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spk04: good day and thank you for standing by welcome to the silence therapeutics 2022 annual results conference call and webcast at this time all participants are in a listen only mode after the speaker's presentation there'll be a question and answer session to ask a question during the session you will need to press star one and one on your telephone you will then hear an automated message advising your hand is raised to withdraw your question please press star one and one again Participants can also submit questions through the webcast platform, which will be answered by the company at a later date. As a reminder, listeners should join the call through either the webcast or the phone lines for the best viewing experience. Please be advised that today's conference is being recorded. I will hand over to Dem Hopkins, Head of IR and Corporate Communications to open the webcast. Please go ahead.
spk00: Good morning and good afternoon, everyone. Thank you for joining us today. My name is Jen Hopkins, Head of Investor Relations and Corporate Communications at Silence. Joining me today on the call are Craig Tooman, our President and CEO, who will provide an update on the business, Rhonda Helms, our CFO, who will review our financial performance, and Giles Campion, our Head of R&D, who will provide an update on our clinical programs. 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. Turning to slide two, 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. 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 of 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?
spk06: Thank you, Jim, and welcome, everyone. Thank you for joining us today. 2022 was an exceptional year at Silence, where we delivered impressive clinical data with SOM360, now known as or LASRAN, for high LP little a and made important advancements across our broader pipeline of SIRNA therapeutics. With Zolaciran, which is a wholly-owned program, we reported up to 98% efficacy in the Apollo study with strong durability after a single dose. These results were simultaneously presented at the ACC 2022 Annual Meeting and published in JAMA, a rare achievement, particularly for a Phase I study. This speaks to how impressive these data were and the growing recognition that Lp is a major cardiovascular risk factor that needs to be addressed. We are very pleased with the overall enthusiasm for this program and believe we have opportunities to differentiate in the category. We also continue to progress our second wholly-owned program, SLN124, in the clinic and reported encouraging preliminary safety results in the Gemini 2 Phase 1 Thalassemia Study. The SLN360, Zerlaciran, and SLN124 programs are great examples of how we can use our proprietary mRNAi gold platform to address a broad range of genetic diseases. We made tremendous progress advancing our platform in the clinic in 2022, and expect to build on that positive momentum in 2023 and beyond. With our partner programs, we started working on the second target under our HANSO Pharma collaboration in December, moved SLN501 into the clinic with MelanCross, and advanced work with AstraZeneca on multiple targets. While we are limited in what we can disclose with our partner programs, I can tell you I'm very encouraged by the continued progress across our collaborations, and we expect to communicate more updates this year. In January, we announced that we initiated both the SLN360 Zolaceram Phase II ASCVD study and the SLN124PV study. Looking forward to the rest of 2023, We have several important milestones, including top-line data from the multiple-dose portion of the Apollo study and high Lp and top-line data from the multiple-dose portion of the Gemini 2 study and thalassemia. We also expect to complete enrollment in the Xerlazeron Phase 2 ASCVD study by the end of the year. We look forward to another year of strong execution in 2023. As we continue to advance our clinical programs across both our proprietary and partner programs, our technology is increasingly being acknowledged as a platform. We look forward to fully harnessing this technology. With that, I'll now turn the call over to Rhonda. Rhonda?
spk01: Thank you, Craig. For the year ended December 31st, 2022, the company recorded 17.5 million pounds in revenues, versus 12.4 million pounds in 2021. The increase of 5.1 million pounds was primarily driven by the advancement of targets in our partner programs, Mellon Crots, AstraZeneca, and HONSO. We also recorded approximately 578,000 pounds in royalty revenue from Manilam during 2022. As a reminder, we record revenue from our collaborations based on percentage of contract completion. Therefore, as our current collaboration programs progress and additional programs are initiated, our revenue is estimated to increase. The expenses related to our partnered 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 10.9 million pounds in 2022. As expected, R&D cost rose in 2022 to 35.6 million pounds versus 30.8 million pounds in 2021. This increase was primarily due to advancing our proprietary SLN 360 and SLN 124 program, which Craig has previously mentioned. We also continue to develop our platform and identify new targets for both internal programs as well as partner programs. General and administrative expenses were 19.6 million pounds in 2022 versus 20 million pounds in 2021. These costs include non-cash share-based expenses related to granting of employee share options and requirements of being a public company. We continue to be prudent in our spending. The company's net loss for the full year of 2022 was 40.5 million pounds versus a net loss of 39.4 million pounds in 2021. The small increase in our net loss is due to the increase in R&D as a result of advancing our programs in clinical development. The company's cash and cash equivalents were 71.1 million pounds or approximately 86 million U.S. dollars at the end of December 2022. As a reminder, we received proceeds of $56.5 million from our registered direct offering of our ADSs in August of 2022. We estimate that our current cash balance will last through the first quarter of 2024. We are committed to responsibly investing in initiatives that will advance our pipeline and expanding our platform into new targets. Our collaborations continue to advance, And we anticipate that we will achieve additional milestones in 2023, which can further extend our cash runway. We also continue to evaluate collaborations that could provide additional non-diluted funding opportunities. With that, I'll turn the call over to Giles for a clinical update. Giles?
spk09: Thanks, Rhonda. I want to start off by saying how pleased we are at the growing recognition of LPA as a key cardiovascular risk factor. Awareness grew substantially in 2022, and we've seen that trend continue into 2023. At the American College of Cardiology meeting last April, the idea of Lp testing as a component of assessment of total cardiovascular risk was just starting to be discussed. At the ACC meeting earlier this month, people were queuing up to get their Lp tested. Major societies are now including Lp in their testing guidelines. A lot of progress in 12 months, and we expect that to continue. It is important to remember that elevated risk to Lp is considered to affect up to 1.4 billion people worldwide, or around 20% of the world's population. And due to its genetic cause, it is not amenable to lifestyle changes such as diet and exercise. As such, this risk factor represents a significant unaddressed health policy issue. As Craig mentioned last year, we reported incredible results from the Apollo single-dose study in healthy volunteers with high LP little a. This chart is showing you a median reduction in LP little a levels after a single dose of SLN360 . We saw up to 98% of the 600 milligrams dose and 96% at 300 milligrams or half that dose. You can also see that we still saw meaningful effects lasting 150 days later. We presented an analysis at the American Heart Association meeting last November that showed participants who received a single dose of Zolaciran maintained median reductions over 80% over a five-month period. That is what is so attractive about the SRNA platform. It's a combination of a well-tolerated safety profile with great efficacy that is long-lasting, facilitating infrequent dosing. We have the multiple dose portion of the Apollo study ongoing. In this study, we're looking at individuals with high Lp and stable ASCVD. We started dosing the last subject and remain on track to report top-line data in Q4 this year. What we're looking for in the multiple dose data is to add to our understanding of drug safety and gain further insight into dose level and dosing frequency. The LACERAN phase two study in patients with high LpA is at high risk of ASCVD events is also underway. In this study, we are evaluating two different dose levels and dosing frequencies. We're also looking at patients with LpA levels greater or equal to 125 nanomoles per liter, a slightly lower threshold than in the phase one study. It's now well recognized that the risk of CV events increases at these levels. We expect to complete enrollment by the end of the year. Turning now to our SLN124 program for rare hemological conditions. What we really like about this program is that we're working with a central mechanism, hepcidin, which is the body's master iron regulator. SLN124 works by silencing tempressor 6 to modulate endogenous hepcidin. This has a range of potential therapeutic benefits. We've demonstrated proof of mechanism in a healthy volunteer study and are currently focused on polycythemia and thalassemia. As a reminder, SLN124 has FDA fast track and orphan drug designation for polycythemia, and orphan drug and rare pediatric disease designation for beta thalassemia. EMA has also granted SLN124 orphan disease designation for beta thalassemia. As Craig mentioned, we were pleased to kick off the Phase 1-2 polycythemia VERA study in January. This is a two-part study. The first part is an open label dose finding study. The study has up to three cohorts and will enroll up to eight patients per cohort. If we find our active dose in the first two cohorts, we can then proceed to the phase two portion of the study. Phase two is a randomized double-blind placebo-controlled study. Polycythemia vera is a disease of unregulated production of red blood cells, leading to increased risk for thrombosis, as well as significant quality of life issues. By limiting the availability of iron at the bone marrow, we expect SLM124 will be able to control red cell mass and improve disease outcome. The primary endpoint for phase one is safety and tolerability, but we will also be assessing the number of phlebotomies at different doses. Phase two will evaluate the number of patients who are phlebotomy-free after treatment. While we are very excited about the potential for SLM124 in polycythemia vera, we recognize this is a rare disease population, and the study will take some time to enroll. We will monitor enrollment over the next few months and provide guidance for data at the appropriate time. We also have the multiple-dose portion of the Gemini 2 Phase 1 study in thalassemia patients ongoing. We've now dosed the last subject, are on track for top-line data in Q4 of this year. Last September, we reported encouraging safety and tolerability data from the single-dose portion of the study as a follow-up to positive data from our healthy volunteer study. In the multiple-dose readout, we'll also be assessing changes in hepcidin, iron parameters, and hematinics such as hemoglobin. If we can deliver an increase in hemoglobin levels around one gram per deciliter with three doses, that would be meaningful. Although the length of treatment required for consistent effect will be more a function of the phase two program. With that, I'll turn the call back over to Craig. Craig?
spk06: Thanks, Giles. We continue to make excellent headway across both our wholly owned and partner pipelines. With three programs now advancing in the clinic, SON360, now Zolaceron, and SON124, and SON501 partnered with Mallinckrodt, 2023 is set to be an exciting year for silence. We see substantial potential for our mRNAi gold platform across a range of genetic diseases and look forward to communicating more as we move ahead. I'd like to thank everyone for listening today, and I'll pass back over to the operator for your questions.
spk04: Thank you. To ask a question, you will need to press star 1 and 1 on your telephone and wait for your name to be announced. Participants can also submit questions through the webcast platform, which will be answered by the company at a later date. Once again, please press star 1 and 1 if you would like to ask a question.
spk03: We will now go to your first question. One moment, please. And your first question comes from the line of Tom Schrader from BTIG Research.
spk04: Please go ahead. Your line is open.
spk05: Good morning and congratulations on all the progress. I have kind of a global LP little a question. I think we're all digesting the incredible negative response to the Asperion result. And, you know, 15% MACE doesn't seem to be enough for investors. We don't know if it's enough for physicians. But as you do work in LP little a, what kind of MACE reduction do you think you need? And if we assume it's about 20% for people to get excited, and based on your data so far that you're going to have something like a 95% reduction, where do you have to start in terms of target population? And is that what some of the lower dose stuff is all about to kind of understand what reductions you'll need for a MACE effect that people will be excited about? Thank you. Giles?
spk09: Yeah, I mean, there are a number of elements to your question. I think the guidance is that generally we need to see about a 70% reduction in LP little a to have a therapeutic benefit. And as we saw in the phase one study, we're getting substantially higher than that. I think the other aspect regarding LP little a, because I think people tend to compare it with with, you talked about Aspirion, talking about cholesterol and other lipids. Just to bear in mind that there is no pharmacotherapy at the moment that can reduce LP little a and that it is a genetic risk factor and that other approaches to reducing risk such as diet and exercise won't work. So I think it's important to bear that in mind. risk reduction looks to an effect rate, well, an effect reduction of 20% or so. That's how some of the studies that are ongoing at the moment are designed. And obviously, hitting that is a feature in terms of the population you choose. And I think the interesting thing about some LpA, again, compared with LDL cholesterol, is that there is a different phenotype, not only affecting the cardiovascular system that we're used to in terms of MACE, but also affecting the aortic valve. So I think it is a different biology. And the reason why Craig said that one of the important things in our development is looking for differentiation. And we think there's a real opportunity to differentiate in this area. So I don't know if that helps in terms of your question.
spk05: I guess just to be more specific, where do you need to start such that your current belief about lowering LP little a leads to a 20% MACE number? And I appreciate that there may be other factors that would make that look even better. Is that a fair question?
spk09: Well, I think people are looking at different levels in terms of um inclusion criteria so um we've seen with with novartis study um in in terms of their um phase study there's two studies they're looking at 60 milligrams per deciliter uh we know that amgen co vot has gone for um expressing in the nanomoles per liter at 200 to substantially higher so i think it's a question of what effect size you want to see it's also related to the study how long you want to study for how many subjects so i think it's sort of a complicated question but what we do know from um more recent data is that there is a a linear effect and the threshold seems to that without a definite threshold i mean originally the threshold was around about 50 milligrams per deciliter but that is clearly um If there is a threshold, it's less than that. So that's why in our phase two, we're actually having a threshold of enrollment there of 125 nanomoles per liter.
spk05: Great. Thank you for the detail.
spk04: Thank you. We will now go to our next question. One moment, please. And your next question comes from the line of Patrick Truccio from HACI, Wainwright & Co. Research. Please go ahead. Your line is open.
spk10: Thanks. Good morning. Just a few follow-ups on Zorlasterin. Just the first is I'm wondering if you can tell us what you would hope to learn from the MAD portion of the Phase 1 trial and how, if at all, new learnings could impact the Phase 2 program or would it impact more so beyond the future potential outcomes trial? Can you discuss kind of the level of enthusiasm among investigators and patients regarding enrollment in the Phase 2 trial and just the level of confidence you have in that 4Q23 timing for enrollment completion?
spk06: Let me say the enthusiasm is very strong, and we have a lot of conviction about our year-end goal in terms of enrollment. And, Giles, I'll let you take it from there.
spk09: Yeah, I think it relates also to, you know, our introductory remarks. I mean, the the visibility of Lp as an untreated risk factor has increased exponentially. And I think it's certainly reflected in the enthusiasm in which investigators are participating in the study. So we're very confident of our commitment to report by year end. Sorry, what was the second part?
spk10: And just around the MAD portion of the phase one trial, you know, what learnings are you looking for there, and how could it impact the phase two trial, if at all, or would that impact the more so on maybe a future outcomes trial?
spk09: I think it's helpful in a number of ways. One, it provides interim data before we start an outcome study and before we have the phase two data. The phase two is running in parallel, so it won't impact the phase two study. but it will provide further information to optimize dose and dose frequency for the Phase III.
spk10: Yeah. And then just one, if I may, on SLN124. I'm just wondering, as we get this additional data in thalassemia, I'm wondering what read-through, if any, could that program provide to the PV program or other potential indications? And what other indications do you presently view as being potentially most relevant for SLN124?
spk09: Well, although we're working through hepcidin for both indications, the approach is different. And if anything, the polycythemia vera indication is more analogous to what we've seen in the healthy volunteer study because these individuals have normal iron distribution. So what we're doing in polycythemia is to restrict iron delivery to the bone marrow to reduce red cell mass. So I think that it's more analogous to what we saw in healthy volunteers because the underlying iron metabolism is normal. In beta thalassemia, of course, you have iron overload. So it's a different situation.
spk10: Right. And then just kind of your current thinking in terms of potential additional indications for SLN124?
spk06: We've not announced any additional areas, but as Giles mentioned, given that it's mechanistic in this general area, we have seen some very encouraging data preclinically, and we continue to evaluate those for the future.
spk10: Terrific. Thank you so much.
spk04: Thank you. Thank you. We will now go to the next question. And your next question comes from the line of Kayna Kay from Chardon Research. Please go ahead. Your line is open.
spk02: Yes. Thank you. You mentioned potential milestones coming in from partner programs. And can you provide any other additional color about what might enter the clinic this year?
spk06: Rhonda on milestones.
spk01: Sure. Yeah, we have from the existing partnerships. We have the potential to receive up to fourteen million dollars within the next twelve months. Again, that is, if we do achieve certain clinical milestones associated with those. And, of course, that does extend our current cash runway.
spk06: Okay. And the new thing additionally entering the clinic, nothing else that we've described today. No.
spk08: No, we haven't announced any further additions to the clinic.
spk02: Okay. And Rhonda, with respect to the cash runway, do you foresee the need at this point to do any further bill tightening?
spk01: What we've announced is, you know, our current cash gets us with our current plans, you know, through Q1 of 2024. And again, if we do achieve those milestones, we can definitely get into Q2 of 2024. You know, when we did raise in August, you know, that amount will get us, you know, largely through at least the enrollment part of the phase two, as well as getting us into the phase one, two, and PV. So we continue to operate with that in mind.
spk02: Okay, thank you.
spk04: Thank you. We will now take our last question for today. And the question comes from the line of Miles Minter from William Blair Research. Please go ahead, your line is open.
spk07: Thanks for taking the questions. First on the lesser end, I'm just wondering whether that population of greater than 125 nanomoles per liter, LP little a, would be the baseline population that you'd be thinking about in a potential outcome study, and what gives you the confidence that that event rate associated with that population wouldn't have you running a study for six to eight years?
spk06: Thanks for the question, Myles. Charles?
spk09: Yeah, I wouldn't take the population that we're studying for the phase two as necessarily indicative of what we're thinking about for an outcome study. So I think what it does is it gives us an understanding. We've gone for a high-risk population, even though the slightly lower LP little a, it does differentiate us from Our competitors and potentially would allow us to explore a slightly broader population So this is something that we're considering as we we consider the design for the outcome study Okay, cool, and then I did want to touch on the sources of differentiation here is that from a molecule specific and
spk07: perspective that you're looking at that or is that more chasing potential different indications than what your peers have or obviously what you just mentioned which is a potential different LP little a baseline level just very cognizant that you know you're probably the third or maybe even the fourth product in line here.
spk09: Yeah, I mean, we see this as a statin-sized market, so we don't necessarily think that the first product to market is inevitably going to be the most successful. And as I said, the biology is somewhat broader with valve disease and other components that I think go into our thoughts about the ultimate target population. The advantage of being where we are is that we can see what our competitors are doing and allow us to take a slightly different route, one that we think will be very attractive and watch this space.
spk07: And the final one for me, it's just data that we've been picking up over the years and particularly at ACC, recently in march um you know does suggest that there might be elevated lp little a levels in females but certainly in the black american population as well just given that the fda especially in large indications is very focused on diversity and certainly payers as well how is that diversity represented in your current trials for this drug and your future outcome studies thanks
spk09: Yeah, I think the diversity is primarily something that we have to consider with the total package that we file. So that will definitely be included in our larger studies. Not so much a feature of the phase two, because there we're really just looking at level of knockdown and dose duration. I think when we're dealing with outcomes, that's where the diversity is critical.
spk07: Okay, thanks for the questions. Thanks, Miles.
spk04: Thank you. I will now hand the call back to Craig Tumann for closing remarks.
spk06: Thank you, everybody, for joining us on this call. I'm extremely proud of our 2022 performance and overall results. As I mentioned in the beginning of this call, 2023 is going to be very exciting for us from an execution and growth perspective. And we clearly highlighted some of the milestones, including the top line multiple dose SLN360 data from Apollo by year end, top line multiple dose data from SLN124 and thalassemia, and the complete enrollment of phase two in the SLN360 ASCVD trial. So a lot happening by year end. And we look forward to keeping you updated on our progress. Thank you and have a great day.
spk04: Thank you. This concludes today's conference call.
spk03: Thank you for participating. You may now disconnect.
spk04: The conference will begin shortly. To raise and lower your hand during Q&A, you can dial star 1 1.
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