Metsera, Inc. (MTSR) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to the Metsera top line results for Phase I trial of MET-233i. [Operator Instructions] 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 and 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 SEC disclosure documents. 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 Marso, our Chief Medical Officer, who will present the data; and Brian Hubbard, our Chief Scientific Officer; and Chris Visioli, 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 MET233'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-incretin 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 agonist. 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 2 important value drivers for amylin. First, in combination with GLP-1 RAs and other NuSH analogs, including Metsera's monthly GLP-1 MET-097; and second, as a monotherapy alternative for consumers who do not tolerate or otherwise prefer not to take GLP-1 receptor agonist. As we surveyed the competitive landscape in building Metsera's pipeline, we believe the ideal amylin agonist would differentiate on 3 attributes. First, it would be ultra-durable, enabling monthly dosing, optimized tolerability and improved scalability. Second, it would be potent against all 3 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 agonist and other NuSH analogs in a simple and scalable device. MET-233 was engineered to deliver on all of these attributes. Preclinically, we observed MET-233 to be extremely durable with an implied half-life intake suitable for monthly dosing and aligned to MET-097. We also observed MET233 to be 3x 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 petrelintide and GUBamy. And finally, we deliberately engineered MET-233 to be soluble across a broad pH range, matching the solubility range of MET-097 and all of the other peptides in our pipeline, enabling combination in a scalable single-chamber device. So 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-097. I'll now turn it over to Metsera's Chief Medical Officer, Steve Marso, to share how we did in delivering on these preclinical 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 1 and week 5; and three, identified well-tolerated starting doses. As you will see from the data, 233 has exceeded expectations in all 3 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 2 parts, a single ascending dose study and a 5-week multiple ascending dose study, each enrolled 40 participants. In the SAD, MET-233 was administered as a single subcutaneous dose across 5 dosing cohorts ranging from 0.15 to 2.4 milligrams using a 6:2 randomization ratio of active to placebo. In the MAD, MET-233 was administered in fixed weekly subcutaneous doses for 5 weeks across 4 cohorts, ranging from 0.15 through 1.2 milligrams using an 8:2 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 2 ultra-long-acting NuSH peptide analogs. The first 097, our GLP-1 receptor agonist; and today, 233, our ultra-long-acting amylin. 233 has an observed half-life of 19 days. 233 also has a delayed Cmax, prolonged absorption and very low variability. These attributes are well suited for both monthly dosing and combinability with 097. In fact, the PK profile of 233 and 097 are so similar that their multi-dose pharmacokinetics are nearly superimposable. This is a pop PK model based upon 097 and 233 PK data. 097 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 the result of 3 things: one, similar half-lives for both 097 and 233; two, a multifold accumulation of both 233 and 097 after 5 weekly doses; and three, the shape of the exposure curves are maintained within week and across the 5 weeks of measurement. These data confirm that 233 is ideally suited to combine with 097. And we have now initiated co-administration studies of 097 with 233. 233 also delivered impressive weight loss data. The figure on the left illustrates placebo-subtracted weight loss 1 week following a single dose in the SAD study. We administered 233 in doses ranging from 0.15 to 2.4 milligrams. The greatest weight loss observed was in the highest dose administered and was 5.3%. Weight loss also persisted 4 weeks following a single dose. In the SAD, we dosed to maximum tolerability. As such, we excluded 2.4 from 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 5 weeks, which was 1 week following the final dose. Doses of 233 range from 0.15 to 1.2 milligrams. Similar to the SAD, there was a dose-dependent weight loss. The highest dose administered resulted in the greatest weight loss, which was 8.4%. MET-233 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 2 to 5 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 097 development program. These data suggest the development of early tolerance following weekly dosing of 233 and indicates the potential for a 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 and 0.3 milligram dose in the SAD and MAD, only 1 participant experience vomiting. To summarize, the MET-233 studies exceeded our predefined scientific objectives. Monthly dosing is supported with an observed half-life of 19 days. The pharmacokinetic profile of 233 is superimposable with MET-097. And after 5 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-097. Our co-administration study of 233 with 097 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 4 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 097, 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. And with that, I'd like to transfer it back to Whit.

Thanks, Steve. So 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. And MET-233 and MET-097 are poised to become -- 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 2 longest-acting therapeutic peptides in clinical development in any therapeutic category with several more to come. And with that, I'll thank everyone for listening, and we can turn to questions.

[Operator Instructions] Our first question comes from Tim Anderson of Bank of America.

Thank you very much for the opportunity, and the data looks quite interesting. Is there the potential -- or maybe you can tell us where you're -- 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. So I know it might only be speculative at this point. But how are you thinking about the utility as a monotherapy versus combination agent? And then just a question here that's similar to 097, which is switching from weekly to monthly, what tolerability might look like and efficacy. We have the limited experience with 097. 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?

Thanks for the questions, Tim. Steve, over to you for these.

Yes. Thanks, Whit. Tim, great question. Look, I think, firstly, it is true that, in general, we think that the adverse events are additive with the GLP-1 within amylin. So 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 097 and 233, we have a starting place, a starting dose, that's exceptionally well tolerated. In fact, numerically, it's very similar to placebo. So I actually think the key to getting combination therapy right is to start with a very effective, well-tolerated starting dose. And look, we're seeing weight loss of 0.5% per week in our lowest doses of 097 and 233, which by the way has plenty of weight loss to initiate combination therapy when we're looking at long-term therapies. So I think that, while I can understand why 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. Yes.

Second part of the question on weekly to monthly, the approach to a monthly dosing?

Yes, we -- Tim, as you know, we think the principles that we learned with 097 will directly apply to 233 for amylin, given the biology, given the PK profile, we've largely derisked our monthly program using an exposure match strategy to go to monthly. And as you know, we're studying monthly dosing in our Phase IIb program, multiple monthly dosing. And so we expect to see very similar concepts when we go from weekly 233 to monthly 233 dosing. So we think the path is -- we've done it once and we expect to do it again with 233.

And if I could just slip in one more. So 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 1 plus 1 is not quite 2, because even though they're distinct pathways, maybe there's actually some overlapping underlying biology. When I think back to the CAGR, some of the data from Novo, it came in a little bit below what the expectations were. And I'm wondering if there was functionally something about those pathways such that 1 plus 1 doesn't quite equal 2.

Yes. Tim, a great question. And I would think of it this way. I actually believe that GLP and amylins are complementary pathways, and it leads me to believe that it's additive. I think there are 2 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. And I think the other thing that's important is tolerability. You have to start well to finish well, and I think that is foundational. And I think as you've seen with the Novo as they redesigned their Phase III trials, they're going longer to give more time for more weight loss. So in many ways, quickly following second, I think, will be helpful for us. So I'm optimistic.

Our next question comes from Umer Raffat with Evercore ISI.

Congrats on the data. Maybe just to clarify the last question, you do expect realistically 25%-plus weight loss on a combo basis, correct? Then I have a couple of follow-ups.

Yes. 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 4 out of 6 the vomiting at 1.2 mg dose in SAD, 4 out of 6. But in MAD, it was 3 out of 8, which, as you can imagine, on a percentage basis, looks different, but again, it's like tiny in. So 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. And then finally, do you think this amylin program has potential to be a stand-alone 20%-plus type of weight loss? Or is that just too hard to say given how early we are?

Yes. So Umer, regarding your question around variability of tolerability in our SAD and MAD, what I would say is, look, we designed the SAD/MAD to explore dose range for efficacy and tolerability. And we pushed the limits on both essentially with respect to early tolerability and early events. And 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. And so 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. And I think as a clinician, 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 amylins are 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 milligram group in the MAD data, there, the distribution -- the sex distribution was 7 men and 1 women. And that drives the very small numerical imbalance across the entire portfolio. And because I'm talking -- I've kind of forgotten the 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. But the thing I am confident about is that, in our mono program, we will design studies that will unlock that answer. So 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. So I think the answer is the data will show us that answer.

Our next question comes from Seamus Fernandez with Guggenheim.

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 redefined 1 and 2 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 GIP to potentially combine with or if it's a unique characteristic of amylin that slows down development. But you guys seem to be really advancing very aggressively forward. And perhaps it's going to be because of the learnings from other programs. But 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.

Yes. Thanks, Seamus. So I'll start on this one and maybe hand it over to Steve for comments as well. So I think to your question on redefine, one, what I would say stepping back is that I think we've clearly shown with MET-097 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 CagriSema, right? We have GLP-1 that's showing higher levels of efficacy, substantially better tolerability, all of that driven by this best-in-class half-life that's driving accumulation and then, of course, ultimately, a monthly profile. And then today, sharing amylin data that very much mirrors that, as Steve said, have a lot of flexibility in how we engineer the combination to really optimize tolerability out to a highly efficacious ending point. And then finally, as Steve mentioned, a lot of opportunity to learn from the challenges of the redefined trials in terms of patient population enrolled and kind of level of flexibility in the protocol. So I think there is a growing understanding out there that this is just fundamentally different substrates, semaglutide and cagrilintide. But Steve, any other comments from you on what you'll be looking for at ADA?

Yes. Look, other than emphasizing which comment that we have a better starting position that I think gives us a potential lane, for me, and others might have different interest in these trials, but I'm keenly interested in the trial design, the patient population, the flexibility and 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 we're participants not dose escalating because of early tolerability, early weight loss or achieved an ideal body weight. I think those 3 things, all of those things roll up into optionality for us as Metsera when we design our Phase II and Phase III program.

And then, Seamus, your question on time lines, it's a great question. Amylin is a new mechanism and so I think it's understandable that others have taken their time in unpacking what they have. I will say our commitment in Metsera has always been to minimize white space in our development programs and bring innovative differentiation therapies to patients as quickly as humanly possible. And I think the 233 program is very much a case in point. As Steve mentioned, we actually have 2 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-in-human study. And then we have the 12-week monotherapy cohorts. Both of those reading out later this year, combination maybe early next year. So effectively, that should set us up for a broad Phase II program with mono or combo in early '26. So I think we plan to keep the pedal to the metal of this program and apply the learnings we've had operationally on MET-097, which has enabled us to deliver really an exceptional speed. So 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. And maybe just one last question. As you look at the amylin mechanism, there had been speculation that there might be some lean mass benefit 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?

Steve, do you want to take that from a clinical perspective?

Yes. From a clinical perspective, I think we're still waiting for validation of that data. And as you know, companies are doing those studies or will be reporting those studies, looking forward to the DXA substudy in REDEFINE and future MRI body composition studies with amylin. So being the clinician, I'm waiting for human validation from the DIO rat 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 you [indiscernible].

Our next question comes from Prakhar Agrawal with Cantor.

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? And what were the reasons for the discontinuation? And I had a couple of follow-ups.

Yes. So 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 3 discontinuations in the MAD, none of which were due to adverse events, and 2 in the SAD, and similarly, no discontinuations due to AEs. So to date, a very clean safety profile.

And 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. So does a weekly titration make sense? Or you plan to go even slower? And what doses will you go up to in the 12-week trial?

You want to take that?

Yes. Look, I think -- the way I think about this is past is prologue, right? And for 097, we learned that 4 weekly dose escalation steps following a PK road map led to exceptional tolerability in our dose-escalation dose. And while they may be orthogonal mechanisms, I think the rules apply for tolerability. So I think look for us to design a 233 dose escalation regimen that mirrors our 097 thinking with respect to 4-week dose escalation steps. And of course, in the 12-week trial, we will study variability, right? So 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. And then with respect to early tolerability, we've seen it twice now. And given the PK profile of these ultra-long agents, we have exposure with weekly dosing increasing and the development of early tolerability. So with the 233 data, I mean, 90% of the GI events, nearly 90% were confined to the first week. And to us, this really confirms the thesis that we develop early tolerability given the half-life and our dosing strategy.

Got it. And lastly from my side, given the data that you have seen today, does it change on how you think about amylin as a monotherapy? And what would we like to see in the 12-week trial to inform this decision of moving amylin as a monotherapy as well?

Yes, that'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 those -- each of those 4-week steps, right? So you can imagine a profile where we get to maximum efficacious doses in 2 steps versus the 5 or 6 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. And so we absolutely plan on letting the data lead us. But 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.

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. Well, 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 7 other data catalysts for 2025, all of which remain on track. We're looking forward to data from VESPER-1, the first of our 3 Phase II studies of MET-097 later this summer, with data from VESPER-3 and Phase III initiation at lead year-end. As Steve mentioned earlier, we're looking forward to amylin monotherapy later this year, and we've extended our Phase I co-administration study of MET-233 with MET-097 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. And finally, really thrilled with the validation of the HALO platform today, and we'll be bringing GIP receptor agonist MET-034, our third HALO-engineered peptide into the clinic with initial data expected in combination with MET-097 in late 2025. So 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'll be 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.