both of our in-line compounds have very competitive profiles, if you know, potentially even best in class, so very, very excited about that. By the way, we have over a dozen programs in development. That is, we have not disclosed many of the programs, obviously, in the preclinical and non-clinical development space, but hope to do that in the near future. Okay, well, very good. We've reached the end of our time here, but thank you so much for joining us. Thank you very much. Appreciate it. Great. Thanks. Yeah, we'll look forward to seeing your data at AHA. Very soon. Yeah. And-