We're going to get started in our next session. I'm Andrew Tsai, senior biotech analyst at Jefferies, it's my pleasure to have Steven Romano joining me today, Chief R&D Officer. Welcome, Steven. Thank you very much. Nice to be here. There are some audience members who may be less familiar with the Silence story. Yeah. Can you walk us through the story? Sure. What programs you're working on, milestones over the next few months or next 12 months could also be helpful. Absolutely. We're a global clinical stage biopharmaceutical company. Our technology is focused on small interfering RNA. Our compounds are 19-mer blunt-ended, double-stranded oligonucleotides. Obviously with siRNAs, you target very specifically the gene transcript that you're interested in. You can silence that transcript. It's a durable effect, but it's reversible. We have a number of programs in the clinic. I can start with our most important one right now is a TMPRSS6 compound. It's targeting TMPRSS6 for polycythemia vera. That is in phase II, and we can talk much more about that in a moment. We did actually develop Lp(a) as well. We have an Lp(a) compound, zerlasiran, that is a phase III-ready asset. We are looking potentially to partner that. That's a large phase III program, a cardiovascular outcome trial that would be required to execute. That would be something that would generally require a partnership. We're very excited about the data we generated, but that's essentially ready to move forward when a partner is identified. I think a lot of folks are waiting for the data to come out from the Novartis HORIZON program to put a seal on the confidence and the translation of the benefit into the real-world setting. That is another compound we have. There is a third compound in the clinic that was actually developed by, or designed by us and AstraZeneca has, but is returning to us, and that's a ANGPTL3 compound, completed phase I. They're presenting that data actually now and throughout the year, but that will be returning to us. We have a number of preclinical programs, and I'll just highlight a couple of those. We have a compound, GPR146, that is a novel target. It's not yet been validated in the clinic, so very excited about that. It's targeting a non-LDL receptor-dependent reduction in the production and release of very low-density lipoproteins. We're very excited about the opportunity there. We would look to pursue that in a rarer condition, such as homozygous FH, so very excited about that. We also have a compound that is targeting activin E, and that's a very, as you know, a very exciting area. There's some compounds that have already been translated into the clinic in early phase development. It's a very exciting opportunity, potentially at obesity and cardiovascular risks. That's something that we would probably choose to do with a larger partner. That's our set of activities. We're also looking at extrahepatic. There are opportunities beyond the GalNAc targeted therapies that we utilize now and the technology that we have currently, and are moving towards and will hopefully be able to share some data later in the year around targeting other extrahepatic cell and tissue types. Great. Thank you. PV, we have data no official guidances by early August or something like that? Yeah. You mentioned catalysts. The two main catalysts for us is there's one external, which is the completion of the HORIZON trial, which will give us a sense of where we stand with Lp(a) and the potential to continue our partnership discussions. I think most importantly is the phase II data on polycythemia vera. That trial has been running very nicely. It's fully enrolled. The last patient, last visit will be by the end of this month, so by July 1st. We'll have results of that to share with the market by probably the second, third week of August, mid-August. Got it. backtrack, big picture. Yep PV, when we think about the market, can you talk a little bit about the nature? Yep of the disease? What is mortality like? How is quality of life impacted? Yeah. What's the unmet need like? Yeah. Polycythemia vera is a myeloproliferative neoplasm, so these patients have clonal expansion of certain cell lines, RBCs in particular. Causes them to have very viscous blood because of high hematocrit, so the volume of red blood cells in their circulation is high. That puts them at risk for thromboembolic events, so cardiovascular death and thromboembolic events. The patients are typically divided into high risk and low risk, the high risk being older patients, usually over 60, and with a history of thromboembolic event, or anybody with a history of thromboembolic event falls into that high-risk category. Low risk is the absence of both of those two. Treatment for these patients. This is a chronic condition. These typically are actually diagnosed in their fifth and sixth decade, so we're looking at older patients generally, although many patients do now come in as early as late 30s, early 40s, but typically 50s and 60s. They can have a requirement for management of their disease for the next 15 or 20 years. What you want to do is reduce the risk of cardiovascular issues, as I mentioned, thromboembolic events, bleeding as well. You do that largely by trying to keep their hematocrit level below 45. Keeping the hematocrit level below 45 has been associated with a benefit in these patients. There's been a study done, an Italian study back in It came out in the New England Journal of Medicine in 2013. It showed that even in comparison to maintaining hematocrit in the range of 46- 50, those patients who were not well-controlled, so were managed in that 46-5 0 range, had a fourfold elevation of cardiovascular death, as well as thromboembolic events. The guidelines really stress maintaining patients below 45. Typically, those patients are managed early on with phlebotomies. They can be anywhere from 250 mL to 60 mL of blood being removed to reduce the volume of the blood that is represented by the high hematocrit percent. That helps patients, but that also can contribute to their general iron deficient status. If patients aren't controlled early on simply with phlebotomies, with an addition of a low-dose aspirin, they can go on cytoreductive agents as well. Some of the high-risk patients may even begin treatment with cytoreductive agents. Those are hydroxyurea, for instance, which is an older medicine, but effective, although has toxicities associated with it. Also a drug, the pegylated interferons are helpful. Even the JAK compounds, Jakafi, for instance. All of that is reserved for second or third line treatment in patients who are not responding well to hydroxyurea. There is a range of available treatments, but the fact is there is a need to have a durable suppression of hematocrit, particularly in patients that we refer to as phlebotomy dependent, and that's the population we studied in phase I and which we're studying in phase II. Those are patients that require a minimum number of phlebotomies, for instance, three, at least three in the previous six months or five in the previous year. That population of patients often requires additional treatment because they don't necessarily tolerate the frequency of phlebotomies required to maintain their hematocrit. There's some compromise in the management of those patients. We feel that's an important population to target. What I didn't say is it's an orphan condition, about 150,000-170,000 patients in the U.S., probably a similar amount in Europe, and probably about 3.5 million worldwide. It's an orphan condition, but it's not the rarest of conditions. You answered almost all my questions. I'm sorry. That's okay. Anyway, what percentage of those 150,000 patients are treated at the moment with these existing drugs? Once diagnosed, the majority are treated. The majority, again, are typically, particularly if they're on a low risk and they start with phlebotomies, and then they can add on other therapies as necessary. Got it. It's a majority. Okay. At the end of the day, as we think about the peak sales opportunity- It's a good sizable chunk of patients. Yeah. How should we think about the price bookends? Well, I can only say that, look, the premium priced medicines that are out there, for instance, BESREMi, which is pegylated interferon, or Jakafi, they are premium priced at over $200,000, the WAC price. It is a premium price market. This is an orphan condition, so there's not a huge hurdle for access. We have actually done research, talked to HTA folks in Europe, talked to some of the major insurers in the U.S. in preparation for our Phase III design, because obviously with any program, specifically a registration program, it's important to hit the registration endpoints, but the payers often have other things that they're interested in as well. We gather that input and it informs the final design for the Phase III. Okay. I meant to say, but by the way, they are expecting that this is going to be a premium priced product. Okay. There will be relatively low hurdles, because again, it's an orphan condition and the need is there. Right. Like you mentioned, the end goal here is to keep patients' hematocrit levels below 45. That's right. When we think about your phase II program. With your product, what's the take home message here? What did you see in the. Phase II is ongoing. It's almost done. What I'll do is reflect on the phase I data. Oh, right. I consider it phase II. Oh, phase I. Okay. Yeah. Yeah. The phase I data that we completed, we showed that we evaluated three different dose cohorts, 3 mg, 6 mgs, and 9 mg/ kg. Each of those cohorts received four doses Q six weeks, so week zero, six, 12, and 18. We followed them out to 34 weeks. What we saw was all the patients, and by the way, in that particular phase I trial, we allowed anybody, regardless of their baseline hematocrit, to come in. In phase II and III, we restrict that to patients who are well-controlled, meaning they enter the trial under 45, because I think it's a fair baseline setting for all patients, and then you address the benefit of drug versus placebo. In an open label phase I, we allowed everybody to come in regardless of their baseline, and we saw a very consistent effect across all patients. If you looked at the patients who were well-controlled who came in, whether they received 3 mg, 6 mg, or 9 mg/ kg, all of them actually maintained their hematocrit below 45 without the need for phlebotomy during the treatment period of the study. We feel very confident that moving into phase II, we chose the 6 mg/ kg dose to take forward, but we're looking at two intervals, Q six weeks and Q 12 weeks. The persistence of the effect that we saw in phase I beyond their completion of the four doses all the way out to 34 weeks in many of these patients actually gives us confidence that we could look at a less frequent dose interval, and that's what we're doing in the phase II. Great. To be crystal clear, you chose 6 mg as opposed to 9 mg- Yep because? Well, like with any phase I study, you're looking at a range of doses. We did not see any particular strong dose effect on the clinical measures, the clinical outcomes, which is whether or not you're maintaining hematocrit below 45 or required a phlebotomy. If you looked closer at some of the biomarkers, like for instance the elevation of hepcidin, you saw what looked to be a more robust elevation of hepcidin in the 6 mg and 9 mg/ kg group. You didn't see any difference between those two or any meaningful difference between those two higher doses, but it did appear that you had a larger and more robust effect on hepcidin. Even though, I just want to underscore this, even though the 3 mg/ kg group, if they were well-controlled when they entered the study, also did not require phlebotomies or had excursions of hematocrit above 45. All those three doses worked, but you see an elevation in hepcidin on the 6 mg and 9 mg. It made sense to take forward one of those higher doses. You never really need to go higher than you need to, and there was no clear indication to go from 6 mg to 9 mg. Six is the dose. Yeah. To be crystal clear, you saw durability maintained. That's right. for all three doses too? For all three doses, generally speaking, because we're looking at averages here across the three cohorts, you see a persistence of effect well beyond their last dose. Yeah. In most of those patients, that actually continued out to week 34. That's a very predictable, consistent, and robust effect. That again gives us confidence to look at a longer drug interval in phase II. Understood. Now the phase II, you're prepared to top line that in August. Right. It is now a placebo-controlled study and testing two different dosing intervals. That's right. What are you expecting on this same similar primary endpoint? Yeah. Yeah. What do you want to see? Again, in the study, everybody is well controlled, and it's blinded, and we have placebo, so it's a two-to-one randomization, as we talked about. If you look at, I think everybody's going to look at rusfertide data because that's the largest study completed in a very similar population, if not the same. They showed a 77% response on drug versus a 33% response on placebo in about 290 patients. You're looking at a placebo-adjusted effect of about 44%. Obviously, we'd like to see a robust effect. I can't predict the placebo response in our study. There's just too few studies to make that claim yet. We anticipate it will be somewhere between 20%-30%, we're looking for a robust effect over placebo. Yep. Like we established, there are two dosing arms. For the study to be technically stats, can either arm be placebo, or it must, I don't know, one arm? The analysis is really largely going to be based on the pool data set, but we'll have enough data for each of the arms to consider I should say, the interval we want to take forward into phase III. Okay, got it. Speaking of rusfertide, ho w are you exactly differentiated otherwise if, let's just say, if you did show same efficacy, how else are you differentiated then? Well, clearly as an siRNA, we have a durable effect. They are giving a mimetic, so essentially they're giving a synthetic exogenously administered hormone. That has to be given frequently, so typically for their product, it's a weekly injection. Obviously, we'd like to make it more convenient, reduce that frequency to at least Q six weeks and perhaps as infrequent as Q 12 weeks. It's just a different mechanism. We want to be able to demonstrate a very robust, durable effect that both patient and physician can be confident can be achieved between intervals. The thing with hepcidin mimetic, obviously, if you skip a dose, you may have some rebound, and that might be a concern in the real world when you translate effect into sort of effectiveness. The bottom line is we want to show, demonstrate a robust and predictable, consistent effect between a lengthy period, a reasonably lengthy interval between injections. Great. Yep. Again, from the phase II, it was basically every patient, so 100% response rate on the efficacy. In the subgroup of patients, about half who were well controlled when they came in because remember. Oh, right, yes. In the phase I, we allowed patients. In fact, we had patients at hematocrit levels of up to 59. Even in those higher hematocrit levels, we saw a very nice improvement. Obviously, they're starting from a higher dose, but you're seeing them come down nicely. In the well-controlled population, you generally see them maintain their hematocrit. That is your current phase II population. That is the population. Yes. Yeah. I think it was it 10 patients worth? Roughly, yeah. within that subgroup? Can you share how many patients were in the 6 mg group compared to 3 mg and 9 mg actually in that hematocrit? I'd have to go back and look. I don't want to throw out the numbers. Sure. Okay. They're small numbers across each of the arms. The bottom line is that's why I can say very clearly that either 3 mg, 6 mg, or 9 mg was effective. on the clinical measures of outcome, which is the maintenance of hematocrit below 45 without the need for phlebotomy. Right. When you look at the data on some of the biomarkers like hepcidin, obviously there was a differential effect. Right. Okay. Yep How does the other treatments like Jakafi and so forth, what do they exactly show on controlling for hematocrit? Well, Jakafi has a different usage. It's for patients who are not tolerant of hydroxyurea or just need something, they're not responding well to hydroxyurea. It's reserved really as a second-line therapy in those patients. You can look at their label, they did a very nice job of demonstrating the effect in that population. I think the response rate was somewhere in the 25% range, again, as a second-line therapy, very, very few patients in their placebo arm responded. Clearly, Jakafi has a role in those patients. We're looking at a broader population of patients, as is rusfertide. We looked at a population of patients, regardless of their standard of care that they're currently on, regardless of whether they were low or high-risk patients at baseline when they entered. As long as they were stabilized on their standard of care, we allowed them to come into the study. We're looking at a broader group of patients, all of whom are phlebotomy dependent, as I mentioned. Right. That's a much broader population than the Jakafi targeted population. Ultimately, should you be approved. Rusfertide approved, where do you think you're going to be positioned in terms of line of therapy? Well, I think again, if you look at the population we're treating and the label we hope to achieve based on what our design of our phase III program will be, you would say for patients who are phlebotomy dependent, regardless of risk profile or standard of care, they're the patients that we would go after. It's a relatively broad population, but of phlebotomy-dependent patients. Okay. Phase II, let's just say it was competitive 70% or so on an absolute basis to be clear. How should we feel about phase II to phase III translation? Well, even looking at phase I, the effect of this mechanism is very consistent. For instance, I'm pretty confident we'll repeat the data we showed in the Q six weeks, for instance. There's no question about it. I think we have a good likelihood or a reasonable probability of demonstrating the longer interval is successful. Then it's just a matter of moving forward and confirming that dose and interval in a much larger study, placebo controlled, which is the requirement of the agency. We have orphan designation, we have Fast Track designation. Our anticipation is we're going to have to do a confirmatory trial. The other companies have done trials in the range of 250- 300 patients. I think I can suggest that the effect size of the drug on the primary measure outcome is such that it wouldn't require such a large study. In a small population, you still need to have a minimum safety database, and I think capturing symptom improvement is going to be very important as well. The rusfertide did a nice job doing that. We would likely make sure we were reasonably powered, obviously, for those important secondary outcome measures. Until I see the results from the phase II, I can't really- Yes sort of clarify that. Okay. The bottom line, we want to have as efficient a phase III program as we can. We're a first in class siRNA. We want to minimize the time lag between the Ionis compound that's being developed and ours. We've done such a good job executing on our phase II trial. We were able to do that very quickly. If I just look at the rate of completion of some of the other trials that were done before us, I feel like we can do an excellent job executing, even with a larger study. Great. Come August, you top line the data. What kind of details can we expect? Efficacy kinetics, or is it just kind of a more simple top line? As is typical of top line results, you really want to preserve your details for your research presentation. Bottom line is we would certainly have the primary outcome measure, which is the response. I'm anticipating that we would look at the response or provide the response, which is the percent of patients that maintain an adequate control without the need for phlebotomy. Obviously, we'd also do some safety evaluation. Yeah. We may preserve some of the details, of course, for a full research presentation. Sure. That includes symptom improvement as well or not necessarily? We have to decide what we want to do. That's a secondary outcome measure here. Clearly we would present that in time. Whether that comes into the top line results or not, remember, this is not a confirmatory phase III trial. Right We want to just stick to the top line on the key efficacy and safety parameters. Sure. What kind of special AEs are you kind of caring about? We don't have any real special AEs. Obviously our drug has been very well tolerated. Our technology has been really well tolerated. It's not just this compound. We've got two other compounds in the clinic off of our technology platform. They've all appeared to be very safe and well tolerated. There's no real issues here. Obviously you always think about events that are significant to that certain population, for instance. You're suppressing hematocrit here, obviously you want to make sure you're not overdoing that and overshooting. We haven't seen that in our programs, obviously that's something you're going to look at. We had relatively low rates of those concerns, it is an injectable, we're giving it subcutaneously. You want to look at your ISRs. That's more of a tolerance issue in our case, but it's a very well tolerated, very few ISRs that were more than a grade one, and all self-limiting. Okay. Back in phase I, you did not see any grade three events? No. Okay. Pretty good. So far, or you expect? It's blinded. I can tell you though, it's blinded. We look at the safety on a regular basis, but the data are blinded, and I can tell you that it appears to be as safe and well tolerated as it was in the phase I. Great. Keep in mind also, we've given this drug to patients with beta thalassemia. We've done healthy volunteer study. We're very comfortable with the profile that's emerged. I see. As we talk about drug versus placebo behavior, why would a placebo patient have a response fundamentally? Yeah. Why would they- Why would there be-? Be a positive response? Yeah. Well, bottom line is the effect of the disease varies, right? I should say the disease activity varies. Right. You're minimizing that concern by making sure you have a history of a required minimum rate of phlebotomies in the previous six months. As long as you identify that, you wouldn't expect them if you're following them long enough. Right particularly during the period when you're going to observe a response. You wouldn't expect patients who required more than three phlebotomies in the previous six months to all of a sudden be able to go 36 weeks without one. I see. You just manage that by extending the period of time. Remember, in this 36-week trial, the phase II, we will take patients up to week 18 on drug just to make sure they're acclimated to the drug and treatment, give the opportunity for a full benefit from the active arms of the study, and then evaluate response between weeks 18 and 36. It would be unusual for someone who required multiple phlebotomies in the previous six months or a year to go so long without one, and all they need to do is have one in order to be a non-responder, right? Yeah. That's how you manage that. Your assumption or presumption where a placebo of 20%, 30% is pretty conservative, you would say? Look, I think that's what we can go on based on what we know from the literature and what we saw with rusfertide. Sure. Okay. That range is reasonable. We're certainly powered with the opportunity to benefit, to show a robust effect size over that range. Okay Hope to see that. Should this be positive. I'm very hopeful it's positive. Yeah. You meet with the FDA. That's right. What's the timeline there before you start phase III? Yeah. Naturally we'll have an end of phase II meeting. We're already preparing for that because fortunately, we have other products ahead of us that have gone through the evaluations and moved into phase III. There's a precedented regulatory pathway. We've pretty much determined that our trial will be similar to the ones that are being conducted, and so that seems like a relatively easy path to clarify. We have to go to that meeting, the end of phase II meeting, determine the minimum safety requirements, and we'll do that. I assume we'll have that end of phase II meeting by the end of the year or early in January, early in the new year, and start the study in the second half of the year. It usually takes six to nine months to start a large multi-regional program. As I mentioned, we feel very confident that we can execute pretty rapidly. We'd look to starting the study in the back half of next year. Yes. Efficiency is what you said earlier. Absolutely. I think rusfertide type phase III, did it take three to four years? I think roughly, yeah. You think you can shorten that? All I'm saying is we're going to do our best job. By the way, until we determine the number of patients, obviously, that is going to be important because even if you can trim 50 patients off of a 250 patient study, that helps with regards to timing for completion of enrollment. Right. We have used, even in phase I and phase II, sites in four different continents, and we expanded our footprint between phase I and phase II. We'll do the same going into phase III. I say this because we already have established KOL relationships, links with a number of different investigators in each of these areas, and we'll just expand on that as we did from one to two. Great. Meanwhile, I believe you're also working on some formulations. Can you maybe talk about that? Well, what we're looking to do is right now we're doing weight-based dosing. We did weight-based dosing in phase I and phase II. We want to move into phase III with flat dosing. We've done some PK/PD modeling that we're sharing with the FDA. We'll update that with the data from the phase II, it seems like we've got a relatively clear path to doing that. We may increase the concentration as well to reduce the number of injections so that no one requires more than two injections as we approach phase III and beyond. Ultimately, should this also, again, be approved as a sub-Q, can a patient handle this by themselves at home? Yeah, that's a good point. What we're planning on is having optionality at the time of launch. What we want to do, and we already initiated the development of a prefilled syringe, and we'll do it in such a way that it can be adapted to either the office or home. We'll determine that based on the work we do in preparation for commercialization. I see. That work is happening in parallel as you. That's right. do the phase III. That's exactly right. Actually, it's started now. Oh. We will do all of that in parallel. Okay. We'll still use a vial and syringe in phase III, but with the new concentration. Okay. I guess my next question is a subject of your FDA discussion. I'm just curious what other kind of major peripheral studies you think you need to do. Well, you need to do your typical requirements for carcinogenicity, et cetera. That's pretty straightforward. Besides a single confirmatory trial, along with a supportive phase II, which we assume our phase II study will be, that's really what's required. Yeah. Okay. Very good. Yeah. Maybe last minute, Lp(a). Yes We're waiting for Horizon. Yep. I don't want to say when I think the data, but I hear certain things, but I think. Second half of the year. Yeah. Anywhere from midyear to the second half of the year. We're looking forward to that. I think everybody is waiting to see that trend. The effect on robust lowering of Lp(a) translates into improved cardiovascular outcomes, so I think that's an exciting point for the field, and I think for us that will obviously hopefully turbocharge discussions with potential partners. Yes. We have a very well-designed phase III program that we've already sort of got an agreement with the agencies on. FDA got very good feedback. Looking to distinguish ourselves from the data that are being generated currently, and the study's ongoing. I think we're just waiting for that page to turn before we can increase those activity around partnership. Okay. Then, over time we'll learn more about your other remaining programs. Absolutely. Exactly. Yes, very excited to talk about those in the future. Okay. Well, I think that's all the time we have. Okay. Thank you, Steven. Thanks very much. Appreciate it. for walking us through, and best of luck on your data- Thank you. coming up. Yeah. Okay. Thank you very much. Thank you, everyone.