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Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'm happy to introduce and welcome Denise Scott-Snight, CEO of Mareo, and John Lewacki, the CSO of Mreo. Thanks so much for joining us today. Thank you so much für hosting oss today, Maury. And we're going to do fireside chat format, so maybe for those who are new to the story, if you can give a one-minute intro to the company. Sure. Thank you. So Mareo, we're a rare disease company. We have two late stage programs, citrusamab for osteogenesis imperfecta, which is partnered with Ultragenyx. And we recently announced the phase three data. We're currently having regulatory interactions, which I know we're going to come on to. And then second program is alveolistat for alpha-1 antitrypsin deficiency. This is an oral neutrophil elastase inhibitor, which is phase three ready. And then finally, we have a program for osteopetrosis, Phantictomab, which has partnered with Ashibio. And we have EU rights in that partnership. And that is being readied for phase two. Got it. Yeah, it's a good overview of the company. You mentioned one of the key updates in your recent first quarter press release is the statement that regulatory interactions have been initiated to determine if there's a path forward for Sertuzumab. Understanding you can't disclose specifics beyond the press release, can you describe at a high level the typical process and expected timeline for such regulatory discussions? Yeah. So I think the first thing to understand is that each of these processes, you know, whether, and we are talking to multiple agencies so so this is not just the fda but we're talking about the ema the mhra um but the thing about these processes that i think everybody needs to understand is that they take several months so for example if you have a type c meeting or in europe if youhave scientific advice meeting you know that is can typically be um two to three months from requesting the meeting to actually having the meeting so they do take time and obviously we didn't succeed in meeting the primary end points so that means makes these conversations much more complex and likely to take more time but what I can say is that we're expecting what we've said is that we will provide updates once we have clarity you know what we don't want to do is drip feed the process. And so we're looking to provide a real clear picture of, you know, if there is a path forward or not and what it looks like. And, so, we're expecting to provide those updates, maybe from individual agencies or multiple, before the end of the year. So, at some point during the next six to seven months. Got it. Okay. That's really helpful. So. Yeah. You have those conversations. You got to wait for minutes from the conversations and kind of make sure you've got everything right. There could be some back and forth there. And then you do public disclosure on it. But it is about having the clarity. Yeah, right. Okay, makes sense. And you've noted that further analyses of orbit and cosmic, including patient subgroups, have been completed. Can you discuss the breadth and maybe the depth of the analyses across age groups, OI severity types fracture types and BMD responders versus non responders yeah I'll take that so is we have an ultra genics have announced we're now focused on pediatric patients age ages 2 to less than 18 so that's really the focus at this point in time recalling cosmic the study that originally is the study that enrolled a higher fracturing in younger patients, ages 2 to 6, although the original powering was lower than that of ORBIT, we nevertheless saw a 20 percent reduction in fractures, relative to IV bisphosphonates, which are used as standard of care, although it didn't achieve statistical significance, but a pretty good trend. You know, the curve separated quite early. We also saw statistically significant improvements in BMD in both COSMIC versus IV bisphosphonates in ORBIT versus placebo, consistent with the powerful anabolic effects of citruzumab. So over the past few months, we in Altergenics have been focused on analyzing both pre-specified Specified an ad hoc analyses of the data and in addition to that trying to get a handle on Confounding factors that have affected the primary endpoint readout You know in terms of confounding factors in orbit despite the fact that there was stratification Based on the number of fractures. We nevertheless and I don't understand how this could happen, but we nevertheless saw a a proportionally twice as many of the patients in the citruzumab arm of type 3 patients. So these are the most severely ill patients in this citruuzumab relative to the placebo arm. So this obviously skewed fractures toward the citrusumab . You know, we also announced that we saw statistically significant reductions in pain in these patients, which is quite significant, and clinically significant improvements in sports and activity in these patient. You know the changes in sports in activity in particular led to behavioral changes in these patients. So in contrast to placebo patients, the citruzumab patients were doing things like karate, climbing walls, bouncing on trampolines, gymnastics, mountain biking, all of the above. Horse riding. Horse riding, which predisposed them, put them in higher risk, and predispose them to activity-driven fractures, right? so contributed to as another confounding factor in the analysis. You know, the patients are doing exactly what we wanted them to do. It was exactly what мы hoped the drug would do, but nevertheless impacted the final outcomes, particularly since it once again biased fractures toward the cetruzumab arm. We also have examples of major improvements in mobility in the phase three patients as we saw in phase two, where some patients have been able to leave their wheelchairs and become independently mobile. So that's very significant. You know, we've talked about BMD, which achieves statistical significance. Alongside of that, we have measures of bone health and also bone biopsies, which really support the mechanism of action and the fact that we are building significantly stronger bone in these patients. And we also have some other positive subgroup analyses, and of course, we've mentioned the vertebral fractures, where we see about a 30 percent decrease in vertebral fractures in orbit and closer to a 60 percent reduction in vertebral fractures in COSMIC associated with a p-value of less than 0.08. These vertebral fractures are obviously very important in the development of young kids and something that we're focusing on going forward. Got it. I mentioned a lot there, maybe digging into a couple of the points. So for the 2x type 3 patients in the cetruzumab arm, if you take out the type 3 patients from the study, i guess what do you see yeah we i mean we yeah we're not disclosing that sort of data at the moment maury so but that's something that you're obviously we've done a lot i mean there's a lot of different data analyses that have been done yeah um and you know what we don't want to get into is slicing and dicing the data so that we end up with you know small populations yeah yeah that makes sense um uh and i guess maybe talk about uh um just with the the bone marrow density improved or bone mineral density well you mentioned the uh the biopsies as well from bones how many patients do you have biopsied yeah again i mean those data are going to be disclosed um at a medical meeting okay yeah yeah okay um with the bone mineral density improvements versus control uh you've highlighted the reductions in vertebral vertebral fractures and patient reported outcome improvements what's the feedback been from clinicians and the clinical meaningfulness of these outcomes given that no fda or ema approved therapies exist for li yeah so i mean what we've done at mario is um you know we've spoken to um a lot of uh clinicians in europe um about obviously the data that we've published and the feedback actually has been very very consistent so we know that pain you know we did the impact survey we know pain is the number one symptom that the patients note that really impacts on them the most but a lot of that pain actually does come from these vertebral fractures whether that's clinical you know the clinical fractures and the clinicians have been telling us and this is including in the UK that actually they treat patients on the basis so if a patient has a vertebral fracture you know a young child has a vertibral fracture they will start with a single vertebral fracture they will stop this phosphonate treatment off label whereas if they have a single long bone fracture that's not necessarily the case and the reason that they do that is that they they want to protect the spine because these vertebral fractures can lead to you know the scoliosis and the kids being wheelchair bound as well and also having one vertebral fracture can actually predispose you to having more vertebral structures so there are really key component of a reason to start treating. Got it. And is there precedence for PROs supporting a label, even if hard endpoints like fracture claims are limited? Yeah, I mean, it's a good question. But, you know, we've talked, I've talked about pain. Pain is an important endpoint. And there are obviously, you knows, other areas where pain is the endpoint. But you You know, we've got the BMD data, we got other bone health data, and we also have these vertebral fracture data. And there are some other fracture data that, you know, that we haven't disclosed yet. So we're not looking to, you, know, solely rely on the PRO in these regulatory discussions. Male Speaker 1. Understood. And for outcomes from regulatory interactions, I guess, what are the range of possibilities there yeah so i i don't really want to speculate on the on the range of possibilities um so i think you know what i can say is when we do update on on these interactions uh it will be with with that clarity and um i also as we've seen with other companies what's important is we're having these multiple interact we're interacting with multiple agencies right because we've seen different with other companies in similar situations we've seen different outcomes from different agencies right so but i don't really want to speculate on the outcomes got it okay um and when you do the update before the end of the year that's going to be uh a perspective from all the agencies or i could it just be one agency it could just be won it i mean it'll be when we get clarity. Got it. Okay. And as patients roll over into the open-label extension, what specific long-term fracture or biomarker trends are you monitoring to validate CitrusMob's clinical profile? So the patients who enter the open label extension, we're basically monitoring the same endpoints as we did during the double-blind treatment period. So we're looking at fractures, including vertebral fractures. all confirmed. We're looking at the PROs such as pain, comfort, and sports and activity, and we're also looking at BMD and other measures of bone health. So we're really collecting the same data that we did during the double-blind treatment period. You know, while a minority of the patients moved to the open-label extension at 12 months as a result of patients transitioning over as part of the rescue protocol, most of the patients or the rest of the patients in the study were in the double-blind treatment period for 18 to 24 months. This includes patients who were receiving citruzumab or placebo in orbit and citruzamab or IV bisphosphonates in COSMET. So once the patients move to the OLE, they're receiving citrusumab only. So what we basically have is we have patients who were receiving placebo and or IV this or or IV bisphosphonates in the in the double-blind treatment period who now have effectively crossed over into a citruzumab arm so that's going to be valuable clinical data and you know we'll be looking at that in great detail you know I should also mention that almost all of the patients in the and Orbit and Cosmic have entered the OLE. And, you know, we talked previously about the phase two data, and 22 of 24 patients still are in an OLE receiving citruzumab after about three years. And we think the fact that so many patients entered the ОLE from Orbit and Cosomic and those phase two patients have stayed on citruuzumab tells us something about what the patients think of the drug yeah yeah it makes sense and for orbit and cosmic is there a certain amount of follow-up time that you want to to just kind of strengthen the conversation with regulators it's something that we're looking at at the moment um but you know we if you think about it um so we reported the data out in in december end of december so you know by the fourth quarter, all of these patients who've rolled over will have had at least 12 months data. So that's coming up in the fourth quarter. Got it. Okay. And so just looking at the Orbit study and the design types of patients that you enrolled, is there, if you had to do it all over again, I guess, would you do anything differently with the study design? Is it just a matter of having more patients or what would you do you know basically we are you know we are comfortable with how the study was powered and how the how the uh you know how the steady was powered in how it was designed so things like fracture adjudication we're comfortable with the way that was done you know the rescue protocol which did impact the number of placebo patients and and citrus amount patients that went on through 18 months it was something we basically had to do in a placebo-controlled trial because you had to give those patients the opportunity to move to citruzumab if they weren't doing well on placebo or you know so so we had it we had to incorporate that into the study you know people mention things like the bisphosphonate washout period that that did that affect us? What bisphosphonates do with respect to fractures in OI is really pretty obscure. So we have no evidence that that had any impact on the study. You know, we've mentioned the activity levels, which we couldn't control for and believe would happen again. And I think one of the factors here, and you've seen a number of rare disease trials that read out and they miss the primary and or secondary endpoints. And I think a big factor there is that we underestimate the heterogeneity in these patient populations. You know, we underestimate the heterogeneITY, and particularly when you conduct a larger trial like we've conducted. So that also impacts the trial. And you know, COSMIC, which had a tighter age group and higher fracturing population actually performed pretty much as we expected. If you recall, we were saying that COSMIC was underpowered and that we wanted to see a numerical trend. We actually achieved that in that study. But it was a little tighter, a little better defined, right? So when you think about the trial, we're comfortable with the trial that was done. We're comfortable mit how it was powered. and we think we understand some of the factors that contributed to the primary analysis. Got it. Okay. And can you walk through just more on the EU reimbursement process and what you need there to just have robust conversations with EMA for a path forward? Yeah, so, I mean, separating the two. So, obviously, there's the EMA and the MHRA in terms of, you know, if there is a path forward, what does that look like? What are any post-marketing commitments? And, you Know, yeah, what might a label look like. And so that then directly impacts into our conversations with the HTAs, the individual country HTA's. Nice. for reimbursement and we've already you know we've got a there's a you have your launch sequence but we've been in discussions for several years with with the national htas um over you know what comparator data they would need to see for example so for example residronate is um sorry So Noridronate is approved in Italy, for example, so you need to have those comparator data. And so we really understand, you know, across the European landscape, if we're able to find a path forward in Europe and the UK, what the reimbursement process, what we need to deliver for the reimbursements and pricing. Got it. And so that's something that you, or those conversations are happening in parallel, or how do we think about that? Well, they have been happening in Parallel. Obviously, at the moment, the focus is on determining if there's a path forward with the regulators. And once we know where we are with that, then we can refresh all the work that we've done. Got it. Okay. So, yeah, next steps for Satruzumab. You guys are working with the regulatory interactions right now. Is it fair to assume that there's back and forth with the regulators and then you kind of get the minutes from or how does that? Yeah, I mean, there's the minutes are one part. I mean you know in the meeting, you know, what the feedback is and then, you get the minute but yeah there's you know as I say it's complex because we didn't hit the primary. So there's multiple ways of interacting. There's the meetings. There's also written communications. And, you know, there's different forms, but it's just going to take time. Okay. And switching gears for the AATD LD market, can you characterize the competitive landscape with emerging oral therapies, gene editing, and explain how Alveolastat's mechanism, development timeline, and regulatory path position it for commercial success. Yeah. So Alveostat's an oral neutrophil elastase inhibitor, daily dosing. And it's designed at the dose that we're taking into the phase three to really inhibit neutrophile elastases at the 90% level, 24-7. Okay. And if you think about, so, you know, obviously there's second generation augmentation therapies in development. And as you said, there's the editing platforms that are working in the AATD space. And I think, you Know, there is lots of discussion at the moment around what is the right level, you know, chronic level, I guess, of AAT, circulating level of AIT? And then what do you need during an acute event, like an exacerbation? And so I think the question for the, not so much the second generation augmentation therapies, but the question für die, the new platforms is, you know what what level of AAT on a steady state can they achieve and then do the we've seen these acute responses in a few patients in one of the platforms and the question is does that improvement in the AAT level in that acute response lead to clinical outcomes okay so what we showed in our phase two in both Astraeus and Atlanta was that with alveolostat, we actually, so we saw these improvements in SGRQ, which is a standard PRO instrument used in COPD studies, and we also importantly saw a reduction in exacerbations, you know, which is a key clinical outcome here. So we have seen, you know, trends at least in these clinical outcomes with alveolus stat already in phase two. And in terms of the regulatory path forward for alveoli stat, so right now the current design, we have these two independent primary endpoints. We have SGRQ for the FDA. And we have lung density by CT for the EMA. And it's a single global trial, so two independent primary endpoints in one study. And the thing that we are doing is obviously there's a lot of interactions going on with the FDA and the EMA right now over pivotal endpoints for these other platforms and also for the second generation augmentation. So we're keeping an eye on those discussions just in case there's an opportunity for us without too much delay to simplify our design. Okay. And so keeping an eyewitness to some of the updates in this space, are there specific competitor programs that you're focused on? No, we're watching eye on all the different platforms as the data evolves. And obviously, you know, there was some data updates from Sanofi at ATS on their three-weekly augmentation. So, yeah, so there's a lot of debate around AAT levels and acute responses. Got it. Okay. That's interesting. And for this opportunity, what could your estimated peak sales and market share opportunity look like for Avilisat? Yeah. So Alveolistat, we're, you know, one of the differentiation factors here is that we're actually, the phase three is designed to enroll both late stage and early, earlier stage patients. So, and when I say earlier stage, I mean, patients who haven't lost so much of their lung function. So they're still at 95% to 100% of their predicted FEV1, but they have got emphysema and they have got the genetic diagnosis. And so the opportunity there with a daily oral is to really try and prevent the lung tissue from deteriorating. So really preventative. Andso that's one area that we're really targeting. The sales of augmentation right now are around a billion dollars annually, but there's only about 10 to 15 percent of patients are actually diagnosed. So I think as these therapies, you know, evolve and are developed, you knows, that 10 to 15 percent will hopefully go up significantly in terms of diagnosis rate. Got it. And maybe going back to the Sanofi data that you mentioned, what's the exact relevance or read-through to your program? Well, I think the Sanufi data was more around the levels of AAT that they were able to achieve. So, you know, they were talking that they don't believe 11 micromolar in a steady state is sufficient. They're focused more on 20 micromola. Yeah. Okay. And then as you engage in active, as we said, partnering discussions, what's a realistic timeline for closing a deal? Again, a very good question. Difficult to answer because you never want to guide when things might close, just in case. But I think what I can say is that we are, you know, we're targeting to start the phase three around the end of the year. got it okay run at the end of this year yes start phaser okay and um and so you'd run the study on your own uh i guess no i mean we we we've said consistently said that you know we plan to partner this to have the cost of the study funded okay and uh so theoretically then you'd have some sort of a partnership in place by that time um how much would a phase three cost so rather than give you the exact cost because it depends on what's included what's excluded uh cmc etc so you know it's it's a around uh 220 patients so you know its a very reasonably its a very reasonable cost um for a study uh given the market opportunity got it okay interesting Um, and for Ventictimab, would you want to provide a brief update on the program? Yes. So just quickly, Ventictumab is an antagonist. It's an antibody that basically blocks Wnt signaling, uh, and, and you know, in various tissues, but most significantly in bone. And what, when you block Wnt signalling in bone, it's actually the opposite of what we do with citruzumab, what you do is you increase the activity of osteoclasts, in other words, increasing bone breakdown. And osteoclasts are deficient or aberrant in conditions like osteoporosis, autosomal dominant osteoporsis type 2 specifically. So what we've done is we have licensed Van Tictumab to Ashy Bio. We've retained the European rights. They're paying for the clinical studies in the CMC and obviously have rights to the U.S. rest of the world. You know, so we so, you know, we've basically completed that with them and, you Know, one of the advantages of Van Tichtumab is that it was in the clinic previously for the treatment of solid tumors, having it in the, it's been in over several hundred patients, and it has a safety profile consistent with its use in ADO type 2. So it's a ready packaged program, ready to go into, back into the clinic, phase two studies, and as we speak, Ashley Bio is completing all the requisite work to move it into the Clinic as quickly as possible. Got it. Okay. So probably no updates on that program this year, but maybe something next year from then. Okay, so we're out of time. Maybe to close out, if you want to highlight cash runway assumptions and key catalyst investors should be focused on over the next six months. Yeah. So, you know, at the end of Q1, we reported that we had just around 36 million in cash on the balance sheet we expect that to give us runway into mid-2027 and so you know that gives then that doesn't include any potential you know income or or milestones from business development so we expect you know That's going to provide us runway to to work through these regulatory interactions alongside ultragenics and also we'll see what happens with alveolus Got it. Okay, Denise John, thanks so much for joining us today Thank you, Mari