All right. Good morning, everyone. Thank you very much for being here. It's a pleasure to welcome you to TD Cowen's 46th Annual Healthcare Conference. My name is Tyler Van Buren. I'm a Senior Biotechnology Analyst here at TD Cowen. For our next session, the first company session of the day, we're very pleased to have a hybrid presentation and fireside chat style Q&A with MBX Biosciences. It's my pleasure to introduce Kent Hawryluk, the President and CEO of MBX, and Salomon Azoulay, the Chief Medical Officer. It's a privilege to have you both here. I'll hand it over to you.
Thank you. I want to thank Tyler and the Cowen team for the invitation to participate in this wonderful conference. I'll remind everyone that we'll be making forward-looking statements. I encourage you to review our risk factors and other disclosures in our SEC filings, which are on our website. For those of you who are newer to the story, MBX Biosciences is pioneering Precision Endocrine Peptides or PEPs with a passion to give patients freedom through convenient and precise therapeutics to treat their endocrine and metabolic diseases. Our PEP platform technology is clinically validated. We take peptides, which are miraculous molecules, and engineer them to deliver slowly rising and steady drug exposure. This is principally to improve tolerability, we can also have less frequent, more convenient dosing regimens. 2025 was a transformational year for the company.
We had spectacular phase II data in our lead program in hypoparathyroidism, HP, and we advanced our first obesity candidate into the clinic, MBX 4291. This is a once-monthly GLP-1 GIP coagonist prodrug. Building on that, 2026 has the potential to be even more important for the company as we initiate a global registrational phase III study in HP with once-weekly canvorparotide and report out 12 week multiple ascending dose data in our 4291 program with once-monthly dosing. We also anticipate expanding and advancing our obesity portfolio overall. Just taking a quick run-through of our catalyst for 2026. In once-weekly canvorparotide this quarter, we have an end of phase II meeting, and coming out of that meeting, we'll be able to share more details on the phase III study design.
We anticipate a update on the phase II with one year follow-up data in Q2 of this year. We're on track to initiate our registrational phase III study in Q3 while we create our commercialization plan anticipating success with this phase III study. In obesity for MBX 4291, I mentioned our 12 week data. This is important and being designed to show better tolerability as well as once-monthly dosing within the 12 week study. That's Q4. We're on track to declare development candidates in Q2 and Q3, new once-monthly candidates that leverage our PEP technology and importantly, target new proven obesity targets or mechanisms, amylin and glucagon. We're in a strong financial position. We have runway into 2029, which enables us quite a bit of flexibility or optionality in advancing these programs toward commercialization.
Given that our PEP Technology forms the basis of this pipeline, let me just share a little bit under the hood of this technology. Our PEP Technology is clinically validated. It's differentiated and proprietary. Its architect is Dr. Richard DiMarchi, our scientific founder, who is a leading light in peptide chemistry. He's the inventor of Humalog. He also invented the first GLP-1 GIP coagonist and the first GLP-1 GIP glucagon triple agonist. He has been a pioneer in the field of obesity for decades. The idea is we start with really innovative peptides, which are optimized for potency, and this includes multiple mechanisms in a single peptide, à la our GLP-1 GIP coagonist. As well, we optimize for dose volume and shelf life, other properties to help patients' lives. Really differentiated is our programmable prodrug, which provides slow release of the active peptide.
This is under physiologic conditions. It's a natural chemical process. No enzymes are required. The idea here is by this slow release, we provide more tolerable experience for the patients. The third is fatty acylation. This is a means of extending the time action or the time in circulation or the bloodstream by binding albumin, a circulating protein. Here we can extend the time action and reduce the dosing frequency, which is a major benefit to patients for convenience. It's the strategic combination of these technologies that allows us to create, in our view, best-in-class product candidates. We're excited about this year to further demonstrate the power of this technology across our existing candidates and as well two new candidates in obesity.
I really believe that we're positioned to become leaders in obesity because while other companies are focused on extending the time action to potentially have monthly dosing. We believe that this slow release will provide, in addition to, monthly dosing, better tolerability.
Wonderful. Thank you so much for that introduction, Kent. We'll start with canvorparotide, of course. The stock has done quite well since the summer, but I still feel like people aren't fully appreciating the data that you guys posted for the Phase II AVAIL data. Maybe we could just start with some brief highlights of the most important aspects of the data and what gives you conviction that you've got a weekly that's at least as good or potentially better than the current daily injection.
Yeah. Thanks, Tyler. Let me start with a reminder of the study design, just to put in the context. It's a 12 week, placebo-controlled study, and we evaluated three doses of canvorparotide, starting dose 400, 600, 800 micrograms as compared to placebo. We could increase the dose by the increment of 200 micrograms up to 1,600 micrograms. That's just to put it in the context. The primary endpoint was a response rate, a response rate at 12 weeks. The response rate was made of a composite endpoint, so hard to reach, which was three elements, three components.
The first was normalization of serum calcium between 8.2 and 10.6 mg/dL, no active vitamin D at all, zero, and the calcium supplement, which is in the dietary dose of a maximum of 600 mg per 24 hours. That to put into context. At the end of this 12 week period, we observed three response rate with canvorparotide overall, when you combine all the treatments, significant, statistically significant versus placebo. At the end of this period, the patient had the option to get into the open-label extension. 94% of these patients choose to, which is a really, really good number. They went into the open-label extension, and we disclosed also the results at six months, and we obtained 79% of responder, which is pretty impressive at the end of the six months period.
Wonderful. Now, maybe that's a good segue going into the upcoming data in Q2, the 52 week OLE data at a medical meeting that you mentioned, Kent. You know, what should the expectation for that data be? Will there be any new endpoints to focus on as we think about the upcoming presentation, or will it be simply just maintaining responses over the long term? And also what did YORVIPATH show in their long-term data?
Yes. At the one-year data, we show the same data that we show at six months, but at the one-year time point. The same retention rate, the response rate. We look at the secondary endpoints such as urine calcium, et cetera. If you remember back, we had excellent results in terms of biomarkers. CTX and P1NP, which is reflective respectively of the catabolism and the anabolism of the bone, which is also a translation of the bone being back into the game, if you want. These patients do not have a bone turnover, and here they are. At one year, for the first time, we are going to disclose a bone mineral density, BMD, evaluated through DEXA, which is the exam.
What we're expecting is to look at a decrease in the BMD because they start very high. The decrease will be within the normal value when you match patient with similar age, gender, ethnicity, et cetera. Decrease, but in the good way. That's what we would expect to release at one year. We'll be also releasing safety tolerability as usual.
Okay.
You asked me, I think you asked me also the question about the response, right?
Yeah.
It's an open-label extension study. The main goal of open-label extension study without placebo, et cetera, is really to look at safety and tolerability. We started very high with 79% responder rate at six months. The endpoint is very stringent. We will be looking, as I said, at the response rate at one year. As compared to or if you look at YORVIPATH at the six months showed 69% in the U.S. label. I'm referring to the U.S. label. 69% response rate dropping around 39% at 52 weeks and 78 weeks. That's what we say so with YORVIPATH.
What led to that decline with the longer follow-up?
That's a good question for which we say haven't found an explanation. We know, and it's well described now. There's a loss of response over time.
Okay. If you guys were able to maintain your response from six months better, that would be impressive.
Yeah. Don't remember. Remember, we start very high.
Yeah, yeah.
79%.
Yep, understood. All right. The phase III trial that you all mentioned, still on track. Can you just tell us what all needs to be done to get that phase III up and running and how long it might take to get to top-line data?
We are very much on track across all the functional areas. Coming into phase II meeting with the FDA, we'll be able to share more details on the study, as I said. We see a clear path to initiating the phase III in Q3. We are working actively with the CRO on site selection, finalizing the Protocol. Also, in other areas, we are scaling up to support the study with our intended commercial device. We think that's really an important feature of our phase III and quite de-risking. All systems go and really excited to get started. As I mentioned, we're already underway with pretty significant pre-commercial activities as an organization, including, by the way, recruiting a chief commercial officer this year.
That's great. Since you mentioned the device, can you elaborate on it at all?
Sure. It's a single-use once weekly device that's very reliable and easy, convenient for the patients. One dose strength and disposable once weekly.
That's great. For the phase III study design and size, can you say anything about that and how it might compare to YORVIPATH's registrational trial, or do we have to wait for you guys to get the FDA feedback and kinda report the final?
Certainly you're right. We need to get the FDA feedback, the final minutes from the Munich meeting. But in terms of sample size, we're in the ballpark between YORVIPATH and what we are proposing being in the ballpark of between YORVIPATH and the eneboparatide. That's as a primary endpoint, we are not going to recreate the wheel, right? It's been paved by Ascendis and AZ, and we are going to follow in terms of primary endpoint, which will be the composite endpoint as I described with some variants, but roughly the same. We'll be looking also at other secondary endpoints such as urine calcium, et cetera.
Great. A lot of focus on the ongoing YORVIPATH launch and the hypoparathyroidism market. Do you have any perspective on how that launch is going, how it might change with more products, and also what you think the ultimate size of the market is?
Believe it's a real advantage to MBX that the launch of once-daily YORVIPATH is going pretty well. It's already on about a $500 million run rate after approximately a year into the launch. What we have found in talking to doctors and patients through, you know, anecdotally and more formally through primary market research is that overwhelmingly the market is demanding a once weekly. This isn't a surprise. We see this in other indications. Typically, when you move from a once daily to a once weekly, you have a quite rapid uptake of the switching to the once weekly. You also see expansion of the market. Patients come in and begin taking a subQ injection. We've seen this in Type 2 diabetes, obesity. You can name the indication.
We found in specifically in our market research that all of the doctors interviewed chose once weekly based on just having a comparable profile in the ballpark in terms of efficacy. That's important, and patients as well. I would just say I witnessed the excitement around once weekly with the docs and the patients at last fall's Hypoparathyroidism Association conference. Salomon and his colleagues presented our AVAIL phase two data, and they were a little bit treated like rock stars, if I may say so. A lot of interest in being investigators in the phase three, which I think will really help enrollment and build a lot of momentum heading into our phase three and potential launch.
That's great. Let's move to obesity. Obviously, a lot of interest continues in that space. The Metsera acquisition was quite exciting. I think, you know, the unique PK/PD profile of your prodrug converting to active drug at kind of a straight line self-titrating, but then straight line infusion-like profile is if you could draw up the ideal profile to reduce GI toxicity with a monthly, that's your profile, right? Really excited to get the clinical data in Q4. Maybe you could walk us through exactly what will be reported in Q4, how many patients, how many dosing arms, what we should expect from that update?
I can start with these Phase I studies at which is running. In fact, it's a Phase I in subject with BMI at or above 30, so in the target population. The study is divided in three parts: SAD, MAD, and the 12 week. Culminate with the 12 week. Each SAD will inform the MAD, the MAD will inform the 12 week, like a stage approach if you want. In the SAD, we are going to test different doses of MBX 4291 and evaluate the tolerability. Back to the PK, the slow raise to the Tmax or the Cmax, we know it's correlated to tolerability and also the fluctuation.
The first, you're going from the SAD, you're going to understand how far you can go in terms of concentration and link it to the tolerability. Also you will learn about your PK. You will learn more in human about your PK and the potential for monthly, right? That's the first stage. The MAD, it's the same thing, but weekly administration for four weeks. You will also learn from the tolerability how much higher in terms of concentration you can go and get a good tolerability. PK, the same thing. The most important thing will be the 12 week administration. For now what we are planning, as I said, each step informs the other.
We are anticipating, and for now we are, we'd like to evaluate a weekly administration for four weeks, followed by a monthly administration. Then you will and a monthly administration, and then you get a result at 12 weeks. We'll have three types of information here. The first one, if I start with the PK, you get the full PK profile with a monthly administration, and you know exactly how far you can go. The second one, which is tolerability. You know exactly how it link now the tolerability with your PK profile. The third one will be an idea about the weight loss. If we combine these three elements, and we are successful, can assume that the compliance will be good. That's a really nice target product profile, if you want. By the Q4 of this year, we will have the picture.
Yep. A very logical kind of stepwise de-risking, a program that you're starting with here with those three phases. I guess as we think about the 12 week weight loss, what do you think is the bar here? There's so much data out there, and every day I feel like we get a new data set, but curious what you guys think is the bar for this early study.
I think that I wouldn't commit on the bar. I think for this monthly administration, the most important thing is to confirm the monthly, to confirm the good tolerability, and to be competitive at 12 week in terms of weight loss. That's what will be my target.
Exactly. These mechanisms are well known. Let's remember that MBX 4291 is a GLP-1 GIP co-agonist. It brings in the two gold standard mechanisms for lowering weight, which time and time again, even recently, win head-to-head against other mechanisms. We know that over time we're going to see the weight lowering, but we're past the point of sort of the race to see a high weight-lowering value because people understand now that you have to have better tolerability or the patients will discontinue use of the drug or they won't be adherent.
We talked about Cmax, Tmax affecting GI toxicity and safety profile, and you'll figure that out with this initial trial going throughout the year. Is there anything else with respect to the PK/PD that you saw pre-clinically that is worth elaborating on for the audience?
I would point out that we have high conviction that our time to half Cmax is greater than 21 days. I think that's really meaningful because you don't wanna just have coverage of the month. You wanna have that kind of lower peak to trough and that steady exposure, Tyler, that you described so well. I couldn't do better myself.
All right. Then, just to, I guess, elaborate on... I mean, I guess you touched on the titration schedule with the weekly for four weeks and then going to the monthly. Do you guys have a high level of confidence that that's what we're gonna see in later-stage trials, and it's just a matter of picking the right dose? Is that how we should think about it? And how it compares to titration schedules with other therapies out there.
I think, back to the trial design, I told you that each step will inform the next.
Yeah.
That where we will be able to define through modeling, et cetera, the best profile in terms of titration for getting to the monthly. As I said, the description I gave you for the 12 week was in our initial thinking, but we can adjust, and we can have more than one cohort, as an example. Really the goal is to get a good tolerability with a monthly administration.
Got it. Before we go to PBH, just triple G, amylin, I guess it's not terribly surprising that you guys picked those targets. I guess curious to hear. It sounds like you guys are pretty close to development candidates. Just curious to get your any additional thoughts on those programs. You know, why you picked them, if it really comes down to your differentiated technology against these targets versus others like we have with MBX 4291 or what your thoughts are on those targets.
These are really important targets. It's our goal to be obesity leaders, as I shared, and to have a quite balanced and robust obesity portfolio. We're excited to round out the GLP-1 GIP with now an amycretin. What this does is combines the amylin or DACRA mechanism with incretin in a single peptide, where you can achieve some synergy with combining these mechanisms in a single peptide. Amylin is interesting to a lot of folks. The data looks promising with other programs, and yet there's still tolerability concerns or limitations. I really believe that this differentiated PK profile, which is now clinically validated with canvorparotide, I believe will be with 4291 in obesity, will carry through.
Glucagon is a mechanism which seems to turbocharge weight lowering. We have a lot of experience with this going back over 20 years. Richard DiMarchi, as I mentioned, was the first to kinda teach the world how you could create a triple agonist and safely lower weight with this mechanism in obesity. I would just say that the recent data for retatrutide showing nearly 30% weight lowering caught people's attention, as did the tolerability. I'm really excited to see how we can kind of get the best of the efficacy as well as better tolerability with our candidate. We are on track to nominate these or select these candidates in Q2 and Q3 of this year.
That's great. Now we'll spend the last few minutes on imapeptide and PBH. I am quite confident you guys are not getting much value for this program at the moment, but you have the upcoming phase two study data in Q2. Can you remind us what we're gonna receive from this update? How many patients? What data points will you be sharing? You know, what can we learn about imapeptide, especially as it relates to competing programs?
It's a phase 2A study in the targeted population. What we are assessing is after mixed meal tolerance test, we are assessing different doses of imapeptide and we're evaluating the glucose nadir. The glucose nadir is exactly related to the symptoms. In the general population, the glucose wouldn't go following a mixed meal tolerance test below 70 milligram per deciliters. Here in this population, it can go below 54, which is emergency, right? You have this. What we are aiming to see is to see an increase in the glucose nadir, which is at the same time parallel to a decrease in insulin secretion. That's what avexitide showed in their POC studies. If we confirm this, benefit in terms of pharmacodynamic effect, we can move to phase II/III.
Okay. Is there anything about imapeptide in particular in the molecule that is special as we think about it relative to competitors?
Half-life?
Yeah.
Yeah. We have a 90 hours half-life as compared to the competition, which is three hours max. In this population, it's also important to cover the night 'cause this event of hypoglycemia can be major issue at night. With 90 hours half-life, we can expect to cover daily and also the night. When in the three hours, we will see what the competition will show. Covering the night might be a challenge, especially with the three hours. They increase the dose up to 90 milligram to show an effect, we'll see.
Yeah.
Yeah. In the primary market research we've conducted in this field indicate, again, not surprisingly, once weekly is preferred by patients and their doctors.
Yep. Yep. Makes sense. If the phase II data are consistent with your expectations, what are the next steps for this program?
We will have a good idea about the dose, and we can go to phase two and phase three or phase two, phase three seamless. We are assessing all options, and obviously it will be discussed with the regulatory agency to make sure that they agree with the path. That's what we would like to go as fast as possible.
POC data in Q2.
Yeah.
A lot of catalysts in Q2.
Indeed. On the PBH market, how large do you think the PBH market is?
We've looked at it. In the U.S. alone, we see a prevalence of north of 125,000. This fear factor of these patients of not knowing when they could get this hypoglycemia indicates that a large, maybe more than half of that population could need a drug for prevention.
Is this something that you think would be temporary treatment or, you know?
It's chronic.
Chronic. Okay.
Yeah. Unfortunately, these patients have PBH for life.
Yeah. All right. Just maybe briefly, current cash levels and runway for folks.
We're in a strong financial position. We ended the year 2025 with $373 million on our balance sheet. We communicated that takes us into 2029. We recently completed an $87 million ATM stock sale. Our pro forma cash balance for year-end would be $460 million. Clearly that gives us a lot of optionality in advancing all of these programs. We will provide an update on our cash coming up here later this month. Safe to say all the catalysts that we talked about are fully funded, including this phase III registrational study, the pre-commercial activities I mentioned. I wanna point out that in our two new obesity programs, these POC studies, similar to the phase I study for 4291, are fully funded. We're already looking ahead to phase II and conducting the phase II enabling activities for MBX 4291. Creating, I believe, a lot of value this year.
Great. Maybe, to wrap up, I'll ask you both what you believe is the most underappreciated aspect of the MBX story by investors at the moment.
I'll quickly lead off. I would say that investors are recognizing that we're unique in having three potential best-in-class candidates in the clinic making excellent progress, as well as a clinically validated platform technology that can continue to generate these exciting candidates, including in obesity. I think when we read out this 12 week data, people will see how that translates to leadership in obesity.
Yeah. Just to reinforce, I think the value of the platform, the potential this platform can create. For me, it's really, really attractive. Now it's validated through canvorparotide. I think it's possible.
Wonderful. Kent and Sam, thank you so much for joining us.
Thank you.
Thank you.
Appreciate it.
Thank you.
Have a good morning, everyone. Thank you.