Great. Good morning, everyone. Tyler Van Buren here, a senior biotech analyst at TD Cowen. Thank you very much for joining TD Cowen's Obesity Summit. For this next session, we are very pleased to have a discussion with MBX Biosciences. It is my pleasure to introduce Kent Hawryluk, Co-Founder, President, and CEO of MBX, as well as Dr. Sam Azoulay, the Chief Medical Officer. Kent and Sam, it is a privilege to have you here. Thank you very much for joining me. With that, I will go ahead and pass it over to you to present a few slides before we get into discussion.
Thank you, Tyler, and the Cowen team for the invitation to participate in this wonderful summit. I will just remind everyone I'll be making forward-looking statements, so please refer to our SEC filings available on our website. For those of you who are new to the MBX story, I will just share that MBX really is building a leading biopharmaceutical company focused in endocrine and metabolic disease. We have three clinical stage programs that each are positioned to be best in class and overtake multi-billion dollar markets. We had outstanding phase II data release recently. This is for our once-weekly canvuparatide program that promises to be the first once-weekly PTH replacement therapy in hypoparathyroidism, which is a growing and validated market. Our pipeline is powered by our Precision Endocrine Peptide, or PEP, platform technology. This provides consistent drug exposure, long time action, and convenient infrequent dosing.
Each of our candidates in the clinic have longer time action than our competitors. This includes a potential once-monthly candidate in obesity, MBX 4291, which is a GLP-1/GIP co-agonist prodrug. We have major value inflection points across each of our pipeline programs in 2026. I'll talk about those. We have funding into 2029, which supports these catalysts, including phase III completion and pre-commercial activities that are already underway in hypoparathyroidism. As you can see, 2026 is going to be a catalyst-rich year, just ticking down very, very quickly. In once-weekly canvu , in the first quarter of next year, we anticipate end of phase II meetings, FDA and EMA. In the second quarter, a presentation of our Avail phase II results at a major medical meeting, and one-year follow-up data also in the second quarter. In the third quarter, initiation of our phase III registration study.
In MBX 4291, 12-week MAD results in the target population for this candidate. In the peptide, these are Q2 and Q2 phase II -A results. I want to also emphasize that we have a robust obesity discovery pipeline and plan to share updates next year on those activities as well. There has been a lot of attention, obviously, for MBX 4291, our obesity candidate, in a world where pharma has pretty much declared that a once-monthly is a must-have. In this case, I wanted to illustrate how MBX 4291 really leverages synergistically two of our key PEP technologies. That is our programmable prodrug and our fatty acylation. As you see there at the top, MBX 4291 is a prodrug, and it is designed to be inactive biologically by design. Under normal conditions in circulation, pH and temperature, we provide gradual controlled release of the active drug.
No enzymes are required. If you look below there, once an active form in A, then B, and C, you see that this active drug is able to bind either GLP-1 or GIP. These are the two gold standard mechanisms in weight lowering today. Think of Zepbound and the success Lilly has had with that dual agonist. I am really excited again for these 12-week data coming in Q4, where we intend to demonstrate definitively once-monthly dosing frequency and show better tolerability. Thank you.
Great. Thanks for that, Kent. We'll get into some questions with most of the focus during the session being on the 4291 obesity program. Maybe you could start with a little bit of MBX history, Dr. Richard DiMarchi, your Scientific Co-Founder, and maybe talk about his previous academic work, how it impacted the current therapeutic landscape, and also if he's been involved with the development of 4291.
Thank you. I believe in many ways, MBX is a continuation of a 20-year collaboration, really 20-plus years with Dr. DiMarchi going back to Marcadia Biotech, which was founded around 2005. Richard is a legend, right? When he set up his lab in Indiana University, Bloomington in 2003, he has really set off a revolution in obesity treatment. He invented the first GLP-1/GIP co-agonist and, lesser known, the first triple G. I am pleased that both of these programs were funded and advanced by Marcadia Biotech and directly inspired Lilly's work. As we all know, they recently crossed the trillion-dollar mark in value cap, many would say largely based on the success of their obesity franchise anchored by tirzepatide and retatrutide. Richard and his team did invent MBX 4291, and that includes that really novel programmable prodrug technology that is featured in that molecule.
Great. Maybe you could talk a little bit about the non-human primate studies that were conducted. What stands out the most between 4291 and tirzepatide? What is unique about the PK profile? Are there any other candidates in development with a similar PK profile?
It's important to highlight the data we showed recently with the infusion-like exposure to the MBX 4291 active drug, so after it's been converted. It really was as flat a PK or peak to trough as you could see, about one. That was really due to the fact that after four once-weekly doses in these normal cynomolgus monkeys, we achieved steady state. It was using the prodrug and the fatty acylation to have that smooth effect. We don't see anyone else in the field developing prodrugs at this point and feel it's really differentiated. There's a reason to get excited about this in terms of tolerability, because the experts tell us that it's the steep rise to Cmax that you see with the other incretins that's causing the GI side effects like nausea, vomiting, diarrhea.
By dampening that and really reshaping the PK curve, we have a strong hypothesis for why we should see better tolerability. There was a hint of that too in the same study that you referenced with the PK, because we were able to see weight lowering in those non-human primates, those cynomolgus monkeys, that exceeded what was seen in the label for tirzepatide. Not a head-to-head study, but looking at the same model. This suggests that we can drive higher tolerated concentrations of active drug.
Got it. Just to follow up on that, with respect to safety in the primate studies, what type of safety did you observe? Were you able to look at GI toxin and think about how that might translate to humans?
We definitely looked at that very carefully. We did not see emesis, vomiting, diarrhea. Of course, it's hard to assess nausea to ask the monkeys, but they were getting on. We think this is really encouraging. We achieved nearly 20% weight lowering after four once-weekly dosing, which, as I said, we just haven't seen before. That is consistent with the prodrug design. I do think it's predictive of what we could see in humans, noting that there is a three times faster turnover of albumin, which is, as you saw from the illustration, that sort of transporter in circulation, which extends the time action. That's why when we dose weekly in monkeys, we think it kind of corresponds roughly to what we can see monthly in humans.
We have done some sophisticated computer modeling as well to support our conviction that we have a once-monthly time action in humans.
Okay. That's great. Now, obviously, thinking about initial clinical data next year from this program is very exciting. You guys are going to wait to make sure that you have a robust enough data set. Can you walk through the phase I clinical trial design and what population you're enrolling and how the part C MAD might differ from the part B MAD in terms of dosing?
Sam?
Yeah. Thanks, Tyler. I think that, first of all, let me reinforce what Kent said about the tolerability. What we saw in the non-human primate usually is predictive of what we would expect in human, which is great. The tolerability was good. The phase I study will be in the target population of obese patients, BMI at or above 30, which is great, like a phase II study on some aspect. We will be looking at SAD, MAD four weeks as usual, but certainly the 12-week will be extremely important. It will provide information about the tolerability, confirm the tolerability. Certainly, we will be looking after monthly administration, confirming the PK profile of potential for one month, and clearly also the weight loss. That means at 12 weeks to be competitive with the other product.
Great. Can you just talk a little bit about the part A, part B, and part C, and why you separated it into the different parts, and also why you're waiting for Q4 to have the full 12-week part C data?
It's very important that the SAD and the MAD will inform the 12-week. The SAD, by definition, which would be a single ascending dose, and we go up to the best tolerability profile you would expect. We will take three doses that we bring to the four-week. We'll be confirming the four-week potential for four-week administration. Most importantly, in the 12-week, we take the dose and we will be testing different paradigms. One of them will be, as an example, administration of four weeks following the MAD written in four-week, the four-week MAD, and followed by a monthly administration. We can be very flexible. Everything will depend on what we'll be observing in the SAD and MAD. In brief, it's a flexible phase I study.
Tyler, I would just add that the 12-week data is really the currency for these ultra-long-acting molecules and what you typically see. I think that's the emphasis that we have as well.
Okay. That's clear. With respect to that 12-week part C obesity data in Q4 next year, what should we expect? I guess, obviously, weight loss at 12 weeks is pretty straightforward, but what else should we expect to be reported? In general, what's the goal that you'd like to see in terms of dosing efficacy and safety?
I would point out that in my view, the ultra-long-acting molecules in development have not cracked the code on tolerability. What we really are looking to achieve is once-monthly dosing, so clear, as Sam said, during the 12 weeks of evaluation, and to provide that with better tolerability. Because when we talk to physicians and we've conducted primary market research as well, supporting the view that weight lowering, while important, is in chronic use not the biggest deal. We know these drugs work, but what good is it if the patient can't stay on it? We already see adherence challenges with the incretins and a high discontinuation rate, approaching half. We are really excited to be able to create a drug that can be used in chronic use conveniently, well tolerated, and deliver comparable weight loss.
If we do that, our market research suggests it will be best in class.
That's great. For weight loss at 12 weeks, what's the benchmark or roughly what should we expect? Is it tirzepatide or are you looking to another long-acting incretin in development?
I would say show me an ultra-long-acting that has monthly dosing frequency and tolerable GI profile, and let's look at that standard.
Fair enough. Fair enough. As you talked about the flat infusion-like exposure that we saw in primates, would you expect that to translate to humans in terms of the rise to Cmax, or might there be any differences like you mentioned on half-life?
Sam?
Yeah. I think what's great is if we can reproduce what was seen in a non-human primate, the smooth raise to Cmax, which we know is absolutely correlated to the GI profile, that would be fantastic. What we saw in non-human primates after four-week administration, weekly during four-week, is really a flat curve with a very, very low or small peak to trough ratio. Considering the albumin turnover, which is three times faster in NHP, in human, you can translate this with the potential for the monthly. As I said, I just want to reinforce what Kent said about the monthly administration with better tolerability. Really, if you can see really good tolerability, you can maybe increase the dose. Certainly, in terms of compliance, that would be fantastic if the patient can stay on drug. That's something that will be an achievement.
Yeah. I guess theoretically, if the half-life is longer in humans versus primates, that kind of very flat profile that you saw in primates probably is even flatter in humans, right?
You said it.
Okay. All right. Assuming that the data in Q4 for 4291 confirm your desired profile, what are the next steps and trials that you plan to run for the program?
Tyler, we're evaluating multiple approaches to advance this program following a successful phase I and just see significant optionality with this program.
Okay. Just would you plan to continue with the four-weekly doses before moving to monthly in later trials, or do you think it's possible that you may start with monthly earlier?
We'll learn a lot from the phase I and to be determined. Think now about how complex the titration process for most patients going on Zepbound, tirzepatide, right? Up to six steps, can be six months. Not so much focus on the front end. Four-month weekly doses is not a high burden of sort of titration given the opportunity for once-monthly chronic use.
Okay. With respect to strategy plans or partnering, obviously, a lot of interest in Metsera lately from Pfizer and Novo going back and forth. How are you guys thinking about potentially partnering? I assume it's probably a similar answer to what you just gave on next steps for trials, but I'm curious if you have anything else to add.
Not really, because clearly can't discuss any specific BD activities. I always think it's best practices for biopharma companies to be speaking with pharma and making them aware of what we're doing. It is the old, tell them what you're going to do, do it, and remind them what you did. That is just good housekeeping. I think the emphasis is that it makes sense that to be a leader in obesity, you're going to need this mainstay monthly, convenient, well-tolerated product in your portfolio.
Great. In the time we have remaining, maybe we'll touch on some of your other programs. Obviously, the phase II canvuparatide data were great, potentially best in class. You've guided to an end of phase II meeting with the FDA in the first quarter. Maybe you could just talk about the goal of that end of phase II meeting, potential discussion topics, and any differences from the phase II to the phase III that are important to note.
I can start here. First of all, as a reminder, it really is a great result we saw in phase II at 12 weeks, but also at six months with 94% of patients moving from 12 weeks double-blind placebo control to the open-label extension for two years and 79% positive results, which really is really good. The phase III is mainly a confirmatory trial, right? The competition has already opened the regulatory pass. It will be likely to be a similar design, six months double-blind placebo control, two arms, one placebo, one treatment arm. Learning from phase II is certainly the starting dose for the phase III. The phase II was a dose-finding study. We will be selecting the dose according to the best efficacy and safety profile we see with the starting dose.
To be direct, between 400 and 600 mcg was well tolerated, showed great efficacy. Between these two doses, with the FDA, as usual, you agree on the design, you agree on the safety, sample size, I mean, how many patients at six months, etc. That is the classical discussion with the regulatory agencies, not only with the FDA, but also with the EMA.
Okay. Do you plan to stratify for PTH levels?
We'll be looking at stratification. PTH level, as we discussed, that could have been an explanation for the placebo response, will be something we would consider and discuss with the FDA in terms of patients with residual PTH activity as compared with patients with no residual activity. Just to be clear, these two populations are sick, but they may respond slightly differently.
Okay. What about urine calcium change? Will the enrollment or measurement of that differ from the phase II of Veltro?
Yeah. I think urine calcium is a key potential endpoint to be discussed again with the FDA. Urine calcium excretion is a marker of hypoparathyroidism, which is the excretion is increased and the goal is to reduce it. We saw it in phase II. We saw good treatment effect in the population with hypercalciuria at baseline. That will be also discussing with the FDA in order to look at it as a key secondary endpoint.
Okay. Maybe just to wrap up the phase III design discussion, in general, would you expect it to be pretty similar to the pathway trial? Should investors expect a similarly sized study of around 85 patients?
It will be something in the ballpark of what we saw between Yorvipath and eniboparatide, but the confirmation after the end of phase II meeting with the FDA to make sure that we align.
Fair enough. With the 52-week OLE data from Avail that are going to be presented in or provided in the second quarter of next year, what should expectations for that update be?
Yeah.
We should expect that we would be providing the relevant data that's going to help them understand our clinical profile. I think Sam can elaborate, but first, just when we did primary market research, a market research firm, ClearView, interviewed 27 physicians. What came across very emphatically is that our blinded profile from our data from Avail compared to the once-daily profile, our profile won the day. They clearly, emphatically said that with comparable efficacy and once weekly, that will drive switching, that will represent the drug of choice for new patient starts, and overall represent category leadership. Really excited to continue to show through the one-year follow-up data that we have best in class profile.
Yeah. Just to elaborate a little bit more, retention, right? We got 94% moving to the study, retention, responder rate with each component of the composite endpoint. We've been looking certainly at urine calcium. We'll be looking at bone biomarker to confirm what we saw in phase II, but also BMD, because now we have enough exposure to look at BMD. We'll be looking at other biomarkers, but certainly safety tolerability.
That's great. And the 79% responder rate that was reported with canvuparatide, obviously, if you guys get that on the label, you'll be best in class by 10%. With the 52-week data, is the goal just to be able to maintain that out to a year with your profile?
Again, comparable efficacy, 69%, we are just kind of in the ballpark of that. Once weekly is best in class. I think we'll just keep referring to that as we share data. Just exciting setup for 2026, Tyler.
Fair enough. Hypercalcemia in the maintenance phase versus the 12-week Avail data, would you expect any difference there?
Sam?
Yeah. Just to say that the hypercalcemia is something you would expect in the phase II study, especially when you titrate up, because that's a competition between the dose and the supplement. That's something you would expect just as a comparison, 54% reported with Yorvipath in the label above 10.6 mg per dl. That's no surprise. Certainly when the patient is maintained, the maintenance phase, you would expect less excursion.
Great. We are approaching time, but have to ask about imapextide and the PBH program. I think investors need to focus on this more, especially as we approach the phase II study data in the second quarter. Maybe you guys could provide an overview of what you expect to report and what the bars for increase in glucose nadir and reduction in insulin peak you hope to achieve.
Yeah, we have the phase II study, which is looking at the pharmacodynamic effect of following single-dose administration of a low dose and a higher dose of the drug. What we would be looking at is the glucose nadir, increasing the glucose nadir while reducing the insulin secretion. As I said, it's a single administration that will be evaluated through the mixed meal tolerance test. Something which has been done by the competition, by Vexetide, and we'll be looking at reproducing this in our phase II study.
Great. Finally, what about safety? Is ISRs kind of the focus? Do you believe that those could come down from what was reported in phase I?
I mean, the ISR, to be clear, they are benign in nature. When we looked at delayed type hypersensitivity, T cell mediated, usually disappearing after multiple administrations. It is a redness, isolated redness, no additional symptom, no general symptoms. I would say overall benign profile. That is the first thing I can say. We are assessing two doses, I told you, one being the lower dose, we can see less ISR. Also, medical measures such as a little bit of steroid cream, cold compress can also alleviate the ISR. Again, insisting on the fact that this ISR is benign by nature.
Right. Tyler, pulling that through, again, we did some primary research, doc calls, and found that the ISRs, when we presented our data, characterizing it, it was not an impediment to their prescribing this drug if approved. This is a major unmet need, no approved pharmacotherapies. We see over 125,000 U.S. prevalence with post-bariatric hypoglycemia.
Great. That's very clear. We're over time, but maybe to wrap up the conversation, we'd love to hear from both of you what you believe is the most underappreciated aspect of the MBX story by investors right now.
I'll go first. I think it's great to see our profile increasing in the market and so much positive momentum. I still think that it's important for investors to realize that we're on track to be an obesity leader, that we beyond 4291 have a portfolio that's based on this clinically proven platform technology that can provide differentiation with this gradual controlled release.
Yeah, I just wanted to say that what Kent said about the potential for the platform. I mean, we have confirmed it with canvuparatide. And really, it's great to see the potential behind.
Yeah. Value inflection points across each of our pipeline programs, cash taking into 2029, I think that's quite unusual. It puts us in an enviable position.
Indeed. A lot of catalysts coming up next year, much less 2027 and 2028. Kent and Sam, thank you very much for a very interesting discussion. Appreciate your time. Thanks to the audience for attending. Have a great afternoon, everyone.
Thanks, Tyler.
Goodbye.