Silence Therapeutics plc Price & Performance (SLN)

Good morning and good afternoon, everyone. Thank you for joining us today. Name is Jen Hopkins, Vice President of Investor Relations and Corporate Communications at Silence Silence. Joining me on today's call are Craig Toomin, our President and CEO who will provide an update on the business Rhonda Helms, our Chief Financial Officer will review our financial performance Stephen Romano, our Chief R and 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 Investors section of our corporate website at www.SilenceTherapeutics.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 the future financial performance of the company. Including clinical development, timing and objectives, therapeutic potential of our product candidates, our operational plans and strategies, anticipated 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.

Thank you, Jim, and thanks everyone for joining today's webcast. I'm pleased to be with you today to discuss our twenty twenty four 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 ZULACERM, our sRNA for high LP delay, The ALPACR360 Phase two study of dulaciran in ASCVD patients with high LPI delivered positive results that were featured in a late breaker in at and published in JAMA. The study showed LP a reductions exceeded 90% effects were durable and zolazarone was observed to be well tolerated. These data support a competitive profile that we believe can be further defined in Phase three. The science team supported by top cardiologists have done an out outstanding job designing what we are confident is a highly differentiated Phase three program for zolaciran. 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 including manufacturing readiness. Turning to diveseron, our first in class sRNA polycythemia vera. The San Rico Phase one study of devasiron delivered positive results that exceeded our expectations.

Data were highlighted at ASH and showed divestron 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 two study and the European Commission granted divester on orphan drug designation for PV. As a reminder, divesoron 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 goal 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 our [indiscernible] where we believe we can deliver on clear unmet needs with first in class and or best in class sRNAs. Divesiran is a great example of that.

We remain confident in our ZELASERON program for high LP delay 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 ZULACERON. We have listened very carefully to our shareholders and made this decision with our collective feedback in mind. I want to reiterate that we continue to believe strongly in 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 diveserum. We announced this morning that we completed follow-up in the Phase one 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 one 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 two study by the end of this year. While we are currently focused on the PV indication for debesiran, we continue to believe it has broader therapeutic potential. Given the outstanding PV results, we have seen in Phase one, we are planning an investor event later this year and look forward to discussing the program in more detail then. In addition to divestiron, we were pleased to announce today that we plan to start a Phase one study of SLN-five forty eight 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 goal 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 Hanzo Pharma collaboration we announced this morning. We are evaluating these programs as part of our broader portfolio and we'll determine which ones we want to bring forward ourselves or potentially partner. 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 extra hepatic 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 Silence. Rhonda? Thank you, Craig.

First, I would like to point out that effective 01/01/2025, Cylance Silence 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 in U. S. Dollars versus British pounds.

Now let me turn to the financials. For the year ended 12/31/2024, the company recorded $43,300,000 in revenues versus $31,600,000 in 2023.

The increase of $11,700,000 is largely due to the collaboration arrangement 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 allow us to receive additional milestones. Turning to the Hanzo Pharma collaboration, we announced this morning that HONTO opted not to pursue further development under our collaboration. As a reminder, this was a collaboration to develop siRNA's using our GOAL platform for three undisclosed preclinical liver targets. [indiscernible] formerly 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 recognized $24,600,000 resulting from a cumulative catch up following the completion of all required obligations to Hanzo under the collaboration. Finally, during 2024, we recorded the remaining royalty revenue from anilum 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 $11,800,000 in 2024 compared to $12,900,000 in 2023. As expected, R and D costs rose in 2024 to $67,900,000 dollars versus $56,900,000 in 2023.

This increase was primarily due to advancing our which Craig previously mentioned. We also strategically invested in further development of our platform and identifying new targets to further expand our General and administrative costs were $26,900,000 in 2024 versus $26,200,000 in 2023. The increase was primarily as a result of additional legal and accounting expenses required to transition to filing as a U. S. Domestic issuer including our transition to U. S. GAAP.

The company's net operating loss for the full year 2024 was approximately 63,300,000.0 versus $64,400,000 in 2023. The decrease in our net loss is due to the increase in revenue partially offset by the increase in R and D costs as a result of advancing our programs in clinical development.

We reported other income of approximately 4,500,000.0 which largely represents the accretion of our U. S. Treasury bills compared to $1,800,000 in 2023. We also reported approximately $13,700,000 from the benefit of our R and D tax credit in The UK compared to $11,900,000 in 2023. The company's net loss for the full year of 2024 was approximately $45,300,000 versus $54,200,000 in 2023. The company's cash, cash equivalents and short term investments were $147,300,000 dollars at the December. This includes cash and cash equivalents of 121,300,000.0 and short term investments of $26,000,000 Turning to Slide eight, and the 2025 cash guidance. As Craig mentioned, we have made a decision only to initiate the Zillow 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 divisiran for PV, which remains a top priority. In addition, we look forward to advancing additional With that, I'll turn the call over to Steve for a clinical update. Thanks, Rhonda. As Craig mentioned, we made great progress advancing to Viceroyne.

A first in class sRNA for PV, 2024. The San Rico Phase one results were impressive and have garnered enthusiasm from the program.

Phase two study is enrolling very nicely and as Craig mentioned, we anticipate full enrollment 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 somatic rig [indiscernible] 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. Fibrosis and acute myeloid leukemia. PV impacts around one hundred and fifty thousand individuals in The U. S. And three point five million worldwide. The aim of the treatment is to maintain an adequate less than 45% level that is associated with a reduced incidence of thrombosis 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. [indiscernible] Phlebotomy, while helpful, is time consuming, may not maintain patients at safer hematocrit levels and can contribute to iron deficiency and overall symptom burden. At the bottom of this slide, we have a quote from Nona, is living with PV. She says the PV aspect means 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 Rio Phase one data devisiran has the potential to greatly reduce and even eliminate the need for phlebotomy. Turning to Slide 12 and divisiran, a first in class SRNA for PV, I'll quickly review how divisiran works for those less familiar.

TEMPOR6 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 dimasiran in PD patients [indiscernible] By silencing Silence six, hepcidin production and released 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 ENRICO Phase one study, the design was open label with three cohorts and enrolled 21 PV patients. We tested doses of three, six and nine milligrams per kilogram. Consisting of six, eight and seven patients All patients were scheduled to receive four doses at six week intervals and then were followed for sixteen additional weeks for a combined total of thirty four 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 twelve months. Patients on stable doses of cytoreductive agents were allowed and given the exploratory nature of the Phase one study, both well controlled patients that is those with hematocrits forty five percent or less and those less well controlled with hematocrits greater than forty five percent were included.

As Greg 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 PB patients with a combined history of seventy nine phlebotomies 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 somaticate levels required a phlebotomy. In other words, one hundred percent of this group maintained adequate control of omadicrit 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, which over forty five percent.

Two phlebotomies occurred in the sixteen week follow-up period following the last administered dose. In fact, no patient with Ithmatocrit 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 divisiran on both well controlled patients, again, with hematocrit levels less than or equal to 45% as well as those with high baseline thematic levels. You can see here that the vibesiran reduced hematocrit levels in all patients regardless of baseline levels. The vesting also demonstrated robust target engagement You can see here we observed early and sustained hep Silence elevation. Importantly, these elevations are within the physiologic range of hepcidin levels Importantly, divisorin was safe, well tolerated all doses tested. Majority of treatment emergent adverse events were mild. None over Grade two. There were no treatment related serious adverse events or TAEAEs leading to discontinuation. So in summary, our Phase one data showed that Vifiran 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 one data and medical congresses this year. Here's a high level look at the design for the ongoing Phase two portion San Rico.

This is a randomized double blind study evaluating divisiran in up to 40 PB patients. Unlike the Phase one where we allow patients to enter with a range of baseline levels, all patients entering Phase two will have a MATICRID level below 45%. The study is thirty six weeks and we are assessing two different dose levels and regimen. The primary endpoint is the percent of patients with at or below 45% without the need for phlebotomies. Will also be assessing the effect of duvicerin in improving PD related symptoms. As we mentioned, study is enrolling nicely we anticipate full enrollment by the end of this year. Turning now to 48, 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 fagocytic 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, lectin pathways. Importantly, both deficiencies and overactivation of the complement a role in a broad range of conditions within human components.

Given the complexity of the complement system pathways, and large number of proteins involved, there are a plethora of potential targets for therapeutic intervention.

SLN-five 48 is an siRNA targeting complement factor B. And could potentially play a therapeutic role in conditions associated with overactivation of the 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 one study design. It is a randomized double blind placebo controlled single ascending dose study that plans to enroll up to 32 healthy volunteers across four dose cohorts. The primary objective is to evaluate the safety and tolerability of SLN-five forty eight 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.

Summary, our decision to only initiate the Phase three outcome study of ZULED 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 [indiscernible] We remain confident in zurlaciran and we'll provide an update when there is one. On this slide, you can see our anticipated clinical milestones for 20 For divasiran, we completed follow-up in the Phase one 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 PD study by year end, We are also planning to host a divestor on focused event later this year so stay tuned for more information on that. For 48, we are planning to start the one study in healthy volunteers in the second half of this year.

We're also looking forward to progressing our extra hepatic work ensuring 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 a question and answer session.

Our first Good morning and thanks for taking the question.

Maybe just one focused on zirlaseran. 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 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, 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 and the timing of the Horizon readout, companies including Novartis have pledged more funding for LP- LLLA studies [indiscernible] Look, we're not a one product company. We've got a portfolio of assets with great potential. And as you know, divisiran is a great example of that. And it is a fine balance to kind of manage the resources [indiscernible] and we want to make sure we get the best returns. So that's our announcements today. Silence has really done an excellent job of giving us all the team all full credit for getting XerLASTRON 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 talked about in multiple occasions And we are actively engaged. So I will say that we remain actively engaged in partnering to discussions and hopeful we'll be able to secure the right partner to bring this very promising program forward, both in development and commercially, So, won't say more on that, but we will update you if there's something to update you on regarding a partner.

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

Hello, everyone. Good morning. Thanks for taking our questions. Maybe one question on the dalacilab and one on dibetiran.

How ready are you for the Phase III trial and specifically from the time you secure a partner, how fast do you think we can start the Phase [indiscernible] 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 path there needs to kind of agree to that. And the second question on divestiramide, would you consider evaluating divesiranine hereditary hemochromat target there. Thank you.

So we are in a logistical phase. We're wrapping up Phase three readiness [indiscernible] Which are on track to complete by midyear 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 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?

Yes, sure, Kosta. So So yes, we're certainly obviously focused on the PV program and we do know because of our mechanism that it applies actually across a fairly broad range of conditions where hepcidin may may play a role or manipulating that cytin pathway may play a role therapeutic 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 trial work, but we're examining the opportunity to expand our program.

Thanks 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 of questions for me.

What is the goal for divalferin regarding differentiation? Can you differentiate clinically from what muscarotide besides dosing frequency? And also, what are the biggest hurdles that you see for partnering Sureseran?

Steve, do you want to take differentiation? [indiscernible] Yes. So first of all, we want to be in the first sRNA to the market for PV. So we're very excited about that opportunity. And clearly, and I would minimize it, but one of the major differentiations 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 evaluate in Phase one. The other things we look for obviously are some [indiscernible] of important dimensions to measure outcome in this disease. But until those that work is done, it's hard to say point of differentiation or points of differentiation will be available. 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 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. It's different 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're we remain very confident in the programs we've discussed The dialogues continue and we will pursue that. As you know, partnerships often don't really happen on a clock. It involves coincident and needs and timing amongst the parties. But we are 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 Chardan. Your line is now open.

Yes, thanks.

Question about the candidates being developed for Hansel.

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 So it actually gives us the control to determine what we want to do with those. But obviously, in the 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.

Yes, 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 Hanzo. 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.

Thank you. One moment for our next question. Our next question comes from the line of Myles Minter of William Blair. Your line is now open.

Hi, everyone. Thanks for taking the questions. First one on Sildasiran, just in your regulatory discussions, did you actually propose a dose to take forward into that Phase three? I know you said three hundred milligrams previously you have not associated a frequency with that. That's the first one.

Second is, I take a lot of questions about how five to ten nanomole per liter increase in hepcidin that you get with divisiran actually confers the efficacy you're seeing when russetide theoretically gets much higher than that. So you can talk about the difference between the endogenous trigger that you're getting with TYMPROS VI inhibition and maybe the safety ramifications between that and giving a head side of mimetic in PV, that would be helpful.

Steve, both of those for you.

Yes. Well, yes, so the question is with regards to the differences in a way of [indiscernible] of intervening on the pathway, the upside and pathway. So yes, obviously, Russratide 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 path physiology, the underlying physiology and increasing the internal production of hep 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, correlating with robust outcome, which is a reduction in the need for phlebotomy and a maintenance of inadequate. So that is very, very clear that we're getting the intended effect clinically, which is 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 baseline.

So I think that's very important.

In terms of the dose frequency in the agency, deliberations Yes. But I should also add that the safety because you asked about safety and we 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 are beginning to see in Phase two is a very safe profile. Okay. And with regards to the the interactions with the agency around the I think the question was around [indiscernible] we have talked to the agency naturally about what we believe is a the reasonable dose, 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 III program, you need to be pretty confident about the decisions we're making. I'll leave it at that.

And as also further advised, obviously, our Phase three 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 Toumann for closing remarks.

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

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.