Good afternoon, everyone, and welcome back to H.C. Wainwright's fourth annual Bioconnect Conference at NASDAQ. I'm Patrick Trujillo, senior healthcare in H.C. Wainwright. It's our pleasure to introduce our next member of the team from Silent Therapeutics, a global clinical-stage biotechnology company developing novel short-infering RNA or siRNA therapies built on its proprietary mRNA-i-gold platform. With a focus on rare common diseases, we're currently living so limited or inadequate. Silent is advancing a differentiated pipeline lipidivecerin, a first-class SIRNA for polycythemia vera, or PV, with phase 2 San Rico top-line data expected in August 2026, alongside Zerlacerin, a phase 3 ready SIRNA targeting LP level A for cardiovascular disease. Earlier programs also include in dyslipidemia SLN 312 and obesity SLN 098. And then it's my pleasure to introduce you to Curtis Ramarin chief medical officer who's representing silence today so thanks for joining us maybe first if you could just provide us with a brief overview of silence therapeutics today including the mRNA AI gold platform the core clinical pipeline and the most important value drivers as you see them

over the next year thank you and it's great to be back for having us again so So Silence is a clinical stage biotechnology company. We are focused on developing precision type medicines based on our sRNA technology. And we have a platform called the miRNA Gold Platform. So the Gold Platform is designed to deliver medicines that are targeted, long duration of effect, and very potent. And we have a pipeline that is a combination of cardiometabolic and hematological assets presently. For cardiovascular, sorry, I'll start with the diviserone, that's of sRNA that's targeting temperature 6. This is for patients with polycythemia vera. we have an SRNA targeting LP gene silencing this is the last run we have completed a phase 1 phase 2 this is a phase 3 ready asset we have a another clinical stage asset SLN 312 that's an SRNA that's targeting ang ptl3 and that's in development for dyslipidemia and we will be presenting data at the end of this month at the AES, the European Atherosclerosis Society meeting, data from the phase one trial. So that's the clinical stage assets. In terms of the key drivers, I think firstly, Divisiran. We have completed the phase one, so we have presented previously very compelling phase one data. The phase two trial is expected to read out in August, and that will be a significant milestone for the company and a significant catalyst so we're very much looking forward to that for the last run for the LP 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 three ready so we are very well poised to move into a phase three trial. For 312, as I mentioned, we presented the phase one data. So this essentially will be a phase two ready asset that, again, we are looking at different options for development. And beyond the clinical stage assets, we do have some preclinical assets under the cardiometabolic realm that we are developing. And we also, again, investing in our extra-hepatic efforts.

So for those who are newer to RNAi, what do you view as the key advantages more broadly for RNAi within genetic medicines, particularly around potency, durability, reversibility and dosing frequency?

So maybe I'll just say a bit about RNA interference itself. So RNA interference refers to a pre-existing cellular machinery that is optimized evolutionarily to degrade viral RNA and sRNAs are short specific sequences of RNA and they sort of co-opt this machinery in a very very nice fashion so they were then to silence some specific targets by associating with specific target messenger RNAs and degrading them so that don't actually get to to the protein-making machinery within the cell. That leads to effective gene silencing. And several things make the SRF very appealing. So historically, we are now able to go off the targets that are previously considered to be undrugable, so not targeted by, say, small molecules of biologics. And the excitement about it partly was because of the potency. so we have seen that one it works on a pre-existing cellular machinery as I mentioned and two very small concentrations of sRNA can lead to substantial knockdown of a target gene so 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's it's has a long duration of effect because the catalytic activity within the risk of the multi-protein complex allows a single sRNA molecule to target multiple messenger RNA transcripts. Then we look at duration of action. We have seen in the clinic that even more phase one and phase two data that this technology clinically can be dosed very infrequently, three monthly, sometimes even longer. As a default 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. So it's very attractive to patients because from a

convenience perspective and from an option perspective. So as RNAi expands beyond this first major wave of liver-targeted medicine, where do you think science is most differentiated? Is it chemistry, target selection, clinical execution partnering strategy or some combination? So science has had a long

history in all the nuclear development so we do have proprietary SRNA molecules and linkers as a first step. We have learned chemical modifications over time and this has led to enhance stability and improve activity. So that's two very key things. Certainly we have been very open to partnerships. We have developed some programs, certainly in our own. We have been very open to looking at different partnership that could work to take the assets further in development.

So just moving on to divestrin and polycythemia vera, can you reintroduce us to this program, its mechanism targeting TEMPR6 and the rationale for

developing it in PV? So divestrin is a very unique molecule. It targets TEMPR6 six gene temperature six is a negative regulator of exciting so when you are suppressed and process six you get increased subsiding levels exciting is the master regulator of iron flux in the systemic circulation so when you increase subsiding three main things happen you reduce iron absorption from the gut you regulate and recycling in the macrophages and you suppress the release of iron from storage. So those three things result in a reduction in iron availability to the bone marrow. So in polycytemia vera, these patients have an exacerbated excessive production of red blood cells. So with Diveserone, what we are doing, we are physiologically shunting iron away from the bone marrow so it's not available for red blood cell production. That results in a reduction in hematocrit because hematocrit is an index of red blood cell formation. And therefore, you get, as we have shown in phase one, a progressive and sustained durable control of hematocrit, the levels below 45%, which is the guideline recommended target that you should go for. And in addition, we have shown that phase one, your divestment is very safe and very tolerable up to nine micks per kilogram. So then the phase two San Rico trial is fully

enrolled, top-line data 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 six-week and every 12-week dosing arms and the primary endpoint of hematocrit control without plebotomy.

Sure. So, the phase two is in two parts. The first part is a placebo-controlled, randomized, double-blind period for 36 weeks. So, this will be data collected on the longest treatment period. The treatment period in phase one was up to 24 weeks so this would be 36. Then after the 36 weeks all subjects go on drug enter an extension phase that's double blind and then open label. We have we have as you mentioned we have recruited 48 PV phlebotomy dependent PV patients. We have three different cohorts. We have placebo, we have diviserone six mix per keg every six weeks and diviserone six mix per cake every 12 weeks. So we have roughly two-thirds of the population on active and one-third on a placebo. The primary endpoint is the proportion of responders between diviserone and placebo versus placebo between weeks 18 to 36. So that's our key period because we felt that that's a time point where the physiological effect of the drug has been dose enough to be able to take place. So we're looking at the response rate and the response responder would be any patient that has the hematocrit that remains controlled meaning less than 45 in the absence of phlebotomies. So we are looking at control of hematocrit, removing phlebotomies during that eight in the 36 week period but we also importantly for some of the other regulatory agencies be looking at the mean change in phlebotomies from

baseline to week 36. And the EHA 2026 poster is going to highlight the phase one data I believe on reduced phlebotomies, improved iron stores, and symptom improvement. So what should investors focus on from that presentation as they think about the August phase two readout? What would

constitute a clear win in San Rico? So we have already presented very compelling phase one data in terms of efficacy and safety. So two new things would be presented at EHA in June. One is the quality of life data, so 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 looked at, we wanted to really get further insights on the duration of action and the durability of the drug. I think it's quite long, and that's why we have gone to 12 weeks in the phase two as a second cohort. We looked at the patients who had the last dose in phase one when their necks went on to have a phlebotomy, that period. And I can tell you it looks very, very, very exciting. So we're looking forward to presenting those two things at EO.

How important is the 12-week dosing arm to divestrin's differentiation? Would a strong six-week profile alone be commercially compelling?

So 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. And Diveseran 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 two. And I think when you see the data from the poster at EHA, I think it does look very, very promising in terms of durability.

And how do you see divestrin fitting into the PV treatment landscape relative to phlebotomy, cytoreductive therapy, JAK inhibitors, interference, and hepcytomimetics such as resveratide? So as I mentioned this is first-in-class

SRNA, 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. So it's across that spectrum of the breadth. And certainly, we're looking at the first-line options, particularly in the

lower-risk patients. And assuming San Rico's positive, what are the next steps from a regulatory and development perspective, how should we think about the phase three path and timing?

So we are doing a lot of groundwork in parallel. We are looking for the leanest phase three design. We're looking at the fastest route of filing. We certainly were planning to leverage our fast track orphan designation. We are resubmitting for breakthrough and we are anticipating to engage there for the end of the year or the next year. So there's a lot of work ongoing, particularly under 011 operationally to position us to be able to start the phase three we would

say in the second half of the next day. So just moving on then to xerolacirin and LP little a shifting here then to cardiovascular disease can you reintroduce xerolacirin and explain why LPA remains such an important untreated cardiovascular risk factor? So as a cardiovascular physician I'm

really excited about LPA because this is the genetic risk factor which we have no treatment for. It's accumulating evidence that it increases the risk of cardiovascular disease, MRI strokes, peripheral disease, aortic valve disease. Unlike LDL it has no effect from fasting or from exercise or diet and one in five of the global population so one in five of us that potentially in this room have high LPA levels and no treatment so this is a huge potential and we developed the last year on as our first entry into the clinic because it's an SRNA designed to specifically lower LPA by targeting the LPA gene and you as we have published very compelling phase 1 and phase 2 data that we need frequent dosing we can substantially lower LPA in a very controlled manner and in with with very robust in terms of a duration of effect and potency.

And so is the last one is phase three ready? So just in terms of the work that's been completed, including manufacturing scale, regulatory alignment with the FDA and EMA, what still needs to happen before cardiovascular outcomes trial could begin?

So when we say phase three 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 ground work also with the CROs. In addition, we have scaled up manufacturing of phase three-ready material, but we did two also very important things. We did a pre-screening study in over 2,500 subjects looking at our phase three enrollment and, sorry, our phase three entry criteria, and so these are patients that can potentially flow into a phase three. Also, I don't think many of you will know, but last week, available online, is we published our Japan phase one study. So we actually have a footprint in Japan, we have developed some experience, and I think that's gonna be very, very useful.

So the LPA Horizon CIVOT for Pella Carson is expected to read out later this year. How are you thinking about the potential upside for the read-through to Xurlacerin if that trial validates LPA, by lowering as a cardiovascular risk reduction strategy?

So we're certainly cheering the field 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 there's one advantage of us not being first. We were able to craft a differentiated phase three design, and we think we can play to the strengths of the SRNA in terms of potency, duration of action, and safety. So we think we are well positioned, once that reads out, to very quickly move into phase three or to seek an adequate partnership.

So just moving on then to SLN 312, this program has been returned to silence from AstraZeneca. So maybe you can talk a little bit about the program, ANG-PTL3, biology, why it remains attractive in dyslipidemia, and what we have to look forward to for the upcoming EAS late-breaking presentation.

So ANG-PTL3 remains attractive because it's a LDL-independent mechanism that when suppressed leads to a reduction in the atherogenic lipoproteins, so LDL, APLB, triglycerides. And if you look at comparative studies that are contemporary studies that are ongoing, data looks very, very promising. For 3.1.2, we are looking forward to seeing the phase one data. This was a study in dyslipidemic subjects, including diabetic subjects. So we're looking at the potency, the safety, and the potential insights on durability.

And 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 SLN-365 targeting GPR-146 for hypercholesterolemia and SLN-098 targeting inhibin beta-E or inhibi for obesity?

Yes, we are equally excited about these novel targets. The GPR146, again, is an LDL-independent mechanism, and we are currently looking at options that may include combination therapy with other assets in the pipeline or externally. And the reason I say that is if you look at, for example, homozygous FH, where ANCHPTL3 has been marketed already, these diseases invariably need combination therapy. So we're definitely looking at the potential for combination. For NEBE, again, strategically and commercially, and in terms of the field, this is another very, very exciting asset, along with obesity and cardiometabolic disease. We have what we think is a very, very good asset. We are completing some in vivo efficacy studies internally. And again, we are looking at options that will include potential novel partnerships, sorry, novel combinations. And 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 extra-hepatic siRNA delivery as the next frontier of the mRNAI gold platform? And what investment is the company making in that direction?

So I think we have established a pretty good track record in the GALNA conjugated, as others So we have learned a lot. But we have certainly generated some data in-house on different cell types. We are continuing to do some experiments on those, so we'll be generating more data this year. And again, these are the sort of things where we are looking at external potential partnerships to leverage the data that we have generated and potentially setting different aspects of our pipeline.

And as a last question, as you look across the pipeline, Diveserans or Laceran, 312-365-098 and extrahepatic delivery, what do you think is most underappreciated about silence today and what would define success over the next year?

So 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. So if you look at Ziloceran for LPA and Diverseran for PV, in both phase two trials, we recruited ahead of time. We recruited actually more numbers that we targeted within our budget. And remember, these are two programs where we are competing with the big boys, the big pharma. So 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 Divisiran, that phase two data will be certainly transformational for the company. We have an asset that's potentially best in class. It's the first in class SRNA. I think for LPA, 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 a tremendous market opportunity starting light. So there will be a clamor from patients for many, many different options. I think 3.1.2, certainly, you'll see the phase one data that will be presented at AES, but that's a phase two ready asset, so we'll have three clinical assets, phase two will be on, so it really adds another dimension to the cardiometabolic aspect, and then in combination with those three, as I mentioned, we are generating, you know, early data in some novel targets, So I think the next year, it should be very exciting. It'll be data, data, data, and you know, we're really looking forward to it. So hopefully we'll come back and share some of that.

Well Curtis, 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 in conference.