Good afternoon, everyone. Thank you for joining us on our next session. I'm Michael Yi, a biotechnology analyst at Jefferies. I am really pleased to have members of the team from MBX here with us, CEO Kent Hawryluk, as well as the CMO, Sam Azoulay. Importantly, the company is going to give a brief overview of what's going on at MBX. Obviously, I'm very excited about the upcoming data in the third quarter. Without further ado, we'll have Kent give a presentation and we'll have some questions.
Thank you, Mike, for hosting us at this conference and for the opportunity to present an overview for you of MBX. This is certainly the most important year in our company's history, with the release next quarter of our AVAIL phase two data for the first once-weekly PTH replacement therapy in chronic HP. A reminder that this presentation will be making forward-looking statements. I encourage you to review our risk factors and other disclosures in our SEC filings that are available on our website. For those of you who are new to the story, MBX Biosciences is a clinical stage biopharmaceutical company founded by global leaders in peptide drug design, development, and commercialization. MBX aims to unlock the full potential of peptide therapeutics through precision therapeutics that have continuous infusion-like drug exposures and convenient, infrequent dosing regimens.
Our novel PEP platform technology has already delivered two clinical stage programs in indications with significant unmet need, including hypoparathyroidism, HP, and post-bariatric hypoglycemia, PBH. We also expect another program to enter the clinic soon in obesity. We have other programs addressing obesity and comorbidities in development as well. This PEP platform technology was invented by Dr. Richard DiMarchi, who is a leading peptide chemist. He's the inventor of Humalog and the first GLP-1, GIP co-agonist. Richard and I have a 20-year history of successfully starting and creating endocrine and metabolic disease-focused companies that have yielded partnerships and M&A with Merck, Lilly, Roche, and Novo Nordisk. MBX is well-funded. We have cash to support our operations to mid-2027, which includes a number of important value-creating milestones across all of our programs. With this PEP technology, we are creating a growing pipeline of differentiated product candidates.
We believe that each of our programs has the potential to be a category leader with blockbuster revenue potential. Our lead product candidate, canvup aratide, is a once-weekly PTH replacement therapy candidate. We note that chronic HP, while a rare disease, affects over 250,000 people in the U.S. and the E.U. Currently, the standard of care, surprisingly, is not hormone replacement therapy, although we see that changing. We published positive phase one data for canvup aratide last year. Our phase two trial is fully enrolled. We are on track to release top-line results in the third quarter. We have orphan drug designation in the U.S. Our second candidate, MBX 1416, is a potential therapy for post-bariatric hypoglycemia, where there is currently no approved pharmacotherapy to treat this disease. We estimate a U.S. prevalence of over 90,000. Again, a significant rare disease as well.
We presented positive phase one data in January and are on track to have an end of phase one meeting mid-year in advance into a phase two study in patients with PBH in the second half of the year. We're excited to have an obesity portfolio of differentiated PEP candidates utilizing our technology. This includes MBX 4291, which is a GLP-1, GIP co-agonist prodrug. We are on track to file an IND this quarter, followed by a phase one in overweight and obese adults, our target population. This study should be able to demonstrate, we believe, once-monthly time action, as well as other areas of potential differentiation, such as better tolerability and greater weight lowering. We'll continue to utilize our discovery engine to increase our obesity candidates using this really differentiated technology.
You notice here, looking at these milestones, that all three of these programs will be set up for clinical proof of concept in 2025 and 2026. With canvuparatide , we conducted a placebo-controlled phase one study in healthy volunteers. The purpose of the study was to evaluate safety, tolerability, PK and PD effects. I'm delighted that the results were exactly as we expected and consistent with this PEP prodrug design. For example, we confirmed that we had a half-life of eight to nine days, which fully supports full-week coverage with convenient once-weekly dosing. We also saw that we had continuous infusion-like flat PK. We peaked to trough over a seven-day period that is comparable to the peak to trough of competitors, products, and candidates over a one-day period.
We saw a rise to steady state after the third to fourth dose and a low to moderate intersubject variability. In terms of PD, we saw the expected effects as well. We saw a disproportional increase in albumin-adjusted serum calcium and decrease in endogenous PTH, which is an indication of calcium increase. These results helped us select the dose and give us high conviction that we will see a treatment effect in the HP patients. In March, we were very pleased to announce that we had fully enrolled the AVAIL study above our initial target. We take that as a testament to interest from patients and study investigators in a once-weekly treatment option. 64 patients with HP were evenly randomized to one of four treatments: 400, 600, or 800 micrograms of canvu given once weekly or to placebo.
The 12-week dosing period is divided into a four-week fixed dose period, followed by an eight-week dose adjustment period, where the patient's dose can be adjusted by 200 micrograms every two weeks. The pill supplements will be reduced during the four-week and eight-week period weekly based on treatment algorithms that are provided to the study investigators. We are very excited about this trial and believe that if approved, canvup aratide can be a game changer for HP patients.
If there's one message I want to be sure you take away from this fireside chat, it is that MBX is unique in having a clinically proven platform technology, multiple high-value clinical programs addressing significant unmet need with near-term de-risking milestones, such as our canvu phase two data readout next quarter and 1416, the advancement into PBH patients this year, and with our obesity portfolio starting at phase one with a potential once-monthly GLP/GIP co-agonist prodrug. Happy to answer the questions in the time we have.
Yeah. I think we could tag team this way is all right. You can stand there. Maybe just obviously, there is a lot of focus on the phase two data coming in the third quarter. I think if you went back to the design of the study, we could go back to that slide, people are trying to determine what would be good data. Appreciating that this is a dose-finding proof of concept study. This is not a randomized pivotal study. There is a lot of things we are going to glean out of this study. Can you talk about when these results come? What are you looking for on the primary endpoints? What defines success or not success? Appreciating that there is a daily out there that people are going to try and compare to.
Sure. The AVAIL phase two study is designed to provide clear and convincing clinical proof of concept and help demonstrate the differentiation and the ability to meet the unmet need in HP. I'm going to ask Sam to provide a little more color on the study and what we're expecting.
Hi. Thanks. Thanks, Kent. What we are looking at is a definition of responder, which is a proportion of patients who are completely independent from active vitamin D, taking calcium supplement at a maximum of 600 milligrams per 24 hours while being within the normal value of serum calcium. That is a definition of responder. We included 64 patients in this study. With 64 patients, we have a power, which is above 90%, to show a treatment of 55% of responder versus 7% in the placebo group. In fact, in the treatment arm, we are going into the treatment group, we are going to pool all the treatment arm altogether because it is personalized, some sort of personalized medicine. Every patient can have a different dose. We are going to pool them. 7% placebo, 55% treatment.
That gives roughly a placebo-adjusted treatment response of 48%. If I put this in the context, Yorvipath, at the same period.
This is a SanDisk.
Yeah. Yorvipath, a SanDisk of product, had over six months, six months in their phase three study, a placebo-adjusted response of 64%. Remember that our result will be after 12 weeks. And it's a placebo-controlled study, right?
Let me repeat that again. Six months, a SanDisk had a 60-something percent delta.
64%.
64% delta.
Yeah, in the label.
In six months. Yours, do we call that a 12-week or a 12-week?
Twelve-week treatment. So that we're going to twelve-week. But we will have an extension up to two years. So we will be able to provide also data at six months equivalent, one year and two years.
Certainly at the end of 12 weeks, what did I get to get through first? If you think you could show at least a 45% delta, which is great at only 12 weeks versus them at 64% at six months.
Yes. It's a result of a discussion with experts in the field, KOL, but also the FDA. We believe that these results open the path to the phase three trial and will be good with a weekly administration, good enough to go and go to the next step.
When you compare the endpoints, are the endpoints the same? Are we comparing the same definition of 64% and 45%? Is the definition the same? Or is there actually a four-point?
So there's.
There's three criteria.
Yeah. The definition of the endpoint is similar. I would like to insist on one thing. Again, it's 12 weeks versus six months. We have to give the chance also to see the results at six months during the open label extension to make a fair comparison with the two products.
Have they given any other data points other than six months?
They showed data at four weeks.
Four weeks.
I haven't seen anything between four weeks and six months.
What do they show at four weeks?
At four weeks, it depends which population you are looking at. If you're looking at the ITT population in the phase two, in the phase two, not in the phase three, because the four weeks was in the phase two. If you're looking at the ITT population, there was a 50% response in the treatment arm versus 27% in the placebo. If you have to go to the modified ITT to get the 50% versus 15% response with Yorvipath.
Okay. Certainly at four weeks, at least on an absolute basis, a daily can get you about 50%. You believe at 12 weeks, you should be certainly well north of that. Should be north of that, do you believe? Or how would you think about that?
First of all, we have to get back to the drug itself, right? One is a daily administration. To get to the steady state, it's more rapid, right? To get to the steady state with MBX 2109, you need three weeks to get to the steady state and to have stable patients, three to four weeks to get that. That's why we had this initial four-week treatment period, fixed dose treatment period.
Right. And it's 35% placebo-adjusted at four weeks for Yorvipath versus what we're talking about is a 48% placebo-adjusted full treatment response at 12 weeks.
Anything in.
In the modified population, just to be clear.
35% at four weeks, 45% at 12 weeks. We should not be looking at 65% plus or their 70%-80% response rate. That was at six months. That should not even be looked at.
I want to bring up another point. Agreed, Mike. Thanks. In the U.S. label, it was very clear, actually, four places in the summary part of the label itself, that the limit of dosing for Yorvipath is 30 micrograms in the United States versus 60 micrograms in Europe. We also saw that there was a waning effect of efficacy such that at weeks 52 and 78, patients became non-responders. That is something to watch for. I think in our case, we see an opportunity with our different device that we intend to take forward in the phase three and commercialize to differentiate and be able to address the full spectrum of HP patients.
What about the titration protocol? A lot of people looking at this are like, "Okay, well, I know that we're running up against 12 weeks, but in the first four weeks, there's a fixed dose. And then the next eight weeks, it's dose adjustment." You're trying to get the calcium and vitamin D down, and you're trying to get the actual calcium levels up by titrating your drug. Is that complicated? Is that a factor in determining success? How do you think about that?
It's not complicated. In fact, it looks at the recommendations that Yorvipath had in their phase two study, in phase three study, and in the label. Very similar. Let's get back to the algorithm, the decision algorithm. The study has two parts. One, which is a fixed dose when patients are randomized between the three treatments, one of the three treatment arms, 400, 600, or 800 micrograms, or placebo. During this period, you cannot change the dose, right? What's happening is that you are going to decrease first vitamin D by one-third, 30%, or 50%. Then you eliminate vitamin D. You go to calcium and the same thing. You start by eliminating in order for the patient to be completely independent from active vitamin D. Then you reduce calcium. As long as the serum calcium is within the normal value, you continue.
That's a fixed dose. When you move to the titration phase, the titration phase, that means every other week, you can change the dose by increment of 200 micrograms every other week. Every week, you can adjust for calcium supplement or active vitamin D if the patient is still taking it if needed. We have also a decision algorithm in the protocol for these two phases in order to make sure that not only it's standardized, but also the physician is guided on how to manage.
It's a similar treatment or titration algorithm to that used in the Yorvipath trial and is familiar to these investigators.
Yeah. That's a standard design. So again, 35% delta at four weeks, 45% plus, you're powered on a delta for 12 weeks. If you are above those numbers that you're saying, you obviously feel very good about your drug being active. We don't need to compare it to a daily at six months. Your drug is clearly active, working, and it's a weekly. Is that a fair statement?
Yeah. It's a fair statement. Again, we are back to how we calculated the sample size for this trial. That's what we are expecting.
Working closely with our KOLs. We agree.
Yeah. Okay. All right. So when is that data reading out? Have you completed enrollment? So can I just calculate out 12 weeks? Or what about this four-week follow-up period? Do I got to put that in and just walk through that?
All the usual steps. We are just remaining clear on the guidance of Q3 for release, and we are on track.
Okay. What's in the four-week follow-up period? Is there anything in that that's helpful at all? Or no? Such as safety?
It's a.
What happens in the four-week follow-up period?
The four-week period, the 30-day visit, is mainly for patients who are not rolled over to the open label extension. For those patients who are rolled over, they immediately roll over to the next study, and it's easy. For patients deciding not to, for any reason, deciding not to get to the open label extension, that way you have the 30-day visit. Like any protocol, what we do at the end of a study.
Do you expect that 90% of plus people are just going to continue getting their weekly doses and going into the extension?
We haven't provided guidance on the percentage that are rolling over. I point back to the popularity of the study in terms of over-enrolling with increasing our target to 64 from the original target of 48 as an indication of how much their interest is in a once-weekly. We think that's a good sign.
Okay. We are aiming to maximize.
Excellent. All right. We will look for that. Now, what also about safety tolerability? Obviously important. One of the things that people look at previously was, in some cases, excursions that could lead to hypercalcemia. Is that relevant? Would you expect to see any in this study? What is good and what is not good?
We are expecting, we are looking at all the safety parameters, the classical ones, serious adverse event, et cetera. We are looking at tolerability, which is defined by hypocalcemia and hypercalcemia excursion. We are not expecting off-target because of the way it's a PTH replacement therapy. We are not expecting that we will have many off-target adverse events. Clearly, what we'll be looking at is hypocalcemia and hypercalcemia. Certainly, due to the PK, the infusion-like PK profile we have, what we are looking at during the maintenance, I define the maintenance as a patient who has reached the right dose, independent from active vitamin D, et cetera, and calcium supplement, is now in the maintenance phase. Because of our PK profile, we can expect to see less excursion in the hypocalcemia and hypocalcemia.
I want to reinforce a point I made earlier that the phase one was in healthy volunteers. That is a very different population from the HP patients that we have enrolled in our phase two, for example. We performed in the phase one exactly as we expected. These healthy volunteers have intact homeostasis. They have endogenous PTH. They are entering typically in a normal calcium range or even on the upper end of normal. We are pushing them to higher concentrations of PTH. We would expect to see some hypercalcemia in the phase one. We did. One at the 600 micrograms, it was asymptomatic, resolved spontaneously. Two in the 900 cohort of the MAD study, the highest dose. Again, asymptomatic, a lab value reading, no other symptoms. We think that that will support the safety profile in the HP patients.
One point to make about the calcium throughout the week, when we look at the exposures and concentrations of active drug in the healthy volunteers, we observe that at the trough concentration for the 900 microgram cohort, it lined up with the 600 Cmax or maximum exposure of active drug, where we also saw a sizable increase in serum calcium. In terms of the drug on board, we would foresee that we would have full week coverage. In the HP patients that are PTH deficient, we're bringing back that function. We'd keep them in a nice tight range. We actually think at maintenance, to Sam's point, we could see fewer excursions into hyper and hypocalcemia versus.
Partly because they actually have the underlying disease in healthies. They have intact, so their calcium levels are already normal. So given the drug, the calcium could spike.
Right. Exactly.
Here, would you expect you could have some cases, but it's not overly concerned because, in fact, here at 800, you look at that first dose, like that is a lot of drug. If they do not titrate down fast enough in the second, they could have hypercalcemia cases. Just for people's understanding, we do not want them to, would you expect some? That is not a concern, is your point.
In general, we would not expect to trigger the homeostatic effect in the HP patients because they are different, right? They are PTH deficient to different degrees. I will let Sam address the question.
Yeah. As you say, we like to refer to being customized treatments, right? So it's very possible that the patient has observed with Yorvipath, enable paratide, we can observe some hypercalcemia or hypocalcemia at the beginning when you try to balance.
I mean, they have a sentence, has some.
Yeah. Exactly.
Is that on the label? I don't know what percent.
Yeah. It's not only in the label, but it's a warning that we have to be careful about hypo and hypercalcemia. And also, it drove a more frequent monitoring of calcium. Usually, it's up to the physician to monitor. In the Yorvipath label, there is a requirement to monitor every four to six weeks. That's an additional requirement. Yeah, it's possible to see. As long as it's asymptomatic, as long as it's a biological effect.
Does it resolve within the week?
Exactly.
If it resolves in the week, and you would have gone to a lower dose as long as it did not drop off.
If it's hypo, you can give, forget, you can give calcium supplement. You can give vitamin D, so it's not a problem. And if it's hype, you can also, if the patient is still on supplement, you can decrease the supplement. If it's not, you can decrease the dose. I don't think that it's manageable. Again, back to the maintenance therapy, as a long run, I think it will be very important. It will be an advantage to see less excursion.
You complete enrollment. We can add 12 weeks plus some time to analyze the data, clean it, and then you'll put the data out in the third quarter. Is that the way to think about it?
Yes. We're on track.
You're on track. And based on this data, if you show a statistically significant benefit, and by the way, just for statistical, it's the pooled analysis that you're looking at?
Yep.
Okay. Not one specific one. It's the pooled analysis.
No. Pooled treatment of 400, 600, and 800. At the end of the pool, at the end of the 12-week, it will not be any more 400, 600. It could be 1,200.
That's just a starting dose. That's why you're pooled, obviously.
Exactly.
Because they're all getting their dose at the eight weeks, whatever, it's customized.
Right. Exactly.
Yeah. That will be pooled. If we get statistical significance north of 45%, you're going to say that's a win. Looks good. March to phase two B, would that be the expectation?
We're expecting to conduct an end of phase two meeting followed by a phase three. We are not looking to reinvent the wheel. There's already been some regulatory path laid down. We will be looking to that as guidance.
Okay. In the last couple of minutes, since that's obviously, we'll wait to see that data. I think we've kind of run a number of scenarios there. We will see the result. Again, you guys are confident that, obviously, based on the phase one, calcium levels are going up. They're going up in the healthy volunteers. It is working. People believe that the calcium levels go down in the back half of the week. That is because those are healthy people. Therefore, there's a natural reaction to push the calcium down because it's a natural response. In PTH patients, it's not going to do that.
That's correct.
A lot. It should last for the full week because your PK coverage of the underlying drug is there for the whole week.
You got it.
All right.
Perfect.
Okay. Very good. We want to see it play out that way. If that plays out, then I have to say that I'm going to skip over the PBH because I do want to say that a lot of investors have been asking about 4291. Given that ADA is in a couple of weeks too, I think there's a lot of focus on obesity. Tell me about your 4291. You're filing an IND in Q2. We're going to hear about that soon.
Yeah. This is really important. As I said, a GLP-1 GIP coagonist prodrug. That means we're combining the two mechanisms that appear in Zepbound, which is the gold standard, right? Demonstrated head-to-head superiority versus the GLP-1 monoagonist. Additionally, we provide this gradual controlled release of the GLP-1 GIP active drug. What that means is that it not only extends the half-life, but also the Tmax or when you reach Cmax. We know that the rise to Cmax, the rate of rise to Cmax is contributing to the gut side effects in the incretins that cause reduced adherence and compliance, the high discontinuation rate. We believe that with our approach, we could potentially see, in addition to once monthly, better tolerability. If we get patients to tolerate a higher dose level, that should also predict a greater weight lowering.
We'll be looking forward to looking at several parameters in our SAD-MAD 12-week part C study in, again, high BMI adults of POC.
How should we think about differentiating that versus, say, MariTide from Amgen, who was here across the room just two hours ago? They've got data in 500 patients for a year with their monthly. Data looks pretty good. They're already in phase three. Lilly, actually, do you know Lilly? They just announced a deal this morning, something like that, on their attempt to go in. A lot of players.
Confirmatory of pharma's interest in longer-acting incretins. We believe that we have a differentiated approach. In terms of looking at our peers and what we would hold ourselves to, look at the side effect profile, particularly around the nausea vomiting. Look at the Tmax. How quickly are you reaching the highest concentration? We believe that the data we intend to present will demonstrate that differentiation.
Based on the platform of the science that Dr. Richard DiMarchi, an expert in this space, has done, that's the advantage is that you believe that he's worked on this. He's an expert in this space.
That's right. Invented the first one.
That would be your claim to why this could be differentiated.
Yeah. I think also leveraging the canvup aratide experience. It is obviously 4291 is a different flavor of the prodrug, but it is analogous here. We have been able to demonstrate that infusion-like PK profile that makes it.
Did this candidate come out of DiMarchi's lab?
Yes, it did.
Came out of his lab.
We have exclusive worldwide rights to all uses.
Guys, thank you very much.
Thank you.
Looking forward to it. Thank you for all of the progress. We'll catch up soon in the third quarter.