We're going to do a fireside chat format. So maybe to start off, for those who are new to the story, Denise, if you can provide a one-minute intro to the company and your program. Okay, I'll try and keep it to one minute, Maury. So our lead program is Setrusumab, which is an anti-sclerostin antibody for osteogenesis imperfecta or brittle bone disease. And this is now in two phase IIIs led by our partner, Ultragenyx, the ORBIT study, which is in five to 25 year-olds, and the COSMIC study, which is in two to five year-olds. And both studies are now fully enrolled. So we're looking forward to the phase III data at some point during 2025, so quite soon. And then also on the Setrusumab program, we have upcoming around mid-year the latest phase II data from the phase II portion of the phase II/III ORBIT study, which is the five to 25s. We have 24 patients in that study, and 23 of those have continued on treatment. And we will have the 14+ months data, as I said, around mid-year this year. Moving on to our second program, which is our neutrophil elastase inhibitor, Alvelestat, for Alpha-1 antitrypsin deficiency. We're focused on the lung disease. Recall, this is an oral neutrophil elastase inhibitor. It's a small molecule. And actually, we were very pleased to see the Insmed data last week in bronchiectasis, in non-cystic fibrosis bronchiectasis, because as you recall, Mereo, we took over this program from AstraZeneca. And when we took it over, they actually had run a small phase II study in bronchiectasis. It was a short study over the course of a month, but actually they did show a statistically significant improvement of about 100 mL in FEV1 and also a 130 mL change in SVC. So we really feel that the Insmed data really support the use of an oral small molecule inhibiting neutrophil elastase to treat these types of lung diseases. It's really built confidence in the mechanism of action for the Alpha-1 program. Got it. Yeah, it's a great intro and setup. Maybe let's start with Setrusumab for osteogenesis imperfecta. This program is partnered with Ultragenyx. Maybe explain that collaboration and the economics to investors, including plans for commercial supply. Okay. So Ultragenyx, I have to say, they've been a great partner. This has been a great collaboration for us. And the way it works, basically on the economic side, we have $245 million in milestones to come now. And we own Europe outright. So on Europe, we pay them a flat double-digit royalty. On the rest of the world, they pay us tiered double-digit royalties. And we believe that on the basis of the forecast, we'll get to the top tier of those royalties. So that's the economics. On the development side, they are funding and leading the global development program, but it is a collaboration. So there's a lot of input from our side to the development program. And on filing an approval of the MAA, we would then take over the MAA in Europe for the commercialization of Europe. On the CMC side, so again, they have been responsible for funding and for leading the scale-up on the manufacturing. We're now in the process of negotiating a supply agreement, which we expect to conclude that in the second half of this year. Got it. Makes sense. Maybe talk about just the market opportunity in the United States and EU5 and what proportion of the OI patients you estimate could be addressable by Setrusumab at launch. Yeah. So in terms of the global market opportunities, so the analyst consensus is around $1.5 billion-$2 billion. And we have typically, we believe that's really supported by what's happened with Crysvita in XLH. And Kyowa Kirin, in their annual report, their forecast this year for Crysvita is $1.3 billion. Now, XLH is lower prevalence than OI. It's 46,000 versus OI is 60,000. So lower prevalence and arguably a less severe disease than OI. So we really think that the Crysvita, what's happened with the launch and that sort of revenue projection, it's a really good analog for a base case, I would say. In terms of Europe, where we are responsible for commercialization, we have already identified 5,000 pediatric patients and 5,000 adult patients. And that's just in the key EU5, which I'm including UK in that. We're now rolling out that patient identification to Scandinavia and to the Benelux. You can see if you apply Crysvita-like pricing to these sorts of patient numbers, and we believe those 10,000 patients, those are potentially a treatable population in Europe. It's a significant market opportunity in Europe. Got it. Is there anything more you're saying about the tiering for the royalties and what could trigger those? Yeah, unfortunately, yeah, we haven't disclosed the tiering of the royalties yet. But the way that we think about it, if we hit that top tier of royalties, and obviously that just falls straight to the bottom line. And so if you build the business case, the business model for Setrusumab for Mereo, it's a significant business case. It's a very attractive business opportunity. Got it. Have you proactively conducted market research to identify prospective patients in the EU5? Or you've done this? Can you talk about that and how that shapes your commercialization strategy? Yeah. So on the basis of all of these patient finding activities, so Europe's kind of divided. There are some countries like the U.K. where there are centralized treatment centers. So in those centralized treatment centers, it's much more straightforward to find not just the pediatric patients, but also the adult patients. Where it's not so centralized, then it's much harder to identify the adult patients. So we've built our model understanding how this works with the different treatment centers and the pediatric versus the adult patients. And we believe that with a field force of around 70, you could actually cover the whole of Europe. And I'm excluding Central Eastern Europe from that because that would be done through a distributor. So a very small field force to really cover the whole of Europe. Got it. And what have you heard based on payer conversations? And do you have a sense of how pricing and reimbursement could look in the EU5, particularly taking into consideration fractures as an endpoint as opposed to like a biomarker? Yeah. So you're absolutely right. Having fracture as an endpoint, it is the endpoint that matters to these patients, particularly in these very young children where they have many fractures as kids. So it's a hard endpoint. What we have done is that we've been interacting with the HTAs and the payers since 2018, 2019. So we were the first company to participate in the EUnetHTa scientific advice process. And we did that. That first meeting was in 2019. And we had nine HTA bodies represented at that meeting. And we've been doing a similar process with the payers. We've had 11 countries represented at those meetings. So this very, very early engagement is super important in Europe. And EUnetHTA is really designed Europe, everybody knows it can take a long time to get reimbursement, pricing and reimbursement, and get those discussions concluded. So this EUnetHTA process is designed to speed that up and also to have equity for treatment across Europe. So early access to treatment across Europe, not just in specific countries. So we're using, again, we use Crysvita-like pricing as our base case. And on the basis of the discussions where we're at, we believe that's realistic. Got it. Okay. The other thing I should say about commercialization in Europe, we shouldn't forget that we have the early access program in France. And so in France, next year before approval, we can actually have an early access program. You set your pricing, we would set the pricing. And so that would generate revenue, but obviously it provides sort of early catalyzation of treatment. Got it. Is there anything more you're saying about that as far as the demand for the early access goes and what your pricing strategy could be there? Yeah. I mean, we're just working through that. It's a little early for that, but we're working through those details now. Got it. Okay. And let's talk about the clinical studies. So your two pivotal studies, the ORBIT and the pediatric COSMIC study, both enrolled rapidly. So clearly there was a lot of interest in the program. The ORBIT phase III was downsized from its initial target of 195 patients to 150 patients and ended with 158 patients. What was the driver behind this change? And can you provide more perspective around the current versus prior powering assumptions? Yes. So initially, the ORBIT study was basically powered very conservatively and used a very low baseline annualized fracture rate. And upon getting additional data such as some of the early phase II data, that annualized fracture rate was actually adjusted up a little bit. And the size of the study was reduced from 195 to 150 patients. As you said, Maury, at the end of the day, we ended up at 158 patients, which really reflects, number one, the enthusiasm of the investigators. And secondly, a really impressive job by the Ultragenyx team with support by the Mereo team in enrolling both of the studies in approximately 10 months. So enrollment really went quickly. The study is still fairly conservatively powered. It has a greater than 80% power to show a 50% treatment effect. Obviously, still uses a fairly low annualized fracture rate. If that proves to actually be higher in the actual trial, then a lesser treatment effect will be required. Got it. And just wondering, were the assumptions behind the annualized fracture rate adjustments, were they primarily based on the phase II or only based on the phase II data? Were the n was small? Or were they based on the phase III screening period where maybe there was a higher rate of fractures? Or were they based on real-world data where fractures are potentially underreported? Yeah, really two things. Number one, the phase II data. But secondly, we really ensure that the trial's enrolling actively fracturing patients. So the inclusion criteria requires at least one fracture in the previous 12 months, at least two fractures in the prior 24 months, or fracture of one long bone over the last 24 months. So that sort of sets a baseline for the annualized fracture rate. And then it potentially goes up from there based on the types of patients that are enrolled. Some of the patients we're enrolling have more than three fractures. So it's a pretty actively fracturing population. Yeah. It's very hard to use the natural history data because a lot of times these patients, they're so used to having fractures, they just get on and manage them themselves. They don't actually go to the hospital and have an X-ray. They actually get on with it. I mean, we've spoken to a mother and her daughter, her seven year-old daughter, and she carries around the equipment that she needs in case there's a fracture. They don't bother going to the hospital. Interesting. There's a lot of focus on the first interim analysis, which is expected by year-end 2024 or early 2025. It has a stringent threshold of having to hit less than 0.001 p-value, which is a high bar. Why was it set that way whereas the next interim has a p-value threshold of 0.01? Yeah. So really based on the phase II data where we saw a 67% reduction in annualized fracture rate and the reality that these patients have no real treatment options, Ultragenyx and we both felt it was prudent to take an early look at the data. So in this initial interim, this trial enrolled fully at the end of April. The initial interim is planned before the end of the year. So the initial interim basically has a p-value of less than 0.001. So it's a high bar, but depending on annualized fracture rates or fracture rates in the placebo group, it still has a shot. Obviously, so it's early. We obviously didn't want to use too much of the alpha spend there. We used 2%, but it still has a shot if the treatment effect is perhaps even larger than we anticipated. Got it. That's really helpful. It's not clear to us if the first interim is driven by a predetermined duration of treatment. If this is the case, can you say more about the specific timing or duration? Or is there a certain number of fractures that have to be achieved? Separately, are you getting real-time DSMB feedback on blinded events? Yeah, well, it's kind of both because the interim is partially event-driven, but if you think about it, it's a two to one randomization of Setrusumab versus placebo. And if Setrusumab is working really well, the events are going to take a long time to accumulate. So as a result, the time element was incorporated in. And it's really planned for prior to the end of the year. And with respect to the second question, we're fully blinded and don't get any data whatsoever from DSMB or other sources. Got it. Understood. And how are you setting expectations for the first interim, and what probability of success would you attribute to that interim? Yeah, like I said, it's a high bar. We're not necessarily out there saying it's likely. We have more confidence in the second interim that I'll talk about in just a minute. But it was prudent to do the first interim and it has a shot. We'll see. Got it. Yeah, definitely wanted to ask about the next interim and then the final analysis. It makes it an interesting situation where you've got these three events, which should be pretty close together overall. Yeah. Maybe talk about that and how those readouts play out and probabilities of success as the study matures. Yeah. So after the first interim, there's going to be a second interim several months later. And the second interim actually uses more of the alpha spend. So it requires a p-value of less than 0.01. And of course, patients are going to be on study for several additional months. And we believe fracture rates may actually wane over time with this agent as BMD increases. So we think the second interim has a really great shot at being successful. We're kind of quite enthusiastic about the possibilities there. If it doesn't succeed, and like I said, we're not expecting that it won't succeed. We're expecting it to succeed. But if it doesn't succeed, 78% of the alpha spend or p-value of less than 0.039 has been saved for a final analysis that would occur several months later. While we hope we don't get there, that's still a pretty darn good backstop to have. It's still in 2025. All in 2025, yeah. Got it. Okay. Really helpful. And we understand the differences between Setrusumab versus Amgen's romosozumab. And Romo is indicated for older patients, but this is still a common question topic that comes up. Can you provide quick thoughts on this? And we're wondering if FDA will view some of Romo's safety warnings as a class effect and basically give Setrusumab the same black box. Yeah. So two real variables here. Number one are the drugs, Romo versus Setrusumab, but secondly, the indication, osteoporosis versus osteogenesis imperfecta. And Amgen was treating an elderly population with a significant number of cardiovascular comorbidities. And while the signals weren't large, there were some evidence of cardiovascular safety findings that really led them to get a black box warning and for their treatment to be limited, their use of Romo to be limited to a 12-month duration of treatment. Conversely, with Setrusumab, we're treating generally a much younger patient population that doesn't have cardiovascular morbidities. The regulatory agencies have certainly been supportive of us dosing for more than 12 months. And at this point in time, we've had a number of patients that have been on study, some for even over 20 months. And we haven't seen any safety findings whatsoever. So we're quite confident that the cardiovascular findings that were evident in the elderly population with Romo don't apply to Setrusumab. And we're not anticipating any safety concerns on that front or the like. Got it. That's helpful. Additional longer-term safety and efficacy data from the phase II portion of the ORBIT study are expected second half of this year. Can you briefly recap these data and set expectations for what to expect in this update? Yeah. So what we're going to be looking for in the update, it's going to be roughly approximately 14 months. So significantly advanced beyond the six-month data that was reported in October. And obviously, we're looking at ongoing fracture rates over that period of time. We expect them to be at least comparable, if not better than what we observed in October. I use the word, if not better, because one of the observations from the six-month data was that while patients in that study had been on study for approximately nine months, there was only one fracture that occurred between six and nine months, suggesting the rate was decreasing over time. So we're going to be obviously taking a real look at that. We're also going to be getting BMD data. That's going to be very important. We expect BMD to continue to increase. We're going to be looking at whether it's increasing in a linear manner or starting to plateau. That will be informative going forward with respect to ultimate potential maintenance dosing regimens. We're going to be looking at the Z scores, which really take BMD and match it with an age- and gender-matched population. Z scores at baseline in these patients were about two standard deviations below the norm or minus two. They had increased by about one standard deviation in the six-month data. We're now going to see if some of these patients are actually moving toward normalization of their BMD relative to the age- and gender-matched population as a whole. So going to be really informative data. We're looking forward to it. Got it. And I want to spend a little bit of time on Alvelestat. Is there anything else for Setrusumab that I forgot to ask that you want to highlight? I think we've covered the most important topics. Thank you. Got it. And for Alvelestat, you mentioned the Insmed update is an important read-through event to the program. Maybe talk a little bit more about that and next steps for the program. Yeah. So yeah, I mean, obviously the DPP-1 inhibitor, by the way, which was also in-licensed from AstraZeneca a year before we in-licensed Alvelestat from AstraZeneca. So that's upstream. It inhibits three proteases, including neutrophil elastase. But the dominant effect, speaking to the KOLs in terms of the clinical outcomes for that bronchiectasis study, was on the basis of the neutrophil elastase inhibition. But again, I think it gives us confidence in inhibiting neutrophil elastase on these types of lung diseases with a small molecule. In terms of our program, so we have completed the initial validation work that we agreed to do with the EMA. And that has demonstrated that the SGRQ, which is the PRO that's used in COPD, is validated for COPD, is fit for purpose in its current form. Importantly, out of those data, this was a dry bench study conducted in the U.S. at three sites. Importantly, those data demonstrate that the two things that we've seen with Alvelestat, which is the activity and physical activity, ability to do physical activity, and the breathlessness are the important parameters for these AATD patients. We're getting ready to submit those data on the validation work, plus the whole update, IND update to get ready for the phase III. That's going into the FDA at the end of this month. Got it. Okay. Anything more on partnering potential with this, I guess? Yeah. I mean, we're working through the partnering. It's progressing, definitely progressing. We continue to have multiple companies engaged. Those include ones for global rights, but also for ex-EU rights, where we would retain European rights. Equally important has been demonstrated by the Ultragenyx collaboration. The actual partner themselves is also the key decision. We want to have the right partner for this asset. That's part of the determination here. Makes sense. So maybe to close out, if you want to highlight key events ahead that you want investors to focus on and. Yeah. So maybe just to highlight, so our cash position was around $ 49 million at the end of Q1. And that doesn't include the phase III for Alvelestat or any deal income. And then in terms of milestones, so next up is the phase II data from ORBIT, the long-term 14-month data. So we're super excited to see that. And then obviously getting phase III ready for Alvelestat and hopefully more progress on the partnering side. Great. Thanks so much for joining us today. Thank you.