Thank you. All right. Good afternoon, everyone, and welcome to the MBX Biosciences session. It's our pleasure to have CEO Kent Hawryluk. Rick isn't here, but Sam Azoulay is here, the Chief Medical Officer. As you know, MBX is developing a pipeline of precision endocrine peptides that can be customizable for extended release. We've got three programs here in the clinic for hypoparathyroidism, post-bariatric hypoglycemia, and now obesity. Two rare diseases, as well as one very, very large one. Why don't I leave it to you? Give a quick overview, Kent, and then we can go into questions. Very good. First, Annabel, I want to thank you for the opportunity to participate in your conference. Just to remind everyone, I will be making forward-looking statements and encourage you to look at our disclosures on our website. Yes, we have three clinical stage programs, and each is potential best in class and positioned to overtake multibillion-dollar markets. The underpinning, or the technology you referenced, precision endocrine peptide, or PEP, is now clinically validated, and it's designed to provide consistent drug exposures, long-time action, and convenient dosing regimens. If you look at all of our peptides, all of our PEP candidates, they're longer acting than the competition. Again, potential best-in-class profile. We are aiming to be a global leader in endocrine and metabolic disorders. We have a rich catalyst-rich year ahead. I'll be talking to some of those in just a second. Just reminding everyone that we're in a strong financial position following our follow-on raise in September, and we have cash into 2029. Let's review some of these upcoming catalysts across our pipeline for 2026 for once-weekly Canvuparatide, a PTH replacement therapy prodrug. We intend to have our end-of-phase II meeting in the first quarter of 2026. In the second quarter of 2026, two important readouts. We're going to present the full avail data at a major medical meeting, and as well, one-year follow-up from our open label extension study. In Q3, importantly, we plan to initiate our phase II global registration study for [Canvu]. For MBX 4291, this is a once-monthly GLP-1/GIP co-agonist prodrug, 12-week data in Q4. This is a really important catalyst for us because in this 12-week study, it's the target population, and we intend to actually demonstrate once-monthly dosing during the 12 weeks and better tolerability. For Emmapextide, as you mentioned, Annabel, our GLP-1 antagonist, this has a readout in Q2, results from our phase two A proof of concept study in PBH patients. I'll also just point out, in our growing obesity portfolio, we have additional programs that are moving through lead optimization and preclinical development. Again, a real catalyst-rich year across all of our product candidates. Excellent. Let's start with Canvuparatide because that's the exciting, most recent catalyst that came out or data readout that came out. Can you just give us a quick review of the key takeaways there just to make sure that everyone is on board with the same information? Sure. I'll lead off. We could not have been more thrilled with the results from our phase II AVAIL study, which showed, in our view, definitive best-in-class profile. We had a 63% responder rate at the 12-week primary endpoint with statistical significance, and that actually grew to 79% at six months in the OLE. I think fair to say that really outpaced many expectations and very clinically meaningful and validating for our PEP platform as well. Sam, anything to add on the phase II? Sure. I mean, Canvuparatide is a PTH replacement therapy. What we would be looking at, the two key organs, the kidney and the bone. If you look at urine calcium excretion, in the target population of patients with elevated urine calcium at baseline, there was a very good reduction in terms of urine calcium. It took more than 200 milligrams per 24 hours. The same thing with the bone. The bone turnover in these patients is reduced, and there is a reactivation of the bone turnover as marked by the two biomarkers, CTX and P1NP. Really good confirmation, not only on the response rate, but also on the organs. I guess that's important. As when we think about this as a chronic treatment, you want to make sure that this is the safest treatment possible, that you're not causing kidney damage, you're not causing bone damage. Is six months enough of a signal for physicians to start getting comfortable with that fact? We've heard that from KOLs. What we've done, too, is provide some market research recently. What we saw when we presented to the market research firm, when they presented our profile, our data from the phase two on a blended basis, and then presented the once-daily PTH replacement therapy profile, which they probably recognized, they chose ours, right? They really emphasized that in terms of switching, they would see switching patients from a once-daily to our once-weekly. As well, for new patients, ours would be the drug of choice. We think that's really validating for the point I made earlier that we believe we could be the category leader in this established and growing blockbuster market. Newly established, kind of. Pretty newly established, but going strong, I would say. Just talking more about feedback from KOLs and even patients to the data, we had the chance to present these data quite recently, last month, I guess, to the hypopara community at the Hypopara Association International meeting. Just a great response. Sam, any insights? Yeah, I think it was very interesting to discuss with the patient. They know their disease very, very well. In fact, in some cases, better than the endocrinologist. They were very, very interested by the weekly administration. Certainly, a daily administration is a progress, but there is significant room for improvement. The patients were very vocal in showing their interest for the weekly administration. Yeah. This is also an interesting treatment because patients actually feel the symptoms of disease if they're not taking the treatment or adequately normalized on their calcium or PTH. I imagine it's motivating for them. What are some of the signals that you got for that quality of life? It's anecdotal, I know, but I like this story. There was one patient who was suffering from hypoparathyroidism, taking a lot of supplements, went into our program, was treated by Canvuparatide, and was able to run a marathon. I can't even run a marathon, so. I cannot, but. I won't. It was a patient feedback, and it was really a nice feedback. Yeah, I refuse. Okay, great. Just the percentage of patients that went into the open label extension study was pretty remarkable as well. Excellent one, which is 94% of patients went from the double-blind period to the open label extension. Excellent number. Post six months, would it still be at that 94% level, or do you see patients dropping off? We'll take a look and then Q2. Didn't you say the 12-month was Q2? Okay. All right. I guess we'll find out then. Aside from the obvious administration profile, what are some of the components that you're baking into the phase III? What's your wish list for phase III, essentially? The phase II was such a success and really an opportunity with the phase III to optimize further. And the physician, going back to the market research, physicians said that with comparable efficacy and once weekly, that will drive category leadership. Looking even beyond that, that's just transformational. I'll let Sam. Yeah, it was a phase II study. One of the goals was to find out what will be the ideal starting dose of phase three. We were able to identify that between 400 and 600 micrograms would combine both great safety with efficacy, great efficacy as well. It's likely to be between these two doses. We will be looking also beyond even being similar to the competition, even further differentiation, such as urine calcium. We can target this as an indication that could be in our label. Did Ascendis just recently come out with any urinary calcium data? It's not in their label. They came up also with something we observed in our study with an improvement of the renal function. That's something also we observed. Okay. So, you're going to be looking at that as well? Yeah. Absolutely. Okay. I guess one of the key issues, well, it's not really a key issue, but the tricks of phase three is you want to balance the starting dose with your AE. The 400-600, I guess, is the target, I guess, dose. Are you going to be looking to start maybe lower or still looking at increments to be able to give patients flexibility to titrate up or down the same way you did in the phase II? That's something that will need to be discussed with the regulatory agencies to agree. Definitely, that's a dose, as I said, the starting dose should be between 400 and 600 micrograms weekly. From there, you increment the dose, likely to be every other week, while at the same time decreasing the supplement. Similar to the phase II. Absolutely. Okay. Similar design. Yeah. Okay. What do you consider success in phase III? What kind of target profile are you looking for? I mean, you already have a good target profile here, but what can you potentially design into the phase III? Yeah, I think that Sam said it nicely. We'll be really pleased to, again, once again, show competitive treatment response and great safety and tolerability profile with a once-weekly, the first once-weekly PTH replacement therapy. Anything else would just be gravy. We'll look at that, but we'll be really excited to confirm what we've already seen. Okay. So, no numbers, but just I got you. I'll be looking at the Ascendis efficacy and saying this is once-weekly. Let's remember that I shared the 79% at six months figure of treatment response. Let's remember that the once-daily competitor in their U.S. label, which they can market to in the United States, has a 69% treatment response. Okay. I got that. All right. Let me move on to 1416, which is the GLP-1 antagonist for PBH. That's the other upcoming catalyst, similar to, I guess, this phase two. You're looking to take a what's potentially going to be a once-daily drug and make that a once-weekly. I don't think we have data yet for the once-daily PBH antagonist, but maybe you can just first talk about the indication, what you're looking to achieve here, and what you've learned about the PBH space since starting this development program in actual patients. Sure, sure. In three parts, just starting with the huge unmet need. This is a chronic, serious, rare disease with high unmet need, no approved pharmacotherapy, and significant prevalence. We estimate over 125,000 U.S., prevalence. We've seen even higher figures used in the market, in fact. Devastating on quality of life, the overhang, the uncertainty of when an episode of hypoglycemia could occur causes folks to really radically change their lifestyle, even possibly not work, drive, etc. A therapy is needed, and GLP-1 antagonism is a clinically validated mechanism of action. You referenced a, I would call it a first-generation GLP-1 antagonist that has a quite short half-life, measured in two to three hours. Importantly, you want to have full coverage, day and night. What we did is, we look at a humanized backbone for GLP-1, and then we have fat acetylation to extend time action, and showed 90-hour half-life in our phase I study in healthy volunteers. That is what we want to show as we continue developing this product candidate. What we have seen in the space is that this need is persistent. Sometimes we get the question, will Incretins reduce bariatric surgery? We are not seeing it. One of the things from that KOL site is the advantages of bariatric surgery in real-world setting for providing meaningful and sustained weight loss, better than Incretins can deliver. We see this market as continuing and growing. I mean, not only that, but the prevalence does not go away. I mean, it's still 125,000 at least. How did you move from 90,000 to 125,000? How are others getting to 130,000-150,000? How are you getting to these numbers? Yeah, and I just heard one from a KOL who was closer to 400,000. I think what we did is did some quantitative market research and just looked at the incidence applied to the bariatric surgeries and then the base or the prevalence from past cases of bariatric surgery. Okay. What are the key metrics that we're looking for in this upcoming phase II, and what does it power to show? Or are we not yet there in terms of that stage of development? This phase II study is in patients, and it's a single-arm study in 10 patients, and we're evaluating different doses of Imipremine. The pharmacodynamic, we're looking really at the pharmacodynamic effect. Translated by glucose nadir, we want to increase the nadir. We want to see a decrease in insulin secretion, and the same thing with the C-peptide. We know that these three parameters are also correlated with the clinical symptoms of hypoglycemia. If you have a good pharmacodynamic effect, it will be translated in a clinical. I didn't tell you, but it will be through some sort of activation of the system through a mixed meal tolerance test. Okay. I see. Are you looking, or are you also measuring hypoglycemic events, or is it not at that stage yet? It's not in this study because it's a single dose. We're evaluating different doses, but it's single-dose administration. It will be later. What we want to see later in the next phase is really the full coverage during the week, including the night, as Kent alluded to. Night is extremely important. These events are completely unpredictable, and it will be very interesting to compare with the other competitors of Excitid, which has a very short half-life. Okay. I guess the AmLex phase II data saw a 50% reduction in hypoglycemic events. Do you see that as a success, or what is meaningful for you? I mean, it's a success. I would say that it's an improvement for the patients who are suffering. Their life is damaged by these symptoms. There is nothing. It's a strong unmet medical need. I would say, yes, it's an improvement. We'll be coming with a weekly administration. It will be a further improvement. Also building on that, what Sam said earlier, look at the timing of these episodes of hypoglycemia, because it's really important to be able to prevent this nocturnal hypoglycemia. Okay. So, I guess we'll be seeing that coming up in second quarter. Okay. And then the last program, which is obviously a program of real interest right now, given the obesity landscape, you're yet another GLP/GIP agonist coming to market. This one's a little bit different, though, because it's a prodrug. So, tell me, what are the benefits of it being a prodrug, and what does that do for your profile? Thank you for highlighting that key difference, because when we look at so-called ultra-long-acting incretins, we don't see any that have firmly established that they can deliver once-monthly dosing with acceptable tolerability. That is the aim of this program, and that's built into the design of our 12-week phase one part C. I would even say you could consider it like a 2A, because it's in the target population of adults with a BMI over 30. Looking at the technology, just briefly, there are two key PEP technologies that work synergistically to create the profile that we think will be best in class, monthly with a better tolerability. We have our prodrug, which provides the gradual controlled release of the active drug at a specified rate, sort of programmed, if you will. We have fat acetylation of the active drug to create the long-time action once converted. Kind of I talk about a two-stage rocket, if you will, to create the long-sustained time action. What is really essential is that we have a gradual rise to the maximum concentration. The KOLs tell us that for the Incretins, the fast rise to Cmax is what is creating the GI distress, the nausea, the vomiting. We think that with our approach, we should not only be able to see exposure throughout the month, but better tolerability. Okay. So, talk about the design of the trial, because you have three parts here, and one of them could potentially, I guess, be extremely informative for you. So, let's go through that trial design. Yes. We have three parts. The first one, which is the SAD. From the SAD, we'll learn about the PK, the PK profile, just to start, which is really this, Kent was referring to, this smooth raise to the Cmax. We will learn about tolerability, how far you can go. We will be going then to an MAD, classical MAD, four weeks. The drug, MBX 4291, will be given, administered every week for four weeks. Again, you will learn about PK, and you will learn about tolerability. The most important part is likely to be the 12-week administration, where we will be giving the drug every week for four weeks, and potentially just after every month. We can think about different paradigms in order to reach the steady state. Really, this piece is extremely important on multiple dimensions. The first one, which is a PK, it will be a real monthly confirmation, because that will be the drug will have been given monthly, opposite to what has been seen with competition. That will be really a confirmation. You will see the tolerability, that confirmation through the 12-week administration. Last, you will see the weight loss. We'll have an appreciability of the clinical benefit. Okay. I guess curious about starting with a weekly dosing instead of going straight into a monthly. Why did you design it that way if you're truly a monthly drug? The goal is to get to the steady state as smoothly as possible with a peak-to-trough ratio, which is as minimum as possible, or the best possible peak-to-trough ratio in order to improve the tolerability. We think that the goal is to get to the monthly, but if you take four weeks to get to this stage in a chronic treatment, it doesn't really matter. Especially, Annabel, when you consider that today, patients going on Zepbound may need to titrate for, say, up to six months. To have a dosing regimen like this would be a real advantage. In terms of the monthly, I think it's just clear that for a chronic disease like this, when you're taking this for the rest of your life, once monthly is going to really make a big difference for patients. In terms of the four weeks, are you doing it in dose increments, or are you starting at the dose that you're going to go with? That's, I guess, the little confusing part. Yeah, likely we'll start at a lower dose than the monthly, and the monthly will be at a higher dose. Okay. So, how does that work? If it's a true prodrug, so are you going to, I guess, if it's a monthly dose and you're like, it's already a prodrug that you're releasing slowly, I guess. It dovetails. It dovetails. It just dovetails onto. That's exactly the steady state I was talking about, reaching the steady state. We've modeled this. We now have really sophisticated models based on all the PEPs that we've been developing, and even others from the field that we can feed into this model. We have really strong conviction that we'll be able to show once-monthly dosing in this 12-week study and have a quite flat peak-to-trough. I think this is a major catalyst for the company. I can't wait to have the results. Yeah, I mean, it's going to come up pretty early, so. Q4, 26. Why do not we talk about the landscape then? I mean, I know there are several who are trying to develop more extended dosing monthly. Can you sort of talk about what you see out there and where you fit in, how that, I mean, obviously, we understand how you differentiate, but what are your thoughts about the landscape now of companies that are going monthly or trying to go monthly? Great. One thing is clear. Pharma has spoken. They want a once-monthly. They need a once-monthly, and they're going to get a once-monthly. That's the bottom line. We believe we have one. We believe that with this 12-week study, we can show that definitively. Importantly, ours is a GLP-1/GIP co-agonist, not a monoagonist. Lilly's done the hard work to show that this is the gold standard, right? Even in head-to-head studies against the monoagonist, these two mechanisms working synergistically. We have a lot of history with these targets. Annabel, you probably know what I'm going to say, but you've probably heard this before, but the inventor of this molecule, 4291, Richard DiMarchi, invented the first GLP-1/GIP co-agonist. I was saying earlier, I know because I was there. This was at our previous company, Marcadia Biotech. It directly inspired tirzepatide, and great that it's having such a benefit for patients. We think now applying our clinically validated PEP technology, we're going to advance the field once again and bring a best-in-class obesity agent that just hasn't been seen others. Again, a monthly with the tolerability in these mechanisms, GLP-1 and GIP agonism. There's one out there that's a GIP antagonist that is not as established. Tolerable. There's that, but also just mechanistically, that is not as established as the dual agonism that we've chosen to advance. Okay. Great. I guess maybe you want to comment in context of, I guess, other people's focus on small molecules, and I guess the scalability of small molecules and the COGs related to small molecules are much better. Maybe talk about it in terms of that side of the market that's developing. I believe small molecules could have a place in the obesity landscape. Let's just remember how large this category is, this market, and it's heterogeneous, right? The patients are different. They will need different treatment options. What is also clear from pharma is that they see a convenient, infrequently dosed Incretin peptide being the mainstay treatment for chronic use. That's where we fit in. I think small molecules remain to be seen in obesity. You have to get it right in terms of efficacy, tolerability, avoidance of off-target tox, which can rear its head very late in development inconveniently. We will see. I'm really excited about our peptide approach. In terms of COGs and API, been in this field and peptides for 20-plus years, there's a bit of a Moore's Law. We're getting to better and better manufacturing synthesis of peptides and the cost coming down, down, down. Okay. I guess we shouldn't forget that these are chronic therapies. Most of those patients who start on therapy will need to stay on the rest of their lives and could potentially be switching between a lot of these Incretins over time. I imagine that's one of the benefits there. I guess at what stage do you think you're realistically potentially going to partner this out? Do you partner this out? When do you partner this out? I can't speak to specific BD activity. Do you want to partner this out? I think when you look at longer-term studies and launching in a general practice kind of indication, a strategic partner can have a real place. I would just say there's also a track record here where Richard DiMarchi and I in previous companies have transacted obesity and metabolic disorder programs with the likes of Novo Nordisk, Lilly, Roche, Merck, and know the players very well. Do you see the current activity in the BD space? What are your opinions on the current activity for BD and MNA? I thought that the Metsera battle was pretty interesting. What do you think that they were going after there? Fervent interest, and it is showing differentiation around the dosing frequency in any other handles. We think what is important is we have an obesity portfolio. Beyond 4291, we have other programs that we will continue to develop and start to talk about. I think we are just in the early innings of this game here. Obesity is a major, it is the disease of our time, and we think we will be leaders in it. Do you think that we could see other combinations before the data on this program comes out? Or are you waiting to validate this program before you introduce any new combinations? I think we've just about used up our time. I think with 4291, that's our main focus today. This catalyst with the Q4 is going to be, I think, really a super exciting one. More to come about our obesity portfolio later. I'll have to say I've never had a company put a hook on me. Congratulations. That's a first. That's what we aim to be. All right. Thank you very much. Out of time.