Hello, once again, I'd like to welcome you to the 19th Annual Morgan Stanley Global Healthcare Conference. My name is David Lebowitz. I'm one of the biotechnology analysts here. Before we get going, I'm going to read the requisite disclosures. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, I'll begin. I'm happy to have in the next session with us, an RNAi company named Silence Therapeutics. From the company, we have President and CEO, Mark Rothera, CFO, Craig Tooman, and Executive Vice President, Head of R&D, and Chief Medical Officer, Dr. Giles Campion. With that, I guess if you could start off by running us through what Silence Therapeutics is, what the company's mission is, and what your long-term objectives are. David, thank you very much for the invitation to the conference. As you said, we're an RNAi company, which surprisingly, actually has been in existence now for 20 years. We're a very well-established company that has a deep-seated understanding of this RNAi field, and in fact, had some of the first patents in this field going back to the early 2000s. Our mission is to design and develop molecules of short interfering RNAi molecules that will precisely address specific diseases associated with the liver, that are genes expressed in the liver. Our goal is to bring these medicines to the world that are going to transform the lives of patients with significant unmet need. We're a long way down that track. We can talk about it later, this year, we had our first clinical data from our GOLD platform that we've developed. It exceeded our expectations, and I think really demonstrated that we can design a study pre-clinically and then demonstrate in man that they do what we're expecting them to do. From a strategy point of view, our goal is to really maximize the GOLD platform that we've developed, and we're doing that through a hybrid model, through a combination of building our own internal pipeline, sort of 50% effort around that, and sort of 50% meeting the needs of our partners. I think that's really how we're going to maximize and make the most of the platform, the GOLD platform that we've delivered. You mentioned your RNAi GOLD platform, and RNAi clearly has been hitting stride the last couple of years with commercial products entering the markets. How is your approach to RNAi different from that of Alnylam, Dicerna, Arrowhead, other publicly traded RNAi companies that people in the U.S. certainly are probably more acquainted with? Yeah. Well, we very much see ourselves in that peer group. We've spent 20 years now developing our platform. There are distinguishing features of our platform. We use 19-mer siRNA molecules. Other companies use larger siRNA molecules. We use 19-mers. We have developed our own approach to chemical modification patents for these siRNAs that we're looking to sort of use to optimize the efficacy of these molecules for a particular target. Also minimize off-target effects, as well as confer stability so that you can get long duration of action from a single injection of siRNA. I think we've developed a lot of capability around that sort of three-dimensional design as we think about how to link to GalNAc. GalNAc is a ligand, as you know, that will bring these siRNA molecules to liver cells and then knock down or silence the expression of disease-causing proteins. How we configure the whole arrangement is also very important. Over the years, as I mentioned, we had some early patents back in 2002, 2003, and since then, we've been developing that knowhow, and we've developed patents both at a sort of a platform level, but also at a target-specific level. What advantages could 19-mer have versus the longer siRNAs? How would it vary in its ability to find the target, as far as efficacy and tolerability? What we've been able to see, and I can invite Giles to say a few words about this, is that we've been able to deliver some really encouraging pre-clinical data that demonstrates very competitive profiles. For example, our Lp(a) program, if you look at our non-human primate data coming out of that program and say compare it against the Amgen program, we've seen a very nice profile of knockdown and speed of knockdown, as well as durability coming from our particular approach. Giles, I'd be happy if you wanted to add anything to that. And you're on mute, just so you know. I think you're still on mute. That little unmute button gets a bit tucked away sometimes. I know. It's a tricky little button, that one. I apologize. Yeah, I think the other element of it, of course, with 19-mers, is that it does give us freedom to operate, and of course, IP is critical in this area. I think that's another element of the design. Got it. Let's move on to your clinical programs. You have two that people are focusing on right now, SLN360 and SLN124. Let's start with 360. Where is this particular asset being studied? This is a single ascending dose, a multiple dose study, so it's in a relatively small number of sites, but it's global in terms of we are using trial sites in the U.S., Europe, and in Australia. I guess, which indications are you going after with this therapy? Well, elevated Lp has recently been recognized as a new factor in determining risk for cardiovascular disease. That's what we're looking at as a means to secondary and primary prevention of cardiovascular risk. Maybe I should add, David, that this is a genetically caused condition, so there aren't treatments out there today for Lp(a), and therefore, I think there is this sort of new effort, this new wave of potential medicines being developed for the first time to really address this risk factor. Let's take a quick step back. Lp(a), when most people think in terms of cardiovascular risk, certainly cholesterol comes to mind, and obviously with a lot of therapies in that area, people always certainly place a lot of emphasis. Lp(a) is kind of new to the scene. What exactly is Lp(a)? What out there tells us that this is a cardiovascular risk, and why hasn't it been targeted up to this point? Well, I think Lp is hugely attractive as a target. Serum levels considered elevated affect up to 20% of the global population. There's no effective treatment. The first thing an individual may know about it is a catastrophic cardiovascular event that comes out of the blue. There's huge medical need. You're right, though, it's relatively recent that people become aware. Lp itself was described first in 1963. It is an LDL-like molecule comprising ApoB linked by a single disulfide bond to Apo(a). It wasn't discriminated by standard testing. It always got hidden away in people looking for cholesterol. What has happened over the past 10 years, there's been a huge amount of observational data in the first instance, and complemented by genetic analysis such as Mendelian randomization, that have shown that the association between elevations in this protein and cardiovascular risk are causal. I think that's what has generated the huge interest in this. Why this RNA approaches, there's antisense approach already in phase III trials, and you're targeting with siRNA. Why do they lend themselves to going after this target? Well, I think it's absolutely ideal for antisense technology. The gene that controls Lp levels is located in the liver, so it really lends itself to the GalNAc type targeting that we use to deliver siRNA, and it's not produced anywhere else, so you're not worried about off-target effects. The other aspect about it is that although, as I said, 20% of the population have elevated levels, there are individuals with very low levels, so you're not worried about super pharmacology with this product. In terms of the approach, when you're dealing with primary and secondary prevention, there are a number of things that are important. One is the intensity of treatment and what we've seen by antisense, and particularly siRNA, is you get really strong knockdown of the target. It's estimated you probably need about between a 70% and 90% knockdown to be clinically effective. The only pharmacotherapy that comes anywhere close are the PCSK9 inhibitors, but they're only 35%, so they're not thought that are really going to play a role in controlling this particular risk factor. The other aspect of it is safety, obviously, and I think that the emerging molecules that are being commercialized, particularly inclisiran, are showing a really excellent safety profile. Then finally, it's durability of action. For example, with inclisiran, that's associated with six-monthly dosing. If you're dealing with people that otherwise have a very active lifestyle, what they want is the intensity and predictability of treatment and long duration of action, so infrequent dosing. I think that's what siRNA promises to deliver. Excellent. Let's move on to the data. Could you talk about what data you have presented to this point with 360 and what we should look forward to in the future? We've already presented preclinical data both in terms of efficacy in the non-human primate model. Non-human primate is relevant because, unlike the rodent, it expresses the target. What we've shown within a dose range is very strong knockdown of the target of the LPA gene, and then long duration of action, and again, associated with good tolerability. We presented that at the American Heart in 2019. Last year, what we showed was the safety data, which is obviously critical for this type of indication. Because of the precision targeting with siRNA, because the fact that the gene is only located in the liver, you get very good safety margins in terms of no effect level. 60-fold safety margin with our initial toxicology studies. The other aspect of this is that you get little distribution outside the liver. There's less than 1% of the molecule in other tissues outside the liver and kidney of peak liver levels. That's what gives you confidence about this technology. Very limited distribution, strong effect, good safety profile. Could you tell us about the phase I APOLLO trial and what we can expect with the data coming up next year? Yes. That's ongoing, and in fact, we just announced that we'd fully enrolled that study, and all subjects have been dosed. We're expecting a data readout first quarter of next year. This is a single ascending dose. We are following subjects up to 150 days so that we can determine what the duration of action is likely to be. There are other therapies out there. Furthest along is Ionis' antisense therapy targeting Lp(a). How would you expect that on efficacy from an efficacy standpoint, these therapies could differ? For these therapies, would you say safety is a more likely area where they could differ? Well, I think people are recognizing that siRNA does offer advantages in terms of safety. That will obviously have to play out. Generally, because of the number of features of the structure of the molecule, one, it's double-stranded, two, it doesn't really get into other tissues because of that double-stranded nature. It's relying on the GalNAc targeting to get it into the hepatocyte. The risk of off-target toxicity is less. Because of the stability, the number of chemical modifications you need to confer stability are less than you need in the straightforward single-stranded antisense. The other aspect of this is because of the prolonged effect, dosing frequency is less. You can see in the current Novartis study, they're doing a cardiovascular outcome study, there's monthly dosing. As we discussed earlier, siRNA has the promise to be dosed much less frequently than that. I think in this sort of indication, it does offer advantages. Ultimately, how large an opportunity do you think Lp(a) offers? Well, I'll get Mark to answer that one. Look, it's a very major market, a bit like the statin market. We're looking at 20% of the world's population with elevated Lp(a) of 50 mg per deciliter or above. That 50 mg per deciliter cutoff is what cardiologists say is the sort of a point above which you'd be looking to treat. If you think about statin market, I think there were something like 12 statins launched into the statin market. As you know, a large number of them with very large peak sales numbers. I think if you're looking at a similar-sized market, here we are in third place. We're also the only unencumbered program. It's a wholly owned program. It's not partnered out. I think it's a program with enormous potential. Excellent. Let's move on to your next asset, SLN124. Could you tell us about the target TMPRSS6, why it's a good target for thalassemia and for MDS? Yes. Happy to do so. TMPRSS6 represents a braking mechanism to control the level of hepcidin production in the body. Hepcidin is the key regulator in terms of controlling iron distribution in the body. This is important when you come to these two conditions, which are essentially iron-loading anemia. You get an excess of iron in the body, causing both impacts on the red cell production, so anemia, and also tissue distribution with tissue damage. Controlling iron is pivotal. The actual target is a bit like the LPA target. It's got a human genetic validation behind it. There are individuals who have a non-functioning mutation of this target, and they replicate what we're trying to do in a therapeutic fashion, and they don't have any features outside the hematopoietic system. Even in the preclinical stage, you can start to be confident that you're going to have an attractive target. What we anticipate is by administering SLN124, we knock down TMPRSS6, we increase hepcidin, we reduce iron levels in the body, and we improve anemia. That sequence of events we've seen pre-clinically, just recently, we were able to show the data from our healthy volunteer study, which showed that we could replicate that in humans too. Could you run us through that data? Yes. We were enormously enthused by it. One, because it was the first clinical data for our platform, and essentially showed we could reproduce in humans what we'd done pre-clinically, but also was validation of the target and proof of principle for the drug. What we were able to show was increase in hepcidin, which is the pharmacodynamic marker, up to four-fold, at peak, and then lasting up to 59 days. Strong action, long duration of action, and good safety profile. Concomitant with hepcidin, what we'd expect is a reduction of ferroportin, and that's what we showed up to 50% at 4.5 mg per kilogram, again, with the same sort of profile. It makes us very comfortable that we will be able to show similar, if not better effects, in the ongoing patient study we're doing. Ultimately, how do you see this therapy fitting into the treatment paradigm for both beta thalassemia and for MDS? Well, as I say, I think two parts to that answer. One is, I think the profile of siRNA, good safety, long duration of action, and potent effect, helps differentiate from other modalities that are working in this field. In low risk myelodysplastic syndrome, which is one of the areas we're focusing on, we would initially use it to treat patients who fail to respond to or are intolerant of ESAs, where the response rate is about 40%-50%, with a median response of 18-24 months. In transfusion dependent thalassemia, it will be used to reduce the number of transfusions and the burden of chelation therapy. By simultaneously ameliorating anemia and iron overload, we expect to demonstrate better and more durable response rates than drugs like luspatercept, which also require more frequent dosing and carry labeled safety warnings. Got it. Could you tell us about the GEMINI II study? Yes. This is a single ascending dose study followed by a multiple dose component enrolling subjects both with non-transfusion dependent thalassemia and very low or low risk MDS in separate cohorts. Importantly, we have a long follow-up period of 150 days in the single dose phase and 201 days in the multiple dose to fully characterize the duration of action. End points, a bit like the healthy volunteer study, include hepcidin iron parameters, and then with multiple dosing then that's when we would expect to see effects on hematinics, particularly on hemoglobin, of course, to be able to show an improvement in the anemia. These are individuals with mild disease but with evidence of iron overload. We announced commencement of enrollment earlier this year and anticipate results being available third quarter next year. What's the primary endpoint of the study? As I say, we're looking at some serum iron parameters, so we'll be looking at serum iron, TSAT, as well as reticulocytes and hemoglobin. Excellent. Let's move on here. The company has a couple partnerships, one with Mallinckrodt, the other with AstraZeneca. Could you tell us about each of these partnerships and what they cover and what you see as the long-term objective of the partnership? This is very much central to our strategy as a company. I mentioned the hybrid model, sort of 50% partnership, 50% go it alone. What's great about this is that through the partnership side, we can make the most of the GOLD platform. We obviously are able to generate non-dilutive funding and progress a number of programs that are essentially funded through our partnerships. If you take AstraZeneca, we signed a 10-program deal in March of last year. We've initiated two programs since we started that collaboration. We're on track for five programs to be initiated within the first three years. We also have generated, as I mentioned, substantial non-dilutive funding in that partnership. For example, we received a $40 million payment in Q2 this year as part of our sort of two-part upfront deal with the timing of the deal. Just to give you the sort of whole picture, if you think about that partnership where we're looking at respiratory, for example, cardiology, metabolic diseases. The total represents up to about GBP 4 billion in milestones plus royalties, if you think about the whole package. With Mallinckrodt, we signed that deal actually the year before in 2019, for up to three targets in the complement-mediated space. Mallinckrodt have taken up all three options, and we've received payments accordingly. The most advanced of that, we've just initiated IND-enabling studies. As I said, the third of those three we announced starting earlier this year as well. I think both are tracking well. I would say that since the healthy volunteer data came out, as Giles was describing, we've had a lot of inbound interest in further partnering opportunities. You can imagine we've now demonstrated that we can design molecules using the Gold platform, we can do the animal experiments, and that now we can also show the mechanism working in man. I think that's given people a lot of confidence as to what we can do. Should we expect in the next year, the company will be entering additional partnerships? In regards to that, what areas would you be looking at? Well, we're always open to those discussions. I think what the benefit we have in a way is we can be quite strategic about the thinking about which kinds of partnerships would make most sense for where we're at, both in terms of the kinds of targets, and as I said, helping balance out sort of the go-it-alone proprietary work that we want to do with the partnership work, but also incremental know-how and capabilities that it can help us deliver. Certainly something we're actively involved in, and we will keep people posted at such time where that makes sense. Understanding that there are lots of available targets in the liver, there's certainly been an effort by a lot of RNA players to try to look for things outside of the liver. How is Silence thinking about that? Just to underline your first point, there are 14,000 genes expressed in the liver, and so far, if you add up Alnylam, Arrowhead, Dicerna, ourselves, we're talking about less than 1% currently all plan to be the subject of a program. I think there is a lot of potential in the GOLD platform and the other platforms that they have. You're right, there's a lot of interest in how do you deliver siRNA molecules to other organ systems and knock down expression of disease-causing proteins in these other organ systems. Our strategy here is to partner with companies that have delivery technology. The tricky part of this is determining which one's going to win. What technology is going to prove itself to be as good as a GalNAc for other organ systems? Really, we're placing a number of bets with a number of partners that have that delivery capability, and our goal is in time to develop a second platform that will allow us to deliver siRNA to other organs. As far as beyond your initial two assets, which of your earlier stage pipeline assets are you most excited about right now? Well, I would perhaps frame that in our goal of having two to three INDs per year by 2023. By that, I mean, both combining partnership work and our own internal work. We have some interesting pipeline assets that we have not yet revealed, that we're working on in the background. We're looking forward to the day we can reveal our next asset in our wholly-owned pipeline. Again, I think this all speaks to the fact that the probability of success leveraging GalNAc siRNA has proven to be very attractive. That when you have a validated target, when you go into phase I in the clinic, it's very likely that you're going to come out with a successful phase III outcome. That is unusual in our industry. I think that's why it's worthwhile us really cranking the engine on discovery and really looking for those targets that are meaningful as part of our sort of making the most of the platform. I'm getting towards my last question here as we're getting to the end. Could you just tell us what your cash position is right now and what the runway is going forward? Thanks, David. We are in a strong cash position, ended June 30th at GBP 81.2 million. We believe that actually gets us at least till the end of 2022 and into 2023. Interestingly, that included that cash balance, both the non-dilutive portions and a PIPE of equal magnitude of about GBP 31 million. Back to that hybrid approach that Mark talked about earlier. Good position today. Excellent. With that, we've reached the end. Thank you so much for your time and attending the conference, and look forward to chatting again soon. Thank you for the invitation, David. Cheers.