Hi. Good morning, everyone. It's our pleasure to have the management of MBX Biosciences here with us today. I have to apologize for the delay. We had some linking problems. We have newly appointed CEO, Steve Hoerter, with us, as well as the Chief Medical Officer, Salomon Azoulay. As you know, MBX has a precision endocrine peptide technology that's allowed for customization of peptides for both potency and durability. Maybe we can start with a quick overview of rare endocrinology and then transition quickly to obesity, which is driving a lot of the excitement today or right now. Steve, maybe you can talk to us about what drove the management transition and where you want to take the company today.
Yeah. Sure, Annabel, and it's great to see you, and thanks for the invitation to join for the virtual symposium today. Sam and I are delighted to be here. Maybe what I'll start with, Annabel, if you don't mind, is just a brief overview, and then we can dive into that exact question about the management change. Happy to address that. For those who are joining who are less familiar with the story, we're a clinical-stage company, and we're focused on the discovery, development, and eventual commercialization of our novel peptide therapies that we have now in the clinic, and we, of course, have a robust early pipeline in IND-enabling studies at the moment. The company's Scientific Co-Founder, Dr. Richard DiMarchi, is a pioneer in the field of peptide chemistry, and so he's the architect of the platform, which we refer to as a precision endocrine peptide platform.
As you noted, Annabel, the platform was designed to overcome some of the key limitations of peptide therapies and to improve clinical outcomes. We do that by engineering peptides to have optimized pharmaceutical properties to extend the time action, and really importantly, to deliver a PK in humans that has a low peak to trough ratio. So it's almost like an infusion-like PK that we see with our engineered peptides. What that allows us to deliver is a very differentiated PK profile, as I just noted, but that translates into a differentiated PD profile for our programs. The lead asset is canvuparatide, which we're developing for the treatment of chronic hypoparathyroidism. We'll talk about this, I'm sure, later. We just initiated the phase III clinical study for canvuparatide in this disease. Then we have a really robust obesity portfolio.
The lead program, MBX 4291, is a true once-monthly GLP-1/GIP co-agonist. This is now in a phase I study, and we're on track to deliver unblinded data from cohort C1 of that study in quarter four, so we're looking forward to that milestone. Then we have two additional obesity programs that are in IND-enabling studies, MBX 5765, which is an amycretin, and then our triple G, our version of retatrutide which is MBX 6180, and that is also in IND-enabling studies. So two programs that we expect will advance to the clinic next year.
Great.
So we have this robust portfolio, all wholly owned.
And we're very well capitalized. As of the end of Q2, we had about $420 million in cash. That gives us a runway into 2029, and the opportunity to deliver on a number of what we think will be value-creating milestones for the company and for shareholders.
Excellent. First wanted to talk about canvuparatide and HP. Obviously, the phase II Avail study was very successful, delivering once-weekly PTH with good clinical meaningfulness and safety. So what are the key takeaways from that trial that you want to pull out, and what you brought into the phase III?
Let me, thanks, Annabel, and very pleased to be here. Yeah. We were very excited by the results of the phase II studies, the Avail study, that showed a benefit with the response rate of serum normalization of serum calcium with independence of supplement calcium and vitamin D versus placebo in the initial 12 weeks. We confirmed this result at six months, at 12 weeks, so durability of effect. But very importantly, it's also the target organ. What we saw is that there is an improvement in urine calcium excretion, especially in patient with elevated urine calcium at baseline. And that's a target population because that's a population which is the most prone for CKD. So that's very encouraging result.
The last part is the bone, that like reactivating the bone turnover with an increase in biomarker, as you would expect, and confirmed by normalization or normal BMD. Everything as a PTH replacement therapy, as you would expect, so great potential for having a best-in-class weekly PTH replacement therapy with canvuparatide. Learning. We learned that the 600 microgram is really the weekly starting dose, and we will be starting the phase III program with 600 microgram. The dose range that we are offering has been confirmed 400 to 1,600 microgram with a dose titration as usual. That's a learning from the phase II.
Okay. Great. There was also quite steady delivery, with PTH concentrations that were in a very narrow band. Maybe you can talk about the significance of that.
Oh, that's a great point. Steve alluded to it through the platform, that having an infusion-like profile, and that exactly what we showed already in phase I with the peak to trough concentration, which were very similar after one week, to the daily administration of YORVIPATH. Very good. We confirmed in the pop PK, we confirmed this result in the target population of patient with hypoparathyroidism with a peak to trough ratio of 1.3, which is really great over a week. What's the implication? Implication is maintaining the serum calcium within the normal value over time. The more stable your concentration is over time, the better it is in terms of control and less excursion in hypo and hypercalcemia. So great PK profile.
Okay, excellent. Just to clarify one point, you're starting at 600 micrograms, but your range is from 400 micrograms- 1,600 micrograms . So patients will be able to titrate up and down by 200 micrograms as necessary.
Exactly right. So that we have confirmed that we want to get the titration up, with exceptional case where you can titrate also down, that's always offered. But the 600 microgram is really a good starting dose that combine efficacy and safety. So that's really the dose that we are aiming to start with. Then you titrate up according to the response in terms of serum calcium that you want to stay normalized while decreasing the supplement. So it's like playing with the supplement and the drug dose, and we offering this large, broad range that we should cover the entire hypoparathyroidism patients.
Okay, great. And so feedback from the physician community regarding what they want to see beyond just weekly convenience. What is the most important feature here that they want to see come out, and how is phase III capturing that?
It's a great question, Annabel. So we've done a lot of market research, both with physicians as well as with patients. And what we've learned from that market research is that patients when presented, and physicians, when presented with a blinded product profile, which is the canvuparatide product profile, they choose that profile both for patients who are treatment naive. But also importantly, are interested in switching patients who are being treated with the currently available daily injectable over to a once-a-week injectable, the canvuparatide profile. So we're very encouraged by that. One of the key drivers clearly is convenience for patients, and for physicians. They desire avoiding having to treat the disease on a daily basis with a daily injection. And if there's a way to make that a once weekly, that's something that's very attractive.
So, what we're aiming to deliver on in terms of the profile from the phase III study is generally in line with what we've demonstrated already in Avail, including with the sustained benefit that we see at one year from the open label extension. So in some ways, the phase III study is really just seeking to validate those phase II results. But we're very encouraged by the feedback that we've heard so far from physicians and patients about that profile.
Mm-hmm. Was there a way that you are going to be able to draw out the urinary calcium aspect a little bit better?
That is a great question. That is also a learning from the phase II, that canvuparatide has a potential to reduce and normalize urine calcium. Again, in the patient with elevated urine calcium at baseline, that is a target population, the one really prone to CKD. What we are aiming at, not only normalizing serum calcium, but urine calcium at the same time, both. The response rate will be based on the classical serum calcium normalization, and the key secondary endpoint will be a normalization of urine calcium in the target population, as I said, while normalizing serum calcium. If we get this endpoint, and has been agreed with the FDA that we can study it and we will see if they will agree to put it in the label, but a great potential to put it in the label, that will be a key differentiator.
Okay, great. The first phase III patient was dosed in August. When can we expect enrollment completion? Maybe, and then data. Have you guided to that? I imagine that the HP population is pretty well-defined, and they are now starting to understand the concept of injecting parathyroid hormone. Do you think this is going to be a difficult enrollment?
There is a lot of enthusiasm, Sam and I, in fact, were at the North American Investigators meeting a number of weeks ago and had a packed room of both coordinators as well as PIs who are going to be on the study. This, of course, is in a market where the daily injectable is widely available. There is a lot of enthusiasm for the study, as you point out, Annabel. We think, while we have not released milestones yet for 2027, we think that in the second half of next year, it is reasonable to expect we would get to full enrollment. As you know, we then have to wait to get to the time point for the primary endpoint. It is probably sometime in 2028, first half when we get to that primary endpoint readout.
We will provide some additional guidance as we get experience enrolling subjects on the study, opening sites and the like, in terms of how the cadence is rolling. We feel very confident that we will continue to see strong enthusiasm from patients and from investigators to participate in this clinical study.
Okay, great. I want to switch to obesity because I know there is a lot of excitement here. You are obviously leveraging the customizability of the PEP platform to develop a monthly drug with more tolerability. Obviously, it is the issue of persistence that you are trying to address. Can you talk about this and differentiation from maybe what some of the others are doing with their longer duration products, whether it is Medisera and now maybe Viking Therapeutics? Maybe you can talk about how you are positioning within this evolving landscape.
It is a good question, Annabel, and we are really excited about MBX 4291 and the initial blinded data that we showed at our company Obesity Day investor event in New York back in May. There are two ways that the platform deliver on differentiation for MBX 4291. The first is about a slow and steady rise to Cmax, and that is different from the so-called burst effect that is seen with currently available therapies. This burst effect is what is believed to drive GI intolerability. We think we have the potential with this differential PK profile to help to solve for the tolerability challenges that have been seen with currently available agents, and even with agents that are in development. The second key differentiator, as you point out, is about true once-monthly dosing.
The PK data that we showed in May clearly demonstrates with a T half Cmax of 26 days, the potential for this to be likely the first true once-monthly co-agonist or mono-agonist that is available to patients. When you look at other competing approaches, and take Medisera's 0971, for example, now under the Pfizer umbrella. It has been interesting for us to note that Pfizer has now launched additional duplicative phase III studies looking at weekly dosing with 0971 instead of once monthly. We also saw just a couple of weeks ago that Novo Nordisk terminated a research collaboration with Ascendis Pharma for their technology to try to deliver on a once-monthly technology for sema. It is clear that this landscape has now been opened even wider in terms of this unmet need of less frequent dosing, true once-monthly dosing.
We think MBX 4291 has the potential to deliver on that promise of less frequent injections for patients. We are excited with the coming up milestone that we have in Q4, where we will then disclose unblinded data from that cohort C1 in that study.
Okay. I guess one interesting aspect of your drug is that you also have the potential to simplify titration. You are starting with weekly dosing first, just explain that a little bit, it almost seems like it is a self-titrating mechanism.
Yeah, Salomon?
Yeah, sure. Absolutely right, Annabel. The data we presented at the Obesity Day, just as a reminder, was 30 milligrams given weekly for four weeks, followed by 120 milligrams monthly. A total of five injections in the limited population of eight subjects. Again, the data we presented were blinded, completely blinded. But what you saw back to the really the great PK profile, what you saw is that when you give the drug, especially during the four initial weeks, there is some dose accumulation, concentrations. The drug accumulate. As you refer to self-titration, it is exactly right. We put it in quote because we do not change the dose. It is the same dose. But by the way you accumulate the concentration is like self-titrating.
The consequence of this, in addition, to have really a slow raise to the Cmax, is really a good tolerability profile because we don't have the burst effect. When you go to 120 milligrams, what we observed is really giving this monthly administration. You have a steady concentration at the peak, but very importantly, very little fluctuation. We know that both the burst effect and the fluctuation around the Cmax are sources of GI intolerability. Right?
Mm-hmm. Yeah.
Also maintaining this concentration as long as possible. Remember that Medisera had a time to have the Cmax of 21 days. We have 26 days as a time to have the Cmax. So great potential for a monthly administration. How is it translated in tolerability? Well, in this cohort, we saw excellent tolerability with only one episode of diarrhea in one subject and no nausea and no vomiting. In terms of weight loss, we got 7% at eight weeks. But again, it was mixed placebo and untreated subject. As we expected, confirmation in a small cohort, but we will confirm, I'm pretty sure, in the larger cohort, the monthly administration, the potential for monthly administration plus good tolerability and really competitive weight loss.
Okay, great. For part C, it looks like you're already getting pretty good weight loss, even though it's blinded. But it seems pretty impressive. You're getting that from the 120 milligrams. But you're pushing now to 180 in part C. So what's the rationale for that? Do you think that you might see any other tolerability issues there once you push to 180? What is the most important aspect of this upcoming part C data that you're looking for?
Yes. I will start off with just a commentary on expectations for the Part C data of cohort C1 in Q4. What we have said, Annabel, is that we would expect at 12 weeks, we think the benchmark here based on competitor data is weight lowering of 6%-8% at that 12-week time point. That is what we see in larger competitor data sets. When you look at placebo-adjusted versus absolute, this tends to be high overlap, right? Because at the 12-week time point in those larger studies, we see placebo ranging from +1% to -1%. So we think 6%-8% is the right range, recognizing that our study, of course, is a smaller study, N of 30, 20 on active, 10 who will be on placebo. So we are looking for that sort of weight lowering at the 12-week time point.
As Sam Azoulay has articulated, we also think the PK profile has the potential to deliver on improved tolerability. There is a pretty wide gap between where we are today with tirzepatide or sema tolerability and what we think we have the potential to improve upon that. So we think there is still the potential to have better tolerability, and we look forward to unblinding the data here in Q4 and presenting it.
Okay. The reason for pushing to 180?
This is a phase I study, but we are continuing to explore dose.
Just exploration.
That is right. Absolutely. To your question about whether we would expect differential tolerability issues, we think that the titration schema that we are following has the potential to avoid any episodic tolerability issues as we continue to escalate. Ultimately,
Okay
this is why we do the study and why we explore the dose and so forth, is to learn from that in preparation for a potential phase II.
Okay, great. Just one question on the PEP technology. The technology itself is a PEP technology with a prodrug technology. For obesity, is this a high cost manufacturing endeavor, or is this something that is generally within the realm of what you would expect for peptides?
Yeah, we're very comfortable that we'll be in a very commercially feasible range as it relates to the commercial image of MBX 4291, but also importantly, in terms of the cost of goods. This is a phase I study, but we're still in vial and syringe. We're optimizing formulation as we speak, as we think about future development.
We feel very good about where we are.
At what point will you have the auto-injector? Would it be for phase II or rolling into phase III?
It'd be a similar approach that we've taken for canvuparatide, which is to have that-
commercial image ready for a phase III study. That is why that work is so important, that is ongoing now, is to determine that commercial image and to have it ready for a future phase III study.
Okay. Maybe it is too premature, but how do you envision phase II trials to be designed based on what you know about the tolerability? Are you going to stick with the current starting dose and regimen, then move into monthly? Or do you think that you might just jump into monthly?
We will be excited to see what the phase I study tells us with cohort C1 and the other data that is being accumulated, and that will guide us in terms of the dose and schedule or doses and schedules that we might take into a phase II study. Our goal and our philosophy all along in the phase I has been to generate the data to inform that phase II. In other words, to get to a narrowed window of potential dose and schedule, that might be a winning formula to meet the unmet need in this population.
Do you envision needing several re-treatments with monthly? Is it going to be a six-month or maybe a year-long trial just to be able to test that monthly durability?
For the phase II, I would say it's too early for us to comment on
Okay
Specific design. As we get to that stage, Annabel will be, of course, thrilled to be able to describe how we're thinking about the phase II and what the potential is for 4291.
Okay. I did want a little bit of time for your other compounds, even though we don't have that much information. You have GLP, GIP, GCG, DACRA all in one compound. That's five different mechanisms. What are you aiming for with these? Is this maybe too much, too many targets addressed at the same time? How did you arrive at deciding to do that?
It's one of the beauties of the platform, is our ability to take multiple mechanisms and pack them into a single molecule. That's what we've done with the amycretin, as we call it, is to put in place a triple, plus a DACRA into one molecule. Whereas other companies, competitors, are taking an approach where they're combining two different agents, like a triple and a DACRA, for example, or a pure amylin, as a way to meet that need of looking at multiple mechanisms, we can do that in a single molecule. That's what our amycretin is all about, and that's in IND-enabling studies.
Okay
As we speak, preparing, we think, to enter the clinic very likely next year. The second molecule that we have that's also in IND-enabling studies is our triple agonist, our triple G. We are excited about that. This is space where there is already good precedent data, and we are able to apply our technology to still solve for the unmet need based on those clinical data, which is a tolerability challenge, right? So using our technology to change the PK profile to have a slow and steady rise to Cmax, and also importantly, to deliver that on a once monthly basis. So, that is the profile we are aiming to hit for our triple G.
Got it. Is there a particular population that you are aiming for with the triple plus DACRA, versus maybe the triple? Are you trying to capture different parts of the population?
Yeah, it is a good question. The obesity market and the unmet need is significant with a number of different segments that are emerging in that large market. We think that our focus and goal is to have compounds that will address different segments as they emerge. So we know, for example, that the combination of a triple plus a DACRA ought to deliver even faster and better weight lowering for patients, and there is clearly going to be a segment in the market for that sort of profile for patients. We also think that co-agonists, for example, will continue to play a very important role in the obesity marketplace. So while I cannot pinpoint for you today, Annabel, with precision exactly what those segments will be for each, that will in part be guided by the clinical data.
But we do think that our platform can be applied broadly to these different mechanisms, and therefore, we can be well-positioned to address the differing segments that will emerge in the obesity landscape.
Okay. That is great. We are just about out of time, so thank you very much for your time today. I apologize for the delay in front.
Great to see you, Annabel. Thanks again for the invitation.
Thank you.
Thank you.