Good day and thank you for standing by. Welcome to the Silence Therapeutics 2022 Annual Results Conference Call and Webcast. [Operator Instructions] Please be advised that today's conference is being recorded. I will hand over to Gem Hopkins, Head of IR and Corporate Communications, to open the webcast. Please go ahead.

Good morning and good afternoon, everyone. Thank you for joining us today. My name is Gem 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 Hellums, our CFO, who will review our financial performance; and Giles Campion, our Head of R&D, who will provide an update on our clinical program. 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.silence-therapeutics.com. Turning to Slide 2, 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?

Thank you, Gem, and welcome, everyone. Thank you for joining us today. 2022 was an exceptional year at Silence, where we delivered impressive clinical data with SLN360, now known as Zerlasiran for high Lp(a) and made important advancements across our broader pipeline of siRNA therapeutics. With Zerlasiran, 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(a) 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 II Phase I thalassemia study. The SLN360, Zerlasiran 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 partnered programs, we started working on the second target under our Hansoh Pharma collaboration in December, moved SLN501 into the clinic with Mallinckrodt and advanced work with AstraZeneca on multiple targets. While we are limited in what we can disclose with our partnered 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 Zerlasiran Phase II ASCVD study and the SLN124 PV 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 in high Lp(a) and top line data from the multiple dose portion of the GEMINI II study in thalassemia. We also expect to complete enrollment in the Zerlasiran Phase II 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?

Thank you, Craig. For the year ended December 31, 2022, the company recorded £17.5 million in revenues versus £12.4 million in 2021. The increase of £5.1 million was primarily driven by the advancement of targets in our partnered programs, Mallinckrodt, AstraZeneca and Hansoh. We also recorded approximately £578,000 in royalty revenue from Alnylam 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 in 2022. As expected, R&D costs rose in 2022 to £35.6 million versus £30.8 million in 2021. This increase was primarily due to advancing our proprietary SLN360 and SLN124 program which Craig has previously mentioned. We also continue to develop our platform and identify new targets for both internal programs as well as partnered programs. General and administrative expenses were £19.6 million in 2022 versus £20 million 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 2022 was £40.5 million versus a net loss of £39.4 million 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 or approximately US$86 million at the end of December 2022. As a reminder, we received proceeds of US$56.5 million from our registered direct offering of our ADSs in August 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 cooperations 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-dilutive funding opportunities. With that, I'll turn the call over to Giles for a clinical update. Giles?

Thanks, Rhonda. I want to start off by saying how pleased we are at the growing recognition of Lp(a) 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(a) testing as a component of assessment of total cardiovascular risk was just starting to be discussed. At the ADC meeting earlier this month, people were queuing up to get their Lp(a) tested. Major societies are now including Lp(a) 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(a) 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(a). This chart is showing you a median reduction in Lp(a) levels after a single dose of SLN360 or Zerlasiran, 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 Zerlasiran maintained median reductions over 80% over a 5-month period. That is what is so attractive about the siRNA 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…

Thanks, Giles. We continue to make excellent headway across both our wholly-owned and partnered pipelines. With 3 programs now advancing in the clinic SLN360, now Zerlasiran and SLN124 and SLN501 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.

[Operator Instructions] And your first question comes from the line of Tom Shrader from BTIG Research.

Congratulations on all of the progress. I've kind of a global Lp(a) question. I think we're all digesting the incredible negative response to the Esperion Result. And 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(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?

Giles?

Yes. I mean there are a number of elements to your question. I think the guidance is that generally, we'll need to see about a 70% reduction in Lp(a) to have a therapeutic benefit. And as we saw in the Phase I study, we're getting substantially higher than that. I think the other aspect regarding Lp(a) because I think people tend to compare it with -- you talked about Esperion talking about cholesterol and other lipids. Just to bear in mind that there is no pharmacotherapy at the moment that can reduce Lp(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. I mean standard risk reduction looks to at affect rate, well -- affect 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 Lp(a), again, compared with LDL's 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.

I guess just to be more specific, where do you need to start such that your current belief about lowering Lp(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?

Well, I think people are looking at different levels in terms of inclusion criteria. So we've seen with Novartis study in terms of their Phase II study, they're looking at 60 milligrams per deciliter. We know that Amgen CVOT has gone for expressing in the nmol per liter, 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 more recent data is that there is 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 if there is a threshold, it's less than that. So that's why in our Phase II, we're actually having a threshold in enrollment there of 125 nmol per liter.

And your next question comes from the line of Patrick Trucchio from H.C. Wainwright and Co. Research.

Just a few follow-ups on Zerlasiran. 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 I trial and how, if at all, new learnings could impact the Phase II program and would it impact more so beyond the future potential outcomes trial? And then how -- can you discuss kind of the level of enthusiasm among investigators and patients regarding enrollment in the Phase II trial and just the level of confidence you have in that 4Q '23 timing for enrollment completion?

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.

Yes. I think it relates also to our introductory remarks. I mean the visibility of Lp(a) as an untreated risk factor has increased exponentially. And I think it reflects -- is 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?

And just surround the MAD portion of the Phase I trial, what learnings are you looking for there? And how could it impact the Phase II trial, if at all? Or would that impact more so on maybe a future outcomes trial?

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 II data. The Phase II is running in parallel. So it won't impact the Phase II study, but it will provide further information to optimize dose and dose frequency for the Phase III.

Yes. 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?

Well, although we're working through hepcidin for both indications, it's -- 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 cells mass. So I think 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 a different situation.

Right. And then just kind of your current thinking in terms of potential additional indications for SLN124.

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.

Your next question comes from the line of Keay Nakae from Chardan Research.

You mentioned potential milestones coming in from partnered programs? And can you provide any other additional color about what might enter the clinic this year?

Rhonda, on milestones?

Sure. Yes, we have -- from the existing partnerships, we have the potential to receive up to $14 million within the next 12 months. Again, that is if we do achieve certain clinical milestones associated with those. And of course, that does extend our current cash runway.

Giles, is there anything additionally entering the clinic, nothing else that we've described today.

No, we haven't announced any further additions to the clinic.

Okay. And Rhonda, with respect to the cash runway, do you foresee the need at this point to do any further belt tightening?

What we've announced is our current cash gets us with our current plans through Q1 of 2024. And again, if we do achieve those milestones, we can definitely get into Q2 of 2024. When we did raise in August, that amount will get us largely through at least the enrollment part of the Phase II as well as getting us into the Phase I/II in PV. So we continue to operate with that in mind.

We will now take our last question for today. And the question comes from the line of Myles Minter from William Blair Research.

First on Zerlasiran, I'm just wondering whether that population of greater than 125 nmol per liter Lp(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, would it have you running a study for 6 to 8 years.

Thanks for the question, Myles. Giles?

Yes, I wouldn't take the population that we're studying for the Phase II 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 through a high-risk population, even though the slightly lower Lp(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 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 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(a) baseline level. It's just very cognizant that you're probably the third or maybe even the fourth product in line here.

Yes. 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.

Okay. And the final one for me is just data that we've been picking up over the years and particularly at ACC recently in March, it does suggest that there might be elevated Lp(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.

Yes, 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 II 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.

I will now hand the call back to Craig Tooman for closing remarks.

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 in thalassemia and the complete enrollment of Phase II 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.

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.