Thank you for standing by, and welcome to the Metsera topline results for phase I trial of MET-233i. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you'll need to press star one one on your telephone. As a reminder, this call is being recorded. I would now like to introduce your host for today's conference, Gbola Amusa, Executive Vice President of Strategic Finance and Investor Relations at Metsera. Gbola, you may begin. Thank you, and good morning. During the course of this conference call, we will be making forward-looking statements. These include results, plans, and expectations with respect to our product candidates, strategies, and opportunities, all of which involve certain assumptions of risks and uncertainties that are beyond our control and could cause actual results to differ materially from these statements. A discussion of these risks can be found in our FCC disclosure document. In addition, Metsera does not undertake any obligation to update any forward-looking statements made during this call. Joining me today are Whit Bernard, our Co-founder and Chief Executive Officer, who will provide opening and closing remarks; Steve Marceau, our Chief Medical Officer, who will present the data; and Brian Hubbard, our Chief Scientific Officer; and Chris Vizioli, Metsera's Co-founder and Chief Financial Officer, who will join Whit and Steve for the Q&A session. With that, I'll turn the call over to Whit. Great, thank you, Gbola. Welcome, everyone, and thank you for joining. I'm excited to share exciting top-line phase I data that confirms MET-233's profile as a first-in-class monthly amylin analog, with a potential best-in-class efficacy and tolerability profile enabling a first-in-category monthly multi-hormone combination for weight loss. Amylin has emerged as an exciting and valuable non-increase in nutrient-stimulated hormone, or NuSH, target with several key advantages. It's additive to GLP-1, enabling potentially category-leading weight loss as a combination therapy. Amylin is also efficacious as a monotherapy. It delivers weight loss with potentially better tolerability than GLP-1 receptor agonists, and amylin may potentiate cardiovascular benefits of other NuSH analogs with reductions in heart rate and improvements in blood pressure and glycemic control. There's emerging consensus around two important value drivers for amylin: first, in combination with GLP-1 RAs and other NuSH analogs, including Metsera's monthly GLP-1 MET-O97; and second, as a monotherapy alternative for consumers who do not tolerate or otherwise prefer not to take GLP-1 receptor agonists. As we survey the competitive landscape in building Metsera's pipeline, we believe the ideal amylin agonist would differentiate on three attributes. First, it would be ultra-durable, enabling monthly dosing, optimized tolerability, and improved scalability. Second, it would be potent against all three human amylin receptors, delivering best-in-class weight loss at very low scalable peptide dose levels. Third, it would be combinable with best-in-class GLP-1 receptor agonists and other NuSH analogs in a simple and scalable device. MET-233 was engineered to deliver on all of these attributes. Pre-clinically, we observed MET-233 to be extremely durable, with an implied half-life in pigs suitable for monthly dosing and aligned to MET-O97. We also observed MET-233 to be three times more potent than cagrilintide, implying substantial efficacy at low doses, and we'll be sharing data at a conference later this year showing that the potency of MET-233 substantially exceeds all other amylin analogs in development, including tetralintide and GUB AMY. Finally, we deliberately engineered MET-233 to be soluble across a broad pH range, matching the solubility range of MET-O97 and all of the other peptides in our pipeline, enabling combination in a scalable single-chamber device. What we predicted for MET-233 going into first-in-human testing was an exceptionally long half-life, high levels of well-tolerated weight loss, and seamless combinability with MET-O97. I'll now turn it over to Metsera's Chief Medical Officer, Steve Marceau, to share how we did in delivering on these pre-clinical predictions in clinical testing. Steve? Thanks, Whit. In our 233 phase I program, we have now characterized: one, the pharmacokinetic profile of MET-233; two, measured weight loss at week one and week five; and three, identified well-tolerated starting doses. As you will see from the data, 233 has exceeded expectations in all three of these key scientific objectives. To accomplish this, we conducted a randomized placebo-controlled trial of MET-233 in otherwise healthy adults living with overweight or obesity. This trial included two parts: a single ascending dose study and a five-week multiple ascending dose study, each enrolled 40 participants. In this SAD, MET-233 was administered as a single subcutaneous dose across five dosing cohorts ranging from 0.15 milligrams -2.4 milligrams, using a six-to-two randomization ratio of active to placebo. In the MAD, MET-233 was administered in fixed weekly subcutaneous doses for five weeks across four cohorts ranging from 0.15 milligrams -1.2 milligrams, using an eight-to-two randomization ratio. The baseline demographics were evenly distributed between the 233 participants and those on placebo. The average age was 43, with approximately 50% being female, and the mean baseline BMI was approximately 32, which put the BMI in the obesity range. It is notable now that we have successfully engineered and reported clinical data on two ultra-long-acting NuSH peptide analogs. The first, O97, are GLP-1 receptor agonists, and today, 233 are ultra-long-acting amylin. 233 has an observed half-life of 19 days. 233 also has a delayed Tmax, prolonged absorption, and very low variability. These attributes are well-suited for both monthly dosing and combinability with O97. In fact, the PK profile of 233 and O97 are so similar that their multi-dose pharmacokinetics are nearly superimposable. This is a pop PK model based upon O97 and 233 PK data. O97 area is shown in shaded red, and 233 area shown in shaded blue, with the overlapping area in purple. This highly overlapped PK profile is a result of three things: one, similar half-lives for both O97 and 233; two, a multifold accumulation of both 233 and O97 after five weekly doses; and three, the shape of the exposure curves are maintained within week and across the five weeks of measurement. These data confirm that 233 is ideally suited to combine with O97, and we have now initiated co-administration studies of O97 with 233. 233 also delivers impressive weight loss data. The figure on the left illustrates placebo-subtracted weight loss one week following a single dose in the SAD study. We administered 233 in doses ranging from 0.15-2.4 milligrams. The greatest weight loss observed was in the highest dose administered and was 5.3%. Weight loss also persisted four weeks following a single dose. In this SAD, we dosed to maximum tolerability. As such, we excluded 2.4 from the MAD as it exceeded an acceptable tolerability profile for a starting dose. The figure on the right illustrates the MAD weight loss data, placebo-subtracted weight loss at five weeks, which was one week following the final dose. Doses of 233 ranged from 0.15-1.2 milligrams. Similar to this SAD, there was a dose-dependent weight loss. The highest dose administered resulted in the greatest weight loss, which was 8.4%. MET233 was safe and very well tolerated in these studies. There were no safety signals in the SAD or MAD. GI symptoms in the MAD were all mild. Participants developed rapid onset of tolerance despite a nearly threefold increase in exposure with weekly dosing, as shown in this onset table. As you can see, the occurrence of gastrointestinal symptoms was largely confined to the first week. Throughout weeks two to five, and despite a nearly threefold increase in exposure with weekly dosing, participants experienced sporadic events, which I've already mentioned were mild. A similar pattern of data was seen in our MET-O97 development program. These data suggest the development of early tolerance following weekly dosing of MET-233 and indicates the potential for very well-tolerated and simplified dose escalation regimens. Lastly, and importantly, candidate starting doses showed placebo-like tolerability. Both the 0.15 milligram and the 0.3 milligram doses had similar tolerability with placebo. In fact, in the 0.15 milligram and 0.3 milligram dose and in the SAD and MAD, only one participant experienced vomiting. To summarize, the MET-233 studies exceeded our pre-defined scientific objectives. Monthly dosing is supported with an observed half-life of 19 days. The pharmacokinetic profile of 233 is superimposable with MET-O97, and after five weekly doses, participants lost 8.4% of their body weight, which is class-leading. We also identified starting doses of 0.15 and 0.3 with placebo-like tolerability. These will be ideally suited to initiate dose titration regimens. Based on these impressive data, Metsera is continuing to advance MET-233 as both a monotherapy and in combination with MET-O97. Our co-administration study of 233 with O97 is ongoing and has been extended to 12 weeks, with 12-week data expected at year-end or early 2026. Our 12-week monotherapy study with MET-233 is also ongoing and is outlined on the right-hand side of this slide. We plan to explore no less than four cohorts, each with 12 weekly doses, including dose titration. We expect 233 to get to maximum weight loss with simplified titration and excellent tolerability. As we did with O97, we will explore exposure-matched candidate monthly doses at week 13 after MET-233 concentrations have accumulated beyond the threshold of well-tolerated receptor saturation. With that, I'd like to transfer it back to Whit. Thanks, Steve. Thrilled to have shared data today on our amylin analog that is ahead of the curve in multiple respects. MET-233 is a first-in-class monthly amylin with the longest observed half-life of any amylin we're aware of in development. MET-233 also has the potential for best-in-class characteristics, including weight loss at the high end of the competitive landscape, inclusive of GLP-1-based medicines and excellent starting tolerability. MET-233 and MET-O97 are poised to be combined as a first-in-category monthly multi-NuSH combination with the potential for category-leading weight loss with excellent tolerability in a simple, scalable single-chamber device. Finally, these data further validate Metsera's HALO platform as a foundational advance in peptide engineering. Metsera now possesses the two longest-acting therapeutic peptides in clinical development in any therapeutic category, with several more to come. With that, I'll thank everyone for listening, and we can turn to questions. Thank you. If you have a question at this time, please press star one one on your touchstone telephone. One moment for our questions. Our first question comes from Tim Anderson of Bank of America. Thank you very much for the opportunity. The data looks quite interesting. Is there the potential, or maybe you can tell us where you come out on the possibility of seeing too much nausea when you combine an amylin with a GLP-1? We have some combination data from Novo. When we had talked to a KOL recently, they raised the specter that amylin might be best off as a single agent versus in combination because the tolerability might kind of be too much. I know it might only be speculative at this point, but how are you thinking about the utility as monotherapy versus a combination agent? A question here that's similar to O97, which is switching from weekly to monthly, what tolerability might look like and efficacy? We have the limited experience with O97. I don't think you have any experience yet with amylin. Is there any reason we would expect amylin to behave differently than a GLP-1 when you go from that weekly transition to monthly? Thank you. Thanks for the question, Tim. Steve, maybe over to you for these. Yeah. Thanks, Whit. Tim, great question. Look, I think firstly, it is true that in general, we think that the adverse events are additive with a GLP-1 with an amylin. I think that thesis holds true. I think historically, we've seen tolerability rates that aren't ideal given the backbone of GLP and amylin. For us, we're encouraged because for both O97 and 233, we have a starting place, a starting dose that's exceptionally well tolerated. In fact, numerically, it's very similar to placebo. I actually think the key to getting combination therapy right is to start with a very effective, well-tolerated starting dose. Look, we're seeing weight loss of 0.5% per week in our lowest doses of O97 and 233, which, by the way, is plenty weight loss to initiate combination therapy when we're looking at long-term therapies. I think that while I can understand what a KOL is thinking in that way, I actually think we see a clear path to combine it with excellent tolerability, getting to a weight loss that will be north of 25% one day once we develop our dose escalation regimens. Yeah. Thank you for the question on weekly to monthly, the approach to weekly and monthly dosing. Yeah. Tim, as you know, we think the principles that we learned with O97 will directly apply to 233 for amylin. Given the biology, given the PK profile, we've largely de-risked our monthly program using an exposure-matched strategy to go to monthly. As you know, we're studying monthly dosing in our phase II B program, multiple monthly dosing. We expect to see very similar concepts when we go from weekly 233 to monthly 233 dosing. We think the path is we've done it once, and we expect to do it again with 233. Thanks so much. If I could just slip in one more. On tolerability, you said that it's probably additive when you combine amylin and GLP-1. Is weight loss purely additive, or could it be such that one plus one is not quite two? Because even though they're distinct pathways, maybe there's actually some overlapping underlying biology. When I think back to the CAGR summit data from Novo, it came in a little bit below what expectations were. I'm wondering if there was functionally something about those pathways such that One plus One doesn't quite equal Two. Yeah. Tim, a great question. I would think of it this way. I actually believe that GLP and amylin are complementary pathways, and it leads me to believe that it's additive. I think there are two challenges when you design these trials. One is the patient population, and I think we need to think about how we want to enroll participants who are open and receptive to losing north of 20%-25% body weight. I think the other thing that's important is tolerability. You have to start well to finish well, and I think that is foundational. I think as you've seen with Novo, as they redesign their phase III trials, they're going longer to give more time for more weight loss. In many ways, quickly following second, I think, will be helpful for us. I'm optimistic. Thanks so much. Our next question comes from Umer Raffat with Evercore ISI. Morning, guys. Thanks for taking my question, and congrats on the data. Maybe just to clarify the last question, you do expect realistically 25%+ weight loss on a combo basis, correct? And a couple of follow-ups. Yeah. We're anchored pretty hard on that, Umer. Thank you. We think that 233 with 097, given the potency, durability, and tolerability, we're aiming for 25% and North of that. Got it. Secondly, on the data shown today from a GI tolerability perspective, it was four out of six the vomiting at 1.2 mg dose and SAD, four out of six. In MAD, it was three out of eight, which, as you can imagine, on a percentage basis looks different, but again, it's like tiny n. I want to make sure we interpret that carefully. If you could just speak to that, as well as if you could also speak to the female ratio in the trial and what that implies for weight loss expectation. Finally, do you think this amylin program has potential to be a standalone 20%+ type of weight loss, or is that just too hard to say given how early we are? Thank you very much. Yeah. Umer, regarding your question around variability of tolerability in our SAD and MAD, what I would say is, look, we designed the SAD and MAD to explore dose range for efficacy and tolerability. We pushed the limits on both, essentially, with respect to early tolerability and early events. What I would say is if you look at the SAD and MAD tolerability data, 0.6 outperformed in the SAD than it did MAD. You see variance as you look at tolerability. I guess the thing I would anchor on that I think is most important is that we've identified starting doses, 0.15 and 0.3, that are exceptionally well tolerated. I think as a clinician, it leads to perfectly acceptable weight loss. I mean, exactly what tirzepatide saw in SURMOUNT-1. That gives us an on-ramp to dose escalate to get to 20% like weight loss if amylin is capable of that. Regarding the female-male sex distribution, as you can see in these trials, approximately 45% were female, and it was pretty well balanced between all of the dosing groups. With the exception of the 0.3 mg group in the MAD data, the sex distribution was seven men and one woman. That drives the very small numerical imbalance across the entire portfolio. Because I'm talking, I've kind of forgotten. Anyone have a third question? Just on total target weight loss for an amylin, can we get 20%? What do you think? Umer. Isn't that a great question? I don't know. Historical data would suggest that it might be less than that if you roll up all the amylin data. The thing I am confident about is that in our mono program, we will design studies that will unlock that answer. When we make a decision about mono versus combination therapy, we'll be confident in what that weight loss will be when we have the data. I think the answer is the data will show us that answer. Thank you very much. Congrats again. You're welcome. Thanks, Umer. Our next question comes from Seamus Fernandez with Guggenheim. Oh, great. Thanks for the questions. And congrats on the data. A couple of things kind of come to mind. Number one, in terms of the competitive profiles and perhaps what the team is going to be looking for at ADA from the REDEFINE one and two data sets that Novo will be publishing, just because I think in a lot of ways, the development of that asset is going to inform thought leaders' views. But your thoughts, I think, there would be really helpful in terms of where you're most focused and perhaps what you hope to learn from those data sets. And then second, the development of other amylin assets has actually been uniquely slow from our perspective. I can't really say whether that's a result of the lack of having another GLP-1 or GLP-2 to potentially combine with, or if it's a unique characteristic of amylin that slows down development. You guys seem to be really advancing very aggressively forward. Perhaps it's going to be because of the learnings from other programs. I'm really interested to just hear the opportunity that you see ahead to advance your programs quite a bit more quickly than perhaps we've seen from other players. Thanks. Yeah. Thanks, Seamus. I'll start on this one and maybe hand it over to Steve for comments as well. I think to your question on REDEFINE one, what I would say stepping back is that I think we have clearly shown with MET-O97, and then today have shown with MET-233 that our starting point for a combination is just fundamentally different from what Novo Nordisk is working with with cagrilintide, right? We have GLP-1 that is showing higher levels of efficacy, substantially better tolerability, all of that driven by this best-in-class half-life that is driving accumulation. Of course, ultimately, a monthly profile. Today, sharing amylin data that very much mirrors that, as Steve said, we have a lot of flexibility in how we engineer the combination to really optimize tolerability out to a highly efficacious ending point. Finally, as Steve mentioned, a lot of opportunity to learn from the challenges of the REDEFINE trials in terms of patient population enrolled and kind of level of flexibility in the protocol. I think there is growing understanding out there that this is just fundamentally different substrates than semaglutide and cagrilintide. Steve, any other comments from you on what you'll be looking for at ADA? Yeah. Look, other than emphasizing which comment that we have, we have a better starting position that I think gives us a potential lane. For me, and others might have different interests in these trials, but I'm keenly interested in the trial design, the patient population, the flexibility in dose escalation, and then ultimately, the reasons why people chose not to dose escalate, right? That's going to be the fundamental issue in the trial is were participants not dose escalating because of early tolerability, early weight loss, or achieved an ideal body weight. I think those three things, all of those things roll up into optionality for us as Metsera when we design our phase II and phase III program. Seamus, your question on timelines, it's a great question. Amylin is a new mechanism, and I think it's understandable that others have taken their time in unpacking what they have. I will say our commitment at Metsera has always been to minimize white space in our development programs and bring innovative differentiation therapies to patients as quickly as humanly possible. I think the 233 program is very much a case in point. As Steve mentioned, we actually have two 12-week studies already ongoing that were kind of informed by interim monotherapy data. We have a combination phase I, which we've extended out to 12 weeks really to answer more questions in that trial in the first inhuman study. We have the 12-week monotherapy cohorts, both of those reading out later this year, combination maybe early next year. Effectively, that should set us up for a broad phase II program with mono or combo in early 2026. I think we plan to keep the pedal to the metal on this program and apply the learnings we've had operationally on MET-O97, which has enabled us to deliver really at exceptional speed. I think you can see this emerging as a high-priority program for us, and we'll continue to operate at the speed we have in the past. Great. Maybe just one last question. As you look at the amylin mechanism, there had been speculation that there might be some lean mass benefits associated with amylin monotherapy itself that may be preferred. Have you seen anything along those lines, whether it be preclinically or in the clinic, that would validate that, or is that also something that you would be looking for in terms of validation from the REDEFINE program? Thanks. Steve, you want to take that from a clinical perspective? Yeah. From a clinical perspective, I think we're still waiting for validation of that data. As you know, companies are doing those studies or will be reporting those studies, looking forward to the DEXA sub-study and redefine and future MRI body composition studies with amylin. Being the clinician, I'm waiting for human validation from the DIO RAD models that people often cite. Brian, anything to add from a preclinical perspective? No. There's certainly data out there preclinically, but as Steve said, I think it's a safe human to push forward. Great. Thank you, guys. Thank you. Our next question comes from Prakhar Agrawal with Cantor. Hi. Thanks for taking my questions and congrats on the data. Firstly, on the data itself, could you talk about the broader safety profile beyond the GI adverse events? What events were common and anything to note of? What were the reasons for the discrimination? I had a couple of follow-ups. Yeah. To date, Prakhar, it's been a very clean safety profile. We've seen nothing in the SAD or MAD that is of concern. The discontinuations, there were three discontinuations in the MAD, none of which were due to adverse events, and two in the SAD, and similarly, no discontinuations due to AEs. To date, very clean safety profile. Thanks. As we look forward to the 12-week trial, could you provide some thoughts on what you expect the titration schedule to look like? The GI rates in the MAD trial were limited to the first week. Does a weekly titration make sense, or do you plan to go even slower? What doses will you go up to in the 12-week trial? Steve, you want to take that? Yeah. Look, I think the way I think about this is past is prologue, right? And for 097, we learned that four weekly dose escalation steps following a PK roadmap led to exceptional tolerability in our dose escalation dose. While they may be orthogonal mechanisms, I think the rules apply for tolerability. I think look for us to design a 233 dose escalation regimen that mirrors our 097 thinking with respect to four-week dose escalation steps. Of course, in the 12-week trial, we will study variability, right? We will lean into it on both fronts and expect to have variation in both tolerability and efficacy at the end of the 12 weeks. Ultimately, that data needs to inform our thinking on our final dose selection for phase III, and that's the scientific objective. With respect to early tolerability, we've seen it twice now. Given the PK profile of these ultra-long agents, we have exposure with weekly dosing increasing and the development of early tolerability. With the 233 data, I mean, 90% of the GI events, nearly 90%, were confined to the first week. To us, this really confirms the thesis that we develop early tolerability given the half-life and our dosing strategy. Got it. Lastly, from my side, given the data that you have seen today, does it change how you think about amylin as a monotherapy? What would you like to see in the 12-week trial to inform this decision of moving amylin as a monotherapy as well? Thank you. Yeah. It's a great question, Prakhar. So I mean, I think everything we are seeing in this data is extremely compelling to us in positioning 233 as a monotherapy, and we are absolutely focused on the 12-week cohorts in unlocking that profile. I think as Steve described, we have this half-life that drives accumulation, that drives early onset of tolerability, and that could eventually drive monthly dosing at week 12. We see a path to an extremely well-tolerated dose escalation profile that's actually substantially simpler than other dose titration and other amylins. Again, that half-life is basically titrating for you during each of those four-week steps, right? You can imagine a profile where we get to maximum efficacious doses in two steps versus the five or six that others may need to take, which is going to drive improvements in patient convenience. From the efficacy we're seeing, we can kind of see out to the future here, and we can see a path to really competitive weight loss. We absolutely plan on letting the data lead us. As of now, we see a very clear opportunity for 233 as a monotherapy, and we're looking forward to learning more later this year. Thank you. I'm showing no further questions. I'd now like to turn the call back to Whit Bernard for any further remarks. Great. Thank you. I think just finally, we wanted to conclude with sort of a reminder of the other upcoming catalysts that we have as a company, and there are many. Metsera has seven other data catalysts for 2025, all of which remain on track. We're looking forward to data from VESPER 1, the first of our three phase II studies of MET-O97, later this summer with data from VESPER 3 and phase III initiation at year-end. As Steve mentioned earlier, we're looking forward to amylin monotherapy later this year, and we've extended our phase 1 co-administration study of MET233 with METO97 to 12 weeks and expect that data at year-end or early 2026. We're also looking forward to weight loss and tolerability data from a selected lead oral GLP-1 in late 2025. Finally, really thrilled with the validation of the HALO platform today, and we'll be bringing GIP receptor agonist METO34, our third HALO engineered peptide, into the clinic with initial data expected in combination with METO97 in late 2025. Really thrilled with the progress we've been able to share today. A lot coming for us as a company, and look forward to more engagement later in the year. We're seeing many of you at ADA. With that, we'll close the call. Many thanks. Thank you for participating in today's conference. This concludes today's program. You may all disconnect. Everyone, have a great day.