Silence Therapeutics Plc

Good morning and good afternoon, everyone. Thank you for joining us today. My name is Jem Hopkins, Vice President of Investor Relations and Corporate Communications at Silence. Joining me on today's call are Craig Tooman, our President and CEO, who will provide an update on the business, Rhonda Helms, our Chief Financial Officer, who will review our financial performance, and Steven Romano, our Chief R&D Officer, who will provide a clinical update. For those of you participating via conference call, the accompanying slides can be accessed by going to the investor section of our corporate website at www.silence-therapeutics.com. I'd like to remind you that during today's call, management will make projections or other forward-looking statements regarding anticipated future events or the future financial performance of the company, including clinical development, timing, and objectives, the therapeutic potential of our product candidates, our operational plans and strategies, anticipated milestone payments, anticipated operating and capital expenditures, business prospects, and projected cash runway. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual report on file with the SEC and any future filings. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to Craig. Craig?

Thank you, Jem, and thanks, everyone, for joining today's webcast. I'm pleased to be with you today to discuss our 2024 full-year performance and share some color on what's ahead for the company. I'll start by quickly touching on a few key highlights about our full-year performance. Starting with Zolaceron, our SRNA for high LP little a, The ALPAC-R360 Phase II study of Zolaceron in ASCVD patients with high LP-Lil-A delivered positive results that were featured in a late-breaker at AHA and published in JAMA. The study showed LP-Lil-A reductions exceeded 90%, effects were durable, and Zolaceron was observed to be well-tolerated. These data support a competitive profile that we believe can be further defined in Phase III. The SILENCE team, supported by top cardiologists, have done an outstanding job designing what we are confident is a highly differentiated Phase III program for Zolaceron. We recently met with global regulatory agencies on the design and received very positive feedback across the board. The SILENCE team has also been successfully executing on core readiness activities for Phase III development, including manufacturing readiness. Turning to Diverseron, our first-in-class SRNA for polycythemia vera. The San Rico Phase I study of Diveseron delivered positive results that exceeded our expectations. Data were highlighted at ASH and showed Diveseron completely eliminated the need for phlebotomy in all well-controlled patients. The safety and tolerability profile continues to look very favorable. In addition, we started dosing patients in the San Rico Phase II study, and the European Commission granted Diveseron orphan drug designation for PV. As a reminder, Diveseron also has FDA Fast-Track and orphan drug designations for PV. In terms of other pipeline advancements, we are pleased to have our third SRNA from our gold platform enter the clinic in 2024 under our AstraZeneca collaboration. We value this partnership very much and are proud of the program we were able to advance together. We look forward to its further progress and the potential to earn additional milestones. We also progressed several preclinical SRNA candidates for hepatic targets. Turning to slide five and what's next for our company. This morning we announced that in 2025 we are prioritizing investment in programs targeting rare conditions where we believe we can deliver on clear unmet needs with first-in-class and or best-in-class SRNAs. Dibeseron is a great example of that. We remain confident in our Zolaceron program for high LP little a and believe we have very differentiated design for our phase three program. However, today we are making clear that we will only initiate the phase three outcome study once a partner is secured. This strengthens our cash position into 2027 and gives us flexibility to invest in our innovative pipeline while we continue partnering discussions for Zolaceron. We have listened very carefully to our shareholders and made this decision with their collective feedback in mind. I want to reiterate that we continue to believe strongly in Zelaceron's potential. There are very few cardiovascular assets in development that aim to treat an unmet medical condition as large as the Lp opportunity. We are hopeful we will secure the right partner to bring this very promising program forward. Until a partner is secured, we do not plan to provide any further updates. Turning now to Deveseron. We announced this morning that we completed follow-up in the Phase 1 portion of San Rico this month and look forward to presenting more data from that study at medical meetings this year. The outstanding data from the San Rico Phase 1 study have generated a lot of excitement from the medical community and patients who want to be involved with the program. In fact, we also announced this morning that we anticipate full enrollment in the San Rico Phase 2 study by the end of this year. While we are currently focused on the PV indication for Deveseron, we continue to believe it has broader therapeutic potential. Given the outstanding PV results we have seen in Phase I, we are planning an investor event later this year and look forward to discussing the program in more detail then. In addition to Deveseron, we were pleased to announce today that we plan to start a Phase I study of SLN548, our wholly-owned SRNA targeting complement factor B, in the second half of this year. Steve will go into a bit more detail on this in a few minutes. In terms of what's next for our gold platform, we have multiple undisclosed programs that have generated encouraging preclinical data. This includes the three targets that we've retained global rights to following the conclusion of the Hanso Pharma collaboration we announced this morning. We are evaluating these programs as part of our broader portfolio and will determine which ones we want to bring forward ourselves or potentially partners. As I mentioned, we will be prioritizing targets in rare conditions where we believe we can deliver valuable, competitive profiles to address patient needs. In addition, we plan to invest selectively in our extrahepatic work where we are seeing promising early data from programs targeting multiple cell types. We look forward to sharing more as we move ahead and these data mature. With that, I will now turn the call over to Rhonda to review our 2024 financial performance and guidance for 2025. Rhonda?

Thank you, Craig. First, I would like to point out that effective January 1st of 2025, silence has transitioned from a foreign private issuer to a U.S. domestic issuer, which requires us to comply with the U.S. domestic reporting requirements under the Exchange Act. We are now required to file periodic reports and registration statements on U.S. domestic issue reforms with the SEC in accordance with U.S. GAAP as opposed to IFRS, and then U.S. dollars versus British pounds. Now let me turn to the financials. For the year ended December 31st, 2024, the company recorded 43.3 million in revenues versus 31.6 million in 2023. The increase of 11.7 million is largely due to the collaboration arrangements we have entered for development of candidates utilizing our SIRNA platform. As Craig mentioned, our AstraZeneca collaboration continues to advance nicely, and we are hopeful that this program will continue to move forward and allow us to receive additional milestones. Turning to the HONSO Pharma collaboration, we announced this morning that HONSO opted not to pursue further development under our collaboration. As a reminder, this was a collaboration to develop siRNAs using our gold platform for three undisclosed preclinical liver targets. formally had options to license China region rights on two of the targets and global rights on the third target. As a reminder, we record revenue from our collaborations based on percentage of contract completion. Therefore, in 2024, we recognize 24.6 million resulting from a cumulative catch-up following the completion of all required obligations to HONSO under the collaboration. Finally, during 2024, we recorded the remaining royalty revenue from an island of approximately 144,000. The expenses related to our partner programs, including the portion of our employees' time dedicated to these programs, are recorded as cost of sales as they are attributable to the revenues. These expenses were 11.8 million in 2024 compared to 12.9 million in 2023. As expected, R&D costs rose in 2024 to 67.9 million versus 56.9 million in 2023. This increase was primarily due to advancing our proprietary Zolasterin and Divisorin programs, which Craig previously mentioned. We also strategically invested in further development of our platform and identifying new targets to further expand our proprietary pipeline. General and administrative costs were 26.9 million in 2024 versus 26.2 million in 2023. The increase was primarily as a result of additional legal and accounting expenses required to transition to filing as a US domestic issuer, including our transition to US GAAP. The company's net operating loss for the full year of 2024 was approximately 63.3 million versus 64.4 million in 2023. The decrease in our net loss is due to the increase in revenue partially offset by the increase in R&D costs as a result of advancing our programs in clinical development. We reported other income of approximately 4.5 million, which largely represents the accretion of our US Treasury bills compared to 1.8 million in 2023. We also reported approximately 13.7 million from the benefit of our R&D tax credit in the UK compared to 11.9 million in 2023. The company's net loss for the full year of 2024 was approximately $45.3 million versus $54.2 million in 2023. The company's cash, cash equivalents, and short-term investments were $147.3 million at the end of December of 2024. This includes cash and cash equivalents of $121.3 million and short-term investments of $26 million. Turning to slide eight and the 2025 cash guidance. As Craig mentioned, we have made the decision only to initiate the Zolasterin Phase III outcome study once we have secured a partner. This allows us to extend our projected runway into 2027. I'll echo Craig's comments that we are prioritizing programs targeting rare conditions where we see the opportunity to deliver on clear, unmet needs with innovative siRNA therapies. This includes Stivisarin for PV, which remains a top priority. In addition, we look forward to advancing additional programs in our pipeline, including our extrahepatic work. With that, I'll turn the call over to Steve for a clinical update. Steve?

Thanks, Rhonda. As Craig mentioned, we made great progress advancing to viscerin, the first-in-class SRNA for PV in 2024. The Sanrico Phase I results were impressive and have garnered enthusiasm from the program. The Phase II study is enrolling very nicely, and as Craig mentioned, we anticipate full enrollment by the end of this year. As a reminder, PV is a rare myeloproliferative neoplasm, a type of blood cancer, that is associated with erythrocytosis, or an increase in the production of red blood cells. Other blood cell types, including WBCs and platelets, may also be increased. The increase in RBC mass corresponding to a substantial elevation of thematic rate leads to a higher incidence of thrombotic or clotting events and an increase in adverse CV outcomes. PV is associated with a range of burdensome symptoms, including fatigue, cognitive disturbance, and pruritus. And additionally, longer term can transform to myelofibrosis and acute myeloid leukemia. PV impacts around 150,000 individuals in the U.S. and 3.5 million worldwide. The aim of the treatment is to maintain a matricrate less than 45%, a level that is associated with a reduced incidence of thrombosis and CV-associated death. Treatment usually requires routine phlebotomy along with a low-dose aspirin. Many patients, regardless of risk level, require the addition of cytoreductive agents to ensure achievement of treatment goals. Phlebotomy, while helpful, is time-consuming, may not maintain patients at safer hematocrit levels consistently, and can contribute to iron deficiency and overall symptom burden. At the bottom of this slide, we have a quote from Nona, who is living with PV. She says, the PV aspect means that you have to have phlebotomies regularly, and I think the most crippling thing about that is the fatigue. We are hopeful, based on the San Rico Phase I data, that Divisorin has the potential to greatly reduce and even eliminate the need for phlebotomy. Turning to slide 12 of Divisorin, a first-in-class SRNA for PV, I'll quickly review how Divisorin works for those less familiar. TEMPR-6 is a negative regulator of hepcidin, the body's master regulator of iron metabolism, including its absorption, distribution, and storage. The therapeutic hypothesis for the use of Divisorin in PV patients is the following. By silencing TMPR6, hepcidin production and release by liver hepatocytes will increase, leading to the restriction of iron to the bone marrow and thus reducing the excessive production of red blood cells, a process dependent on the availability of iron. Turning to the Sanrico Phase I study, the design was open-labeled with three cohorts and enrolled 21 PV patients. We tested doses of 3, 6, and 9 mg per kg, consisting of 6, 8, and 7 patients, respectively. All patients were scheduled to receive four doses at six-week intervals and then were followed for 16 additional weeks for a combined total of 34 weeks of treatment and follow-up. Key inclusion criteria for the trial subjects included a diagnosis of PV based on WHO criteria and a history of requiring a minimum of three phlebotomies in the previous six months or five phlebotomies in the previous 12 months. Patients on stable doses of cytoreductive agents were phase one study, both well-controlled patients, that is those with hematocrit 45% or less, and those less well-controlled with hematocrit greater than 45% were included. As Craig mentioned, all patients completed the follow-up period this month, and the phase one study is now complete. The data slides I'm about to show you are from the ASH presentation in December and include 19 PV patients with a combined history of 79 phlebotomies in the six months prior to enrollment. You can see historic phlebotomy details are in orange shades to the left of center and capture all events up to day one, the time of the first dose administration. To the right of center, in blue shades, are any phlebotomies recorded during the trial, both the treatment period as well as the follow-up period. No patients entering the trial with well-controlled hematocrit levels required a phlebotomy. In other words, 100% of this group maintain adequate control of hematocrit as per treatment guidelines. Only five phlebotomies occurred during the treatment period. All were in patients who entered the study with high baseline hematocrit levels, those over 45%. Two phlebotomies occurred in the 16-week follow-up period following the last administered dose. In fact, no patient with a hematocrit less than 50 at baseline required a phlebotomy during the treatment period. These data are very promising. Given the fact that we included a range of patients in this trial, regardless of baseline hematocrit, It's important to evaluate the effect of Divisorin on both well-controlled patients, again, those with hematocrit levels less than or equal to 45%, as well as those with high baseline hematocrit levels. You can see here that Divisorin reduced hematocrit levels in all patients regardless of baseline levels. Divisorin also demonstrated robust target engagement. You can see here we observed early and sustained hepcidin elevations. Importantly, these elevations are within the physiologic range of hepcidin levels. Importantly, divisorin was safe, well-tolerated, all doses tested. The majority of treatment emergent adverse events were mild, none over grade 2. There were no treatment-related serious adverse events or TEAEs leading to discontinuation. So in summary, the Phase I data showed that Tavisserine eliminated the need for phlebotomy in all well-controlled patients, lowered hematocrit levels in all patients regardless of baseline levels, and the safety tolerability profile continues to look very favorable. We look forward to presenting additional Phase I data at medical congresses this year. Here's a high-level look at the design for the ongoing Phase II portion of San Rico. This is a randomized, double-blind study evaluating Tavisserine in up to 40 PV patients. Unlike the phase one, where we allowed patients to enter with a range of baseline hematocrit levels, all patients entering the phase two will have a hematocrit level below 45%. The study is 36 weeks, and we are assessing two different dose levels and regimens. The primary endpoint is the percent of patients with hematocrit at or below 45% without the need for phlebotomies. We will also be assessing the effect of divisorin in improving PV-related symptoms. As we mentioned, The study is enrolling nicely, and we anticipate full enrollment by the end of this year. Turning now to FLN548, our wholly-owned siRNA targeting complement factor B. The complement system is a critical component of the innate immune system and is made up of several dozen liver-derived proteins and protein fragments. It complements the ability of antibodies and phagocytic cells to rid the body of foreign microbes as well as help clear cellular debris, including damaged cells. It plays an important role in inflammation. There are three distinct biochemical pathways that can lead to activation of the complement cascade and include the classical, alternative, and lectin pathways. Importantly, both deficiencies and overactivation of the complement system play a role in a broad range of conditions with immune components. Given the complexity of the complement system pathways and the large number of proteins involved, there are a plethora of potential targets for therapeutic intervention. SLN548 is an siRNA-targeting complement factor B and could potentially play a therapeutic role in conditions associated with overactivation of this pathway, including complement-mediated renal diseases, among others. The long-acting profile of our gold platform compounds could allow for the development of an infrequently-dosed therapeutic option. We're excited to advance this compound into a first-in-human study in healthy volunteers later this year. This slide is a brief summary of the Phase 1 study design. It is a randomized, double-blind, placebo-controlled, single-accending dose study that plans to enroll up to 32 healthy volunteers across four dose cohorts. primary objective is to evaluate the safety and tolerability of SLN548 in healthy subjects, as well as the pharmacokinetic and pharmacodynamic profile. It incorporates sentinel dosing, and all patients will be vaccinated and receive prophylactic antibiotics as appropriate. We look forward to sharing more details about this program, including our development strategy at a future time. As Craig mentioned, we anticipate starting the study in the second half of this year. With that, I'll turn the call back over to Craig.

Thanks, Steve. In summary, our decision to only initiate the phase three outcome study of Zolaceron once we've secured a partner extends our projected cash runway into 2027. This gives us flexibility to invest in our innovative pipeline while we continue partnering discussions. We remain confident in Zolaceron and will provide an update when there is one. On this slide, you can see our anticipated clinical milestones for 2025. For divestiron, we completed follow-up in the Phase I San Rico study this month and will present additional data at the medical meetings this year. We anticipate full enrollment in the Phase II San Rico PV study by year-end. We are also planning to host a divestiron-focused event later this year, so stay tuned for more information on that. For SLN 548, we are planning to start the Phase I study in healthy volunteers in the second half of this year. We're also looking forward to progressing our extra hepatic work and sharing these data at the appropriate time. The silence team remains very, very focused on executing to deliver life-changing SRNA therapies to patients in need. With that, I'll pass back over to the operator for your questions.

Thank you. At this time, we'll conduct the question and answer session. As a reminder to ask a question, you'll need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. And our first question comes from the line of Mike Walsh of Morgan Stanley. Your line is now open.

Good morning, and thanks for taking the question. Maybe just one focused on Zerlazarin. I guess to the extent you can, if you could provide some color on partnership discussions. And then just how important is the horizon data to those discussions, which we're expecting, I guess, first half of next year now. And then maybe secondly, just talk about some of the types of partnership structures you're considering. Thanks.

Thanks, Mike. We're not going to comment specifically on the ongoing partnership discussions today, but it is interesting to note that since the recent shift in the timing of the horizon readout, You know, companies, including Novartis, have pledged more funding for LP little a studies. So interesting phenomenon. Look, we're not a one product company. We've got a portfolio of assets with great potential. And as you know, the best around is a great example of that. And it is a fine balance to kind of manage the resources, you know, amongst the products. And we want to make sure we get the best returns. So that's our announcements today. You know, Silas has really done an excellent job. I give the team all full credit for getting their last round to this point, which is designing this highly differentiated phase three program. We continue to believe in its high value potential, very competitive profile, substantial market potential that we've talked about on multiple occasions. And we are actively engaged. So I will say that we remain actively engaged in partnering discussions and hopefully we'll be able to secure the right partner to bring this very promising program forward, both in development and commercially. So I won't say more on that, but we will update you if there's something to update you on regarding a partner. Great. Thank you.

Thank you. One moment for our next question. Our next question comes from the line of of BMO Capital Markets. Your line is now open.

Hello, everyone. Good morning. Thanks for taking our questions. Maybe one question on the last one and one on the veterans from us. How ready are you for the phase three trial? And specifically, from the time you secure a partner, how fast do you think you can start the phase three? And will the partner be able to potentially make changes to the phase three design? Or do you think the phase three design is set and the partner needs to kind of agree to that. And the second question on Dvesuran is, would you consider evaluating Dvesuran in hereditary hemochromatosis given the relevance of the target there? Thank you.

So we are in a logistical phase. We're wrapping up phase three readiness activities, which are on track to complete by mid-year. So we're in a little bit of a period where we can make some fine-tuning if we needed to do that with a partner. But we've advanced very, very nicely across the team in order to be prepared, including, as I mentioned, manufacturing preparedness, which is very important. So there is some time, a bit of time, before the track that we had outlined before really gets more fixed, if you will. In terms of HH, Steve, do you want to comment on HH?

Yeah, sure, Costa. So yes, we're certainly obviously focused on the PV program and executing that, but we do know because of our mechanism that it applies actually across a fairly broad range of conditions where hepcidin may play a role or manipulating the hepcidin pathway may play a role therapeutically. So we're looking at that. And HH is one of those, of course. So we haven't declared any additional work specifically with regards to trial work, but we're examining the opportunity to expand our program.

Thank you very much.

Thank you. One moment for our next question. Our next question comes from the line of Richard Law of Goldman Sachs. Your line is now open.

Thanks. Good morning, everyone. So a couple questions for me. What is the goal for Divisorin regarding differentiation? Can you differentiate clinically from busfer type besides dosing frequency? And also, what are the biggest hurdles that you see for partnering Silicerin? Thanks.

Steve, do you want to take differentiation, Divisorin?

Yeah. So, you know, first of all, we want to be the first sRNA to the market for PV, so we're very excited about that opportunity. And clearly, and I wouldn't minimize it, but one of the major differentiations, of course, is going to be the infrequency of dosing. And in fact, as I mentioned, as we move forward into completion of the phase two, we may have an idea of even less frequently dose regimen versus what we evaluated in phase one. The other things we'll look for, obviously, are symptomatic improvement, et cetera. So we'll look across the range of important dimensions to measure outcome in this disease. But until that work is done, it's hard to say what point of differentiation or points of differentiation will be available. But the bottom line is the convenience factor is going to be a very important one. and we hope that that long-term effect could have an impact on the likelihood that patients maintain hematocrit at levels that are safe and below 45 consistently. So more to come on that as the profile of the drug is known.

In terms of partnering and hurdles, really no single item for the parties is different for every one that we've had dialogue with. The dialogues do tend to be a little bit around the notion of business strategy and recognition and intrigue in the very large market opportunity. So we remain very confident in the program, as we discussed. The dialogues continue, and we will pursue that. As you know, partnerships often don't really happen on a clock. It involves coincidence and needs and timing amongst the parties, but we are very active, I can tell you that. And thank you for the question. Thank you.

Thank you. One moment for our next question. Our next question comes from the line of Kenaki of Tartan. Your line is now open.

Yeah, thanks. Question about the candidates being developed for HANF. So is there anything there worth continuing to pursue on your own? Or how do we view the status of that?

Yes, thank you. We're very interested in the programs that we have been developing in that productive partnership. We have seen and continue to see encouraging preclinical data in each of the programs. Now we will actually retrieve those programs and have the opportunity either to develop them ourselves or potentially partner or license. So it actually gives us the control to determine what we want to do with those. but obviously in a context of having good data. I don't know, Rhonda, if you want to reiterate a little bit of the financials on that because it's not abundantly clear perhaps.

Yeah, sure. So as I mentioned, the revenue did show the cumulative catch-up. So because we have no further obligations in our collaboration, all the original upfront milestones are basically recognized at the end of the year. So we don't anticipate further from HONSO. However, we will continue to have revenue from AstraZeneca as that program continues. And then all the other additional new targets from the AstraZeneca collaboration could potentially add some revenue to that as well.

Okay, thank you. Thank you. One moment for our next question. Again, as a reminder to ask a question, you will need to press star 11 on your telephone. Our next question comes from the line of Myles Minter of William Blair. Your line is now open.

Hey, everyone. Thanks for taking the questions. First one on Zolaciran, just in your regulatory discussions, did you actually propose a dose to take forward into that phase three? I know you said 300 milligrams previously, but you have not associated a frequency with that. That's the first one. Second is, I take a lot of questions about how a 5 to 10 sort of nanomole per liter increase in hepcidin that you get with Divisoran actually confers the efficacy you're seeing when Rusfetide theoretically gets much higher than that. So maybe you can talk about the difference between the endogenous trigger that you're getting with TMPRF6 inhibition and maybe the safety ramifications between that and giving a hepcidin memetic in PV. That would be helpful. Thanks very much.

Steve, both of those for you. Yeah, well, yeah. So, yeah, the question is with regards to the differences in a way of intervening on the pathway, the upside and pathway. So, yes, obviously, rust for tide is an exogenously administered hormone. So, naturally, it's not a surprise that you typically get larger exposures based on that. Ours is manipulating the pathophysiology, the underlying of physiology, and increasing the internal production of hepcidin. It's less important, the level, as we've already learned in phase one, than the correlation with that increase on clinical benefit. And what we see very clearly, as we've shown you, is with that increase in hepcidin within the physiological range, which, by the way, is 20 to 40-fold higher than the baseline of these patients who come in in our phase one study with very low levels of hepcidin, is corresponding, it appears, or correlating with robust outcome, which is a reduction in the need for phlebotomy and a maintenance of hematocrit. So that is very, very clear that we're getting the intended effect clinically, which is, in fact, the registrable endpoints for this program and other programs. And we're doing that by increasing hepcidin within levels of the physiological range, but much above the baselines. So I think that's very important.

In terms of the dose frequency and the agency deliberation.

Yeah, but I should also add that the safety, because you asked about safety, and you cannot really comment comparatively on safety until you actually conduct your program. And even then, it's going to be cross-program comparisons. We want to be very careful about that. But clearly, our compound is very safe. What we're seeing in phase one and what we're beginning to see in phase two is a very safe profile. Okay, and with regards to the interactions with the agency around, I think the question was around Zerlacerin, and that we have talked to the agency naturally about what we believe is a the reasonable dose, or I should say the optimal dose and frequency. This is a very competitive space, so we're not sharing that information at this point, but obviously when you talk to regulators about a Phase 3 program, you need to be pretty confident about the decisions you're making. I'll leave it at that.

And it's also further advised, obviously, our Phase 3 planning and design.

Thank you. Makes sense. Thanks for the questions.

Thank you. Thank you. Thank you. I'm showing no further questions at this time. I would now like to turn it back to Greg Tooman for closing remarks.

Just want to thank you all for joining us on today's call. We really look forward to keeping you updated on our progress, very excited about the opportunities in front of us, and have a great day.