Good afternoon, everyone. Welcome to our Piper Sandler Healthcare Conference. My name is Yasmeen Rahimi. I'm a senior biotech analyst here. Excited to have the MBX Biosciences team with us and lots to cover. I cannot believe this year went by, and this has been a phenomenal year for you guys' team. Obviously, 2026 is going to be even more of a big year. Let's start off at MBX 2109 in hypoparathyroidism. Team, obviously, you guys reported very strong Phase II AVAIL top-line data, and you were planning to engage with the FDA in terms of end-of-year meeting in Q1. Maybe help us understand, in preparation for that meeting right around the corner next quarter, sort of how you're preparing, what are the sort of things that you're putting together in preparation with the agency.
First, let me thank you for including us, Yaz, in this wonderful event. And I'll just mention to remind you that I'll be making forward-looking statements, so please refer to our disclosures and our SEC filings available on our website. And thank you for mentioning our AVAIL study for once-weekly canvuparatide. Just taking a step back, that was really the transformative milestone for the company last quarter in September. And we've been really pleased to hear from investors that they went and looked at the data, they did their own analysis, they did their doc calls, spoke to KOLs, concluded that we have a drug that works and, as we've been saying, could be best in class. And that's been supported by some primary research we've conducted as well. But it sets us up really well for 2026, which will be a very catalyst-rich year.
Just our lead program alone, once-weekly canvuparatide, like you point out, kicking right off in first quarter with our end-of-phase I meetings. That's FDA and EMA scientific advice. Really expect those to go very well. There's no rate-limiting steps. We're on track for that. Viewed as pretty confirmatory to align on the design and get started on the global registration study, phase III.
Maybe help us understand, given that you're going to have your meeting in Q1 and you have guided that you're going to start your phase III in third quarter, what is sort of the time? Why do you need that six months? Is it maybe I'm naive to just think about it? You could go back to your phase II sites and just scale out.
As I said, we reported the top-line results for AVAIL in September. It's pretty typical to be starting the study roughly four quarters out. This will be in Q3, and it is a global registration study. No rate-limiting steps. We're already working with the CRO on pre-launch activities in order to set us up for another efficient, well-executed study. Maybe one point I'll make is that we expect this phase III study to include our planned commercial device, which is something we're really excited about because in this case, we'll have a single-use patient-friendly device that's disposable. We've heard really good reaction from the patients to this.
What did you have in the AVAIL study? How does that compare?
We had AVAIL and syringe.
Oh, okay. A VAIL and oh, vial and vial and syringe. Okay.
Not AVAIL end, but AVAIL and syringe. Anything else?
No, just because we reconstituted the product with a little bit of water and it was very easy to use, but the phase III commercial device will be really the one that will be making a big difference in terms of it will be an injector and it will be very easy to use, and especially, it will be reliable, very reliable. It will be one dose, one device, and you discard it.
Perfect. And what are you thinking about? What is the dose wanting to move forward into a registration study? And what would that volume be for this simple device?
I'm going to start with the volume, which will be 1 mL . 1 mL .
Oh, okay. Small volume.
And in terms of dose, we will be, you know that phase II was a dose-finding study?
Yeah.
The most important thing for a dose-finding study in this special case is to determine what will be the starting dose. The starting dose will be the ones that combine the best efficacy and also with the best tolerability profile. It will be between 400 and 600 micrograms weekly.
Very helpful. And team, obviously, one of the changes will be the duration of the study of phase II studies for dose-finding, but then when you go to a pivotal program, it's a longer duration. So help us understand, I think it would be, what, a 24-week study at a minimum. And how do you think about sort of treatment response over prolonged? And I know we're going to talk about the OLE data shortly, but would love to kind of think about, before we go into OLE, how would placebo change when we go from 12-week studies to a longer duration?
Just to quickly lead off, we had 79% treatment response at six months, which I think blew a lot of folks' expectations out of the water. Certainly more than clinically meaningful and when you consider that the once-daily competitor has 69% at six months in their U.S. label, that's from phase III, that just shows you how great our data is, so we think this is really quite validating. It was a three-part endpoint, primary endpoint that we use that's very comparable to the phase III endpoint, so in some ways, we look at this phase III coming up as a confirmatory study, but Sam, you can elaborate.
Yeah, that's exactly right. So six months, it will be a six-month double-blind placebo control. And so roughly 26 weeks. And the primary endpoint will be, as Kent alluded to, which is very similar to the one we used in phase II. I mean, the regulatory path has been paved. So we are going to follow the same process, if you want.
Just to kind of go back with the approved daily injections by Ascendis, at that 12-week time point, what was your response? You guys got 79?
We had 63% response at 12 weeks, which, as I indicated, increased to 79%, which was in the OLE portion.
From 63- 69.
Increased from 63%- 79%.
Oh, wow.
We had statistical significance at our 63%, so we met our primary endpoint at 12 weeks. I think, again, that sets us up really well for the phase III. We would expect placebo to be pretty low in the phase III. We saw the once-daily had a placebo rate of just 5% in their phase III. It's just very hard for these patients with PTH deficiency, right? That's the hallmark of the disease, to be a responder for any length of time if they're not either getting the supplements or a PTH replacement therapy.
Sorry.
No, go ahead.
Yeah, in the ITT, there was no data, by the way, at the 12-week for Yorvipath. So if you look at the four-week data, it's roughly 50% versus 27% in the placebo group in the ITT. And the study was not significant at four weeks.
Okay. Team, you noted that, Kent, like you guys have done a lot of market research to show the product profile. Could you maybe shed some light on how physicians, when they look, assuming, of course, high POS translation in phase III, what is the hierarchy of importance in terms of, is it the more higher potency? Is it the longer durability, convenience in the administration of once a week? Help us understand sort of what matters to prescribers and patients.
We had a market research firm interview 27 physicians who treat patients with HP. What they did is present our blinded profile with our phase II data and the once-daily data as a once-daily profile. It was very reassuring to hear the feedback that the physicians looked at our profile as best in class and would suggest category leadership. So that breaks down into switching. So they said they would switch patients from a once-daily to our profile. And also for new patients who are going on a PTH replacement therapy, they would choose ours. So in terms of hierarchy, convenience matters. The once-weekly dosing is totally differentiated. We know from talking to patients that they don't want to think about their disease every day. They would like to be able to take something that's easy once a week and get on with their lives.
So the physicians, through this research, said that with comparable efficacy and once-weekly, that wins the day. And I think maybe.
We went to two things. We went to the HypoPARA Association meeting last October. And there was really a good enthusiasm about the weekly when we presented the phase II data. Patients were absolutely on board. And some funny things, they said that they wanted to participate weekly because they were very interested, but not being the placebo. So just.
And the picture.
Yeah. And I had one PI who said, "Well, you have to tell me if you want my site to be in the study. I will reserve my patients to your trial because they are very interested by the weekly." So again, good enthusiasm around.
We had 94% of those patients who completed AVAIL opting to enter a two-year open-label extension, which is a big testimony to how they view our once-weekly treatment option.
No, that's amazing, and obviously, that is going to be the next catalyst. Another key milestone for the company is the one-year data upcoming in Q26 of the AVAIL study. Maybe help us understand sort of how large will that cohort be at that time, and what do you hope to see at that longer period, both across efficacy and safety?
We want to continue to show that we have comparable efficacy because, as I said, with once-weekly, that's best in class. So just at a high level, we'll be wanting to show that we continue to have the benefits, this sort of consistent PTH exposure, and good safety and tolerability. Maybe you can elaborate for the one year.
Yeah. So in addition, we will see the urine calcium. We will get the data on urine calcium, but also the bone biomarkers. And at that time, at one year, we will have a DEXA, the DEXA that shows a BMD. So it will be very interesting to see the connection with the bone biomarkers. We'll expect to see a little bit of decrease in the BMDs. You know that these patients don't have a bone turnover to start with. And then safety and tolerability, obviously.
Okay. And you don't really need this OLE data for engagement with the agency, right? I mean, they've already seen the 24-week data point. And so it's just continued to be data transparent with investors. That's great. And obviously, that will continue, right? So there will be many cuts as this is a two-year study then?
It is a two-year open-label extension. So we would expect to show periodic updates that are meaningful. And one year, clearly, yes. So we do think, as you say, an important catalyst in Q2 of 2026.
Okay. Excellent. Team, is there any reason to believe that the EMA regulatory path is any different from the FDA? Not really. It should be the same, pretty streamlined.
I mean, again, example.
Yeah, asundus.
The once-daily therapy paves the way for both EMA and the FDA. And the endpoint has been the same for the two agencies. No expectation there that it will be anywhere different.
Good. Perfect. Let's spend some time on 4291 because that's going to be a very important inflection point. So this is a very differentiated product profile too. It's a GLP-1/GIP agonist. And maybe first, before we go into the study design and expectations, maybe walk us through its differentiation versus other GLP-1/GIPs. I think the mother is tirzepatide, then we have a Viking, then we have the Roche compound that came from Carmot. So maybe a few others.
Well, it's been.
Yeah.
Thank you. It's been a really interesting period in obesity. And I would say that our team has as much experience in obesity as anyone, starting with our scientific founder, Dr. Richard DiMarchi. And he was the inventor of the first GLP-1, GIP co-agonist. That was at our previous company, Marcadia Biotech, that ultimately wound up with Novo Nordisk. And Richard spent about four years there. I think that recently, pharma has pretty much declared that once monthly matters. We also remember we were talking last June, we had your obesity summit, and tolerability at ADA conference was being talked about. And it's really great that physicians have moved to a point where they recognize that what's important is you'd be able to provide sustained benefit for patients in terms of weight lowering, but with convenient dosing, right? Because this is chronic use for the rest of your life.
And tolerable, better tolerability because the GI side effects for the Incretins are real. So in our case, where we've come to is we're applying our clinically validated PEP technology that's been used in once-weekly Canvuparatide. In this case, we've tuned it for a once-monthly product profile. And think about this programmable prodrug that enables us to provide gradual controlled release of the active drug. Why that's important is we know from the KOLs that it isn't just CMAX or maximum concentration that causes the GI side effects with the Incretins. It's the rate of rise to CMAX and the fluctuation. So that infusion-like that we've demonstrated with once-weekly Canvuparatide, think about that applying in obesity and how that can be differentiated.
Okay. And obviously, it has this very novel technology, this PEP technology, right, that could highly improve tolerability, which is going to be really key. So this 12-week MAD data, right, it's part C, it's 30 patients, it's on track to read out in the fourth quarter, right?
Of '26.
Of 2026, yep. I guess what do you need to, and we understand monthly is going to be key, but beyond that, what do you need to see on a 12-week placebo-adjusted weight loss? What do you have to see in discontinuation and GI tolerability to be competitive?
Going back to what we hear from the physicians, it's not a race to weight lowering. I think we've kind of evolved from that point. People know that these mechanisms work, right? In fact, dual agonism is the gold standard today. It's really important that we're able to show in 12 weeks that we have once monthly. There was this bidding war that I kind of alluded to, and that was over a company that has what I would indeed call ultra-long-acting, but what hasn't really been definitively shown is once monthly and with appropriate tolerability. So that's an opportunity for us and what we're committed to showing in our 12-week study.
But I guess when investors ask, what is the weight loss to establish that you're effective at? You don't need to achieve. I think investors understand, you don't need to achieve to be the most effective weight loss, but what is sort of the semi-.
Just fairly comparable.
Yeah.
Just in the ballpark on weight lowering, but to do that with once-monthly and improved tolerability. That's really where we're focused for differentiation.
Do you think with a monthly, there is a cadence of difference in GI tolerability that maybe the first week, is it being tracked in a way that you could look at the cadence of how it changes from week one to week two to week three to week four before you get your second injection?
Right. Maybe it's an opportunity to talk about how we've designed this phase I from SAD through MAD.
Yeah.
So this phase I is in the target population of obese subjects, which will be like a phase II A, if you want. It's great. So it will be divided in three parts. The first one, which is a single ascending dose, SAD. So we will be exploring different doses. And it will give us a really good idea about tolerability and also the potential for monthly PK, right? Then we will go to the MAD, so it will be a four-week administration. Again, a good idea about tolerability, the PK profile, but it will culminate with 12-week. So the 12-week, which will be the most important thing, because as Kent said, the way you get to the monthly, you do not need to rush. And the most important is to get to the steady state with a product which is well tolerated.
And so we will be looking at least one treatment paradigm, such as giving the drug on a weekly basis for four weeks and then test the monthly. But for sure, what we want is a monthly proof that it works and we have a PK which is monthly. We want to really show it with a good tolerability. Then we'll be looking at weight loss, right? And if everything goes fine, we can imagine that the compliance will be good and it will be the four-dimensional product, right?
But then the titration is sort of extended because you don't really need to be aggressive every month titrating them up to do so. Yeah.
That's exactly what we'll be looking at during this part C.
As you recall, yes, when we got together in June, we presented for the first time to the public our four-week non-human primate in Cynomolgus monkey. We're really pleased that we saw with four once-weekly doses, totally flat PK. You know that monkeys have three times faster albumin turnover. That's a mechanism with fatty insulation. So you kind of have to view that as it will be longer in humans. We have sophisticated computer modeling that gives us very high conviction we'll have monthly with a very nice peak-to-trough ratio, this sort of infusion-like.
Okay. And team, so fast forward, you have the data in 4Q. Is this something that you're interested in partnering for a larger phase II B study, or is that something that obviously there's a crazy bidding war on that? Or is that something that you would want the capital needs to run a phase II B is not super intensive? You could continue doing it on your own.
We're exploring multiple approaches to advance this program in development following positive POC data.
Okay. And then team, I know we have like four minutes. You also have a third program, 1416, and post-bariatric hypoglycemia. You have a phase II A data upcoming here in 2Q26, which is, I think it's like a 39-day study in 10 adult patients with post-bariatric hypoglycemia. And you're doing a postprandial glucose test after a meal tolerance. So maybe help us understand what do you need to see there to wanting to warrant further development and moving it to a phase II B or slash phase III?
Yeah. This is our third clinical stage program that we have in the company and really, again, massive unmet need. We've done our primary research, which supports a prevalence in the U.S. alone of over 125,000, and there's no approved pharmacotherapy. It's chronic illness. There's a major devastating impact on quality of life and so we're highly motivated to advance, again, what we believe could be a best-in-class treatment option and we conducted similar market research, as I described, for once-weekly canvuparatide in this program, similar feedback on our data set, our profile and so with this 2A, this is an opportunity for us to show proof of concept in PBH patients. There's a good benchmark in what the once-daily competitor, which is in phase III currently, has shown.
But I would say that they have clinically. That molecule has clinically validated GLP-1 antagonism as a mechanism in treating PBH.
Yeah. So this phase II A will be some sort of POC study, and we'll be looking at the pharmacodynamic effect and translated by glucose nadir. We know that the glucose nadir lower it is, more translated into hypoglycemia episode, clinical episode. So you want to increase it, right? And you want to see a reduction in insulin secretion and C-peptide. That will be a proof of concept. We are going, in the same patient, we are going to evaluate baseline, the MMTT, the mixed meal tolerance test, the baseline, then after a low dose and after a higher dose. So that will give us a good idea about the range where we can expect the pharmacodynamic effect.
Wonderful. And then, team, maybe last question is, what is sort of the cash-to-cash runway and funding through the pivotal programs? Yeah.
We're in a strong financial position, having raised about $200 million in gross proceeds last September following our AVAIL readout, and we have cash to support our operations into 2029. So that supports all of the catalysts across these programs that I've shared today: full completion of the phase III registration study for once-weekly canvuparatide, the pre-commercial activities that are in full swing, and a buffer, a cushion. So we've been really thoughtful about that, and just think it's an exciting entry point for the company with these catalysts heat up across every one of our clinical-stage programs, plus continued discovery. We have this discovery engine working closely with Richard DiMarchi and team and with our own capabilities as well. I would look forward to next year sharing more about our discovery efforts as well.
Wonderful. It's been such a pleasure hosting you. Thank you again for being part of our healthcare conference, and hope to see you soon as we are located in my hometown, Indianapolis. So yes. So let's give a big shout-out to the team.
Thank you.