Welcome, everyone, to the 43rd JP Morgan Annual Healthcare Conference. Today, we have the pleasure of having with us Denise Scots-Knight, CEO of Mereo BioPharma. For logistic purposes, please hold on to your questions till the end of the presentation. With that, we'll let Denise have the floor. Great, thank you. It's great to be here at the JP Morgan Conference for the first time, presenting the Mereo story. I have with me John Lewicki, who's our Chief Scientific Officer, and John will be helping with the Q&A. Just move quickly through the disclaimer to the interesting stuff. Mereo, when we founded Mereo, the aim was to basically take deprioritized programs sitting in pharmaceutical companies and unlock them as potentially novel treatments for individuals with rare diseases. Here we are. We now have two programs, one of which is in a pivotal study, the second of which is ready for a pivotal study. We have setrusumab for osteogenesis imperfecta, or brittle bone disease, which we acquired from Novartis, which is now in a phase III study with our partner Ultragenyx, and with Mereo retaining European rights. Our second program, alvelestat, which is a neutrophil elastase inhibitor for alpha-1 antitrypsin deficiency, and we're actually focusing on the lung disease. And this one we licensed from AstraZeneca. We've successfully completed phase II, and now the program is essentially phase III ready, and we're in a partnering process. Both of these programs had significant investment when we took them over, with great CMC packages, tox packages, and some clinical data. And that's really translated into relatively rapid development of the programs. We're a lean and mean company. We're still less than 50 employees, and we have a very capital-efficient model. We do a lot of outsourcing with very senior people internally managing that outsourced resource. And we have cash into 2027. So that's going to allow us to go through some really key milestones through 2025. The two rare diseases, osteogenesis imperfecta and alpha-1 antitrypsin deficiency, so these are not ultra-rare diseases. We've targeted quite prevalent rare diseases, as you can see from the patient populations of 60,000 and over 100,000. They're both genetically diagnosed, and they both have high unmet needs. You can see for osteogenesis imperfecta, there are no FDA or EMA-approved therapies. And for alpha-1 antitrypsin deficiency, the standard of care is augmentation, which is weekly IV. And this has not really been shown. It was approved on the basis of biomarkers, AAT levels. And those have not really been shown to translate into clinical outcomes, which is what we're aiming to do. Our approach, setrusumab for osteogenesis imperfecta, it's an anti-sclerostin antibody. It is a bone builder as well as an anti-resorptive. It's a very powerful agent for this particular disease. And then for alpha-1 antitrypsin deficiency, we have alvelestat, our neutrophil elastase inhibitor, which is really targeting the neutrophil elastase, which causes the lung damage. And that's an oral therapy. So here's our pipeline. And I'm going to talk about the milestones later, but we're super excited that this year we will have the phase III data from these two phase III studies, which I'm going to talk about later. And then for alvelestat, we're looking to start the phase III study this year alongside a partner. So one of the key things that we do as we're looking at the development of these rare diseases is really try to maximize all the opportunities we have to help the development, to guide the development. Then also for setrusumab, we've also been a member of the pilot scheme, EUnetHTA pilot scheme, which is aiming to provide equal access for rare disease therapies across Europe. As part of this EUnetHTA scheme, we have HTAs represented in one meeting so we can understand what they're looking for to reimburse therapies in particular diseases. We were one of the first companies to be selected for this pilot scheme. Now, all of these designations except the breakthrough therapy, which our partner Ultragenyx obtained last year. These are all designations that Mereo obtained prior to our partnership. That includes the PRV designation, the orphan designations, and the PRIME. For alvelestat, we're going along a similar process. In fact, we just announced that the program's been recommended for orphan drug designation in Europe. That was a hard, probably not quite apparent from the release, that was a hard-fought approval because in Europe, it's not just enough for the population to be a rare disease population, nor for alvelestat, for example, to be an oral versus an IV therapy. We actually have to demonstrate with data that we could potentially be better than the standard of care. I'm going to walk through a little bit of those data that we use to get that European designation. Moving on to the programs, I'll start with setrusumab. It used to be called BPS-804 when we were running the study. Osteogenesis imperfecta, brittle bone disease, we are looking to treat around 80%-90% of the patient population, so the type 1s, type 3s, and type 4 patients. And these individuals, it's not just about the fractures, is the key thing, but it's not just about the fractures. They have pain, they have respiratory problems, they have skeletal deformities, especially the type 3s and 4s. And they can also lose their hearing by the time they're 18 years old. It's a very well-diagnosed disease. And I've shown a picture of Tinus. So Tinus came to talk to us about his transition from pediatric care to adult care. And Tinus is a type 4 patient, and he'd had 200 fractures by the time he was 16. And you can see that he's in a wheelchair. So Ultragenyx ran a phase II part of a phase II/III study, the ORBIT study. And what you can see here are the BMD changes in these 5-25-year-olds out to 12 months. And it's really impressive changes in BMD, the 22% mean, but if you go down and you see at the bottom, in the 5- to 12-year-olds, it was actually almost 30% change in BMD. It's really striking data. And importantly, the Z-score, which compares your BMD to an age and gender-matched individual, we're starting to normalize the Z-scores in these OI patients. And that was irrespective of whether you're a type 1, type 3, or type 4. And we're often asked, how does BMD translate into fracture reduction? So here we are in this same phase II study. We saw a median 67% reduction in annualized fracture rate in this group of patients post-treatment compared to pre-treatment. But what we're also, and I should mention that's the phase III endpoint for the ORBIT pivotal study. What we're most excited about, apart from the reduction in fractures, is the sort of photograph on the right, where you can see this little boy. He was six years old when he started treatment. He's in a wheelchair. He progressed during treatment from the wheelchair to the walker and then actually scaring the life out of his parents by playing football in the playground unaided. That's why we believe setrusumab has the potential to be a really transformative treatment, especially if we can treat these very, very young children and treat them early. The two phase II studies, they were fully enrolled last year. There are two studies, the ORBIT, which is the five to 25-year-olds, that is comparing setrusumab to placebo, and then COSMIC, which is the two to six-year-olds, which is comparing setrusumab to bisphosphonates. Both have primary endpoints of annualized fracture rate with slightly different fractures included or excluded. So we've been through, there was an interim analysis which used only 2% of the alpha. We've gone through that. We were not informed that we'd hit that, so we haven't hit that. And we're now moving through to the second interim analysis, which is going to be mid this year, just around the corner. And that's using more of the alpha. That's using 20% of the alpha. So we're very hopeful that we may hit that endpoint mid-year. But if not, we've got a final analysis in Q4, which uses the rest of the alpha. So moving on to how are we preparing, how is Mereo preparing for a successful launch in Europe? I hear a lot of feedback that it's very difficult to commercialize products in Europe. And so we believe we know how to do it. And I'm just going to walk you through some examples of that. So first of all, when we started the program and we started in phase II, we really built some long relationships with the patient organizations. And this was deliberate and really in a collaborative fashion. These patient organizations, some of them have been established for 50 years. So they're very well established, and they're very ready now to advocate for new therapies for OI. The physician community is very tight. There are a small number in Europe of specialized treatment centers. They all know each other. And again, they all understand, as we've been talking to them, the limitations of bisphosphonates, which, although not approved, are actually the standard of care. But they have a lot of limitations. And so there's a huge readiness within the physician community for a new therapy in Europe. And then most importantly, perhaps, is capturing and articulating the value of setrusumab to the healthcare systems. And we have a hard endpoint of fracture. So this is not something that we need to demonstrate that a biomarker will lead to a clinical outcome eventually that will be of value. We have fractures. So that gets us on a very good footing from day one for these conversations. And as I mentioned at the beginning, we've had very early engagement with a lot of different countries through this EUnetHTA pilot scheme. And we know what we need to deliver. But it's very clear that setrusumab could have a very high economic value to the healthcare systems. And then finally, how are we resourcing? So I mentioned at the beginning, we do a lot of outsourcing. So we currently have medical access and med affairs individuals who are consultants in each of the key EU5. They've been able to identify an initial patient population of 10,000 patients, both pediatrics and adults in total. And we believe that to hit all these centralized treatment centers throughout Europe, we need an in-field force of 65. And that's at peak. So very, very targeted, focused in-field force. So in terms of articulating the value to the healthcare systems, the other pillars are shown here. So we conducted IMPACT in collaboration with the patient organizations. This is to establish the burden of disease on the patients, on their caregivers. And we had over 2,000 responses to this questionnaire, which is unprecedented in terms of the number. So that's really given us a very rich data set to establish the burden of disease. The second thing is we've sought to have scientific advice from Germany with the G-BA and from NICE, who we say sometimes are not so nice in the U.K. And that really gives us both ends of the spectrum in terms of understanding what is it going to take to get setrusumab reimbursed across Europe because we have both ends of the spectrum. So we know what we need to do. We know what we need to deliver. And part of that delivery is SATURN, which you see on the right-hand side. SATURN is not a registry. Across Europe with these specialized treatment centers, there are centers where they have up to 30 years of longitudinal data about treating OI patients and also treating them with bisphosphonates and how they progress. So we're going to be doing more data mining on existing data sets rather than setting up a registry. And we've had the advice already, and we know this is going to deliver what we need to do. And then finally, I'm quite often asked, well, what could launch look like in Europe? What could the numbers look like? What's the market opportunity? So here we're taking some learnings from the CRYSVITA, which is for XLH in Europe. That was launched in Europe by Kyowa Kirin. And you can see the nice curve here with the revenue growth. A couple of things to point out here. First of all, their initial approval in 2018 was only for pediatrics. And they achieved the approval for adults almost three years later. And then thirdly, they did launch in adults during COVID. So we're looking to launch both pediatrics and adults together. Hopefully, there won't be another pandemic during the launch. But also, OI is a more prevalent disease than XLH. So we believe for a setrusumab launch, there's lots of upside potential in these numbers. But it's great to see another bone product like CRYSVITA set to do last year around $330 million of revenue. And finally, our Ultragenyx partnership. So when you look at the potential revenue from setrusumab in Europe, assuming we have approval, and then you look at the OpEx costs, which I mentioned, the 65 in the field force at peak, and then you combine that with the milestones of up to $245 million from Ultragenyx, the share of the PRV, which we have, and then the tiered double-digit royalties on sales from Ultragenyx in the rest of the world, it really represents a compelling business opportunity. It looks like a great, when you model, a really great P&L, so moving on and switching gears to our alvelestat. I've talked about AAT augmentation being the standard of care. That's actually the revenue from augmentation is currently over $1 billion despite this lack of clinical outcomes. So there really is nothing else, and this presents as shortness of breath. These individuals are usually 20 - 50 years old. They're going about their daily activities, and they experience COPD-like symptoms. I've mentioned augmentation. Augmentation is not reimbursed throughout many countries in Europe, nor is it reimbursed for earlier stage patients, so if you're a patient who hasn't lost very much of your FEV or your lung function, unfortunately, augmentation isn't generally reimbursed at the very point when you could maybe help stop progression of the disease. We ran two phase IIs, one with an investigator-led study, the ATLANTA study, and the second, ASTRAEUS, total of 162 patients, and one with augmentation and one without, and also including some of these earlier stage patients who hadn't lost as much of their lung function. In those two phase II studies, we showed a reduction of the neutrophil elastase. We inhibited the neutrophil elastase in serum, at least, down to 90% at the high dose. We also showed statistically significant changes in desmosine, which is a breakdown product of elastin in the lung. We also showed in ATLANTA changes in the St. George's Respiratory Questionnaire, which is a questionnaire that's very commonly used in clinical studies in COPD. It's a PRO instrument. In addition, before we took over the program, AstraZeneca had done several studies in COPD and in bronchiectasis. And we also did a study in COVID. And what's striking as you look across all the data from all these different diseases where our alvelestat has been tested is any place where there is a bronchitic component, so the subset of COPD patients who were bronchitic, the bronchiectasis, the COVID, and where neutrophil elastase is playing a role in the lung damage, we see efficacy. And in some cases, we see efficacy in terms of lung function. And that's really striking across all of these different diseases. So I mentioned we had to demonstrate to the EMA that we may have potentially a better therapy than augmentation to get our orphan drug designation. And these are part of the data that we used in support of that. So as we looked, we pooled the data from both ASTRAEUS and ATLANTA. What you can see here is that across the GOLD categories measure the severity of the disease. The higher the GOLD category, the more the severe disease. So you can see that's reflected. These are exacerbations. You can see that's reflected in the percentage of exacerbations going up with the increasing GOLD category. But as you can see, our alvelestat across these earlier and late-stage patients and in the pooled data showed a 50% reduction in exacerbations in this three-month study. Augmentation has never shown anything like this in terms of exacerbations. These were part of the data that convinced the EMA for the orphan drug designation. This is one of the secondary endpoints in the phase III study. So as we plan for phase III alongside our partnering process, as I mentioned, we're looking at these earlier stage as well as the later stage patients, so potentially a broad label for this, and we're looking at a phase III study, which is 220 patients with 18 months treatment. The primary endpoints for the FDA are the SGRQ, the St. George's Respiratory Questionnaire, and for the EMA, we have lung density by CT, and they have said that a p-value of 0.1 may be acceptable, so we have a study with two independent primary endpoints. These are not co-primaries, they're actually independent primary endpoints, and so with this program, as I mentioned, we're looking to start the phase III alongside the partner, so 2025, we're here in January, is set to be a very exciting year for all of us at Mereo, and indeed, a pivotal year. So we have the cash to execute on our plan into 2027. And as I mentioned, we're very excited about the interim analysis to mid-year, but also the final analysis. And for our alvelestat, it's about starting the phase III alongside a partner. So thank you very much, and we're ready for the Q&A. Thank you, Denise. Now we'll open it up for questions. If nothing from the audience as of now, I'll just get things started. Can you maybe help us understand what would be the implications of not meeting the interim readouts for OI? Yeah. So basically, there are no implications to not hitting the first interim analysis. That was an extremely high bar. It used 2% of the alpha spend, so required a p-value of less than 0.001. And as Denise mentioned, the phase IIIs were fully enrolled last April. And we took a look when all patients had been on roughly six-to-eight months, and some patients a little bit longer than that. But what's important to understand here is that for setrusumab to build sufficient bone to prevent fractures, that takes a couple of months. We start counting fractures when we first dose setrusumab. So there was a limited time for the curves to separate. Like I said, the bar with a p of less than 0.001 was extremely high. And we had been saying since the beginning that it was unlikely that we would hit IA1. It was a prudent thing to do because these patients don't have any approved therapies, and if you can get them off placebo earlier, you would want to know, so it was good to take a look, but we knew with it that it was very unlikely. We're much more enthusiastic, as Denise highlighted, about IA2. That's going to take place roughly mid-year. Instead of 2% of the alpha spend, we're using 20%, so it requires a p-value of less than 0.01, and it gives additional months, a significant number of additional months for more events to occur, so statistically, that has what we believe is a really good chance of hitting. I mean, Denise showed the data from the phase IIs. The reality is, once patients are treated with setrusumab, fractures become very infrequent, so we think IA2 is set up to be successful. Should we have to go to a final analysis, that would take place late in 2025. We still retain 78% of the alpha spend, so a p of less than 0.039. Obviously, at that point, you'd have more events accumulating, but we're pretty confident that we have a great shot with IA2. Yeah. One of the reasons that if we're going to be asked the same question again if we don't hit IA2, but one of the reasons clearly we're not using a lot of the alpha on the second interim, but we also have to take into account the variability across these. So if we don't hit IA2, it's not necessarily because of the treatment effect. It may be just because there's more variability than we expect. Great. So in terms of osteogenesis imperfecta landscape of the ongoing trials, where do you think setrusumab fits in? So I mean, as I said, there's no FDA or EMA-approved therapies. Neridronate is approved in Italy, but I have spoken to some of the physicians who use neridronate. And look, they said, "Look, if setrusumab works, it should be standard of care." So I think there's a lot of limitations with bisphosphonates. They're an anti-resorptive, so they're not building bone in the same way. And they also cause the bone to be put down in layers. And what the physicians tell us is that does make it difficult to do surgery on these patients. Great. So maybe in that vein, how big do you think the population, the addressable population, is in Europe? Yeah. So the prevalence numbers would tell you it's 25,000. And we have already identified 10,000 patients. So it could well be more than that 25,000. But I think the other important thing is if you look at those CRYSVITA revenue for 2024, that almost $350 million, that actually is only, if you do calculation on the basis of a rough price, that's actually only treating around 5,000 patients. So it's a really great market opportunity in Europe. So maybe shifting gears to our alvelestat, you mentioned earlier that you're looking forward to 2025, big, big year. Can you maybe provide some guidance on the timing for partnership and what you're looking for in that aspect? Yeah. So we don't ever provide guidance on partnerships. It's a great question, but we don't provide guidance on partnerships. But look, so what's been happening since we started the partnering process, and I think that comes through in the presentation, we've just been improving the program month after month, getting the CMC right, making sure we've got real proper alignment with the FDA, in particular around these endpoints. Getting the orphan drug designation in Europe was important for partnering. And that just happened recently. So we've been improving the program significantly throughout the process. And now it's all about getting the right partner. We want a really good partner for this program and the right deal structure. So there's a lot of focus on this at the company, but that's what we're looking for. Amazing. So if we don't have any other questions, we'll wrap it up. Thank you, everyone. Thank you. Thanks very much.