Great. Welcome, everyone. My name's Jess Fye. I'm a biotech analyst at J.P. Morgan, and we are continuing the 43rd Annual Healthcare Conference today with MBX. First, you're going to hear a presentation from the company. Then we're going to go into Q&A. If you're in the room and have a question, just raise your hand, or you can send them to me through the portal, and I'll read them off the iPad. Without any further ado, let me introduce the company's CEO, Kent Hawryluk.
Good afternoon. I want to thank each of you for attending today, and as well, thank Jess Fye and the J.P. Morgan team for hosting us at this wonderful event, and I'm delighted to be here and providing an update on MBX Biosciences. Last year was really a transformative one for the company, and this year is already off to a strong start. I'd like to remind you that this presentation includes forward-looking statements and encourage you to review our risk factors and other disclosures in our most recent SEC filings, all of which are available on our website. MBX Biosciences is a clinical-stage biopharmaceutical company founded by global leaders in peptide drug design and development. We are pioneering a novel precision endocrine peptide, or PEP, platform technology.
PEPs are engineered to have optimized pharmaceutical properties, including extended time action and consistent drug exposure, as well as convenient, less frequent dosing. This week, we are unveiling the non-proprietary name for our lead candidate, canvuparatide, formerly MBX 2109. Canvuparatide is an investigational parathyroid hormone, or PTH, peptide prodrug therapy for hypoparathyroidism, or HP. We have orphan drug designation in the U.S. and are conducting a phase II clinical trial. Our second program, MBX 1416, is a long-acting GLP-1 antagonist and potential therapy for post-bariatric hypoglycemia, or PBH. We recently presented positive top-line results from our phase I study and intend to take the program forward into phase II in the second half of this year.
MBX is also developing an obesity portfolio of differentiated PEP candidates, including MBX 4291, which is a GLP-1/GIP co-agonist prodrug, which we believe has the potential for once-monthly dosing, as well as improved GI tolerability and greater weight loss than current market leaders, and we have additional obesity programs for the treatment also of comorbidities, and we'll be sharing more on those developments later in the year. We have raised over $400 million to date, including over $250 million in gross proceeds from our financings last year, so our 2024 year-end cash balance was approximately $262 million, which we expect to fund our operations into mid-2027. We have considerable momentum and important value-creating milestones in 2025 and beyond, and our seasoned team brings together exceptional expertise from large pharma and clinical-stage development companies.
Members of our team have collaborated successfully over several decades on the discovery, development, and commercialization of first-in-class endocrine therapeutics, including Forteo, Humalog, and Byetta, and we'll continue to grow our team to support the ongoing development and intended commercialization of our product candidates. Our expanding pipeline is really powered by this precision endocrine peptide platform, and it's designed to overcome key limitations of unmodified and modified peptide therapies and to improve clinical outcomes, as well as simplify disease management for patients, so it's based on fundamentally innovative peptide design, and this is to enhance pharmaceutical properties, including increased potency, stability, and solubility, and we can engineer multiple mechanisms of action into a single peptide. For example, our GLP-1 GIP co-agonist prodrug, MBX 4291. Second, a programmable prodrug technology, which provides drug activation at a precisely controlled rate, and this can flatten peak-to-trough concentration ratios and improve clinical outcomes.
Canvuparatide and MBX 4291 are prodrugs. Third, fatty acylation to extend time action and reduce dosing frequency. Now, this approach has been used in tirzepatide and semaglutide. It is compatible with non-injectable formulations, including oral. And it's designed into all of our PEP candidates. Now I'll provide an overview of our pipeline. Our lead investigational drug, canvuparatide, is a potential best-in-class drug candidate for hypoparathyroidism, or HP, which is designed to provide continuous infusion-like exposure to PTH with convenient once-weekly dosing. We recently published our positive phase I results, and we have a phase II clinical trial called AVAIL that's ongoing. We are expecting to complete enrollment this quarter and present top-line results in the third quarter of this year. Our second compound, MBX 1416, is a potential therapy for PBH, employing a clinically validated mechanism of action, GLP-1 antagonism.
We are pleased to present positive results from our phase I study last week and are working to take that forward to a phase II later this year. And our first obesity candidate, MBX 4291, it's a GLP-1/GIP co-agonist prodrug with potential for once-monthly dosing. And we're very excited that we have completed our IND-enabling studies, and we're preparing to file an IND next quarter and follow that up with a phase I study later in the year. And we'll continue the development of our other obesity portfolio assets and be providing more about those additional obesity candidates later in the year. We estimate that the market opportunity for each of our rare disease programs exceeds $1 billion annually, with considerable upside potential for our obesity portfolio. So now let me take you through our lead program, canvuparatide. Chronic HP is a serious condition.
While rare, we estimate that it affects more than 250,000 people in the U.S. and Europe combined. It really carries a high burden of illness. It's caused by a deficiency in PTH, generally from the inadvertent removal of the parathyroid glands during neck surgery. PTH is responsible for maintaining calcium homeostasis in the blood and tissues, such as muscles and nerves that really rely on PTH for proper functioning. HP causes hypocalcemia, which has really serious adverse effects on patients, including seizures, tetany, and brain fog. The complications mentioned on the right result from PTH deficiency, but also the standard of care. It can be associated with symptoms of hypercalcemia as well, which include GI issues and weakness. The standard of care today for HP patients is very onerous.
And it consists of large doses of calcium and active vitamin D, on average, at least seven or eight doses spread throughout the day and night. And importantly, these do not address the underlying cause of disease. So HP patients can experience large fluctuations in their serum calcium levels. And this causes the symptoms and the long-term complications that affect multiple organs, including the kidneys. And in contrast to the products and candidates that are administered daily, canvuparatide is a potential first once-weekly PTH replacement therapy prodrug, which is designed to provide flat infusion-like PK. And we believe that canvuparatide can reduce the hypo and hypercalcemia excursions and improve clinical outcomes. So in addition to patient preference for less frequent injections, we believe that canvuparatide can offer better clinical outcomes and greater adherence.
And when you just look at what's happened in, say, obesity, when you transition from a daily to weekly treatment option, it's pretty clear that the physicians and the patients quickly adopt the weekly dosing based on certainly greater convenience, but also better clinical outcomes. We conducted a phase I trial, a single and multiple ascending dose, and it was in healthy adult subjects. We're delighted with the results. It reinforced the candidates designed, and it was exactly in line with expectations. The primary endpoint was safety and tolerability. The secondary endpoints were to evaluate the PK profile and to examine pharmacodynamics, or PD, increased serum calcium and reductions in endogenous secretion of PTH, which is a marker of increased serum calcium. So let's take a look at what the results showed. First, that canvuparatide generally well tolerated with a favorable safety profile.
Also, we saw a half-life of eight to nine days for the canvuparatide active drug, with a flat peak-to-trough over a seven-day period that was comparable to what is seen with the daily products and candidates over one day, and we saw a dose-dependent PD response, which helped us to select phase II doses, so we're just extremely excited with this program and feel that if approved, this could really be a game changer for HP patients, so this is where we are today. We have this AVAIL phase II trial that's ongoing and on track for completion of enrollment this quarter and reporting of top-line results in the third quarter of this year.
AVAIL is a randomized, double-blind, placebo-controlled study in approximately 48 patients with HP who are randomized to one of four treatments: 400, 600, or 800 microgram doses of canvuparatide given once weekly or to placebo. The primary endpoint is the proportion of patients who are able to discontinue from active vitamin D and reduce serum calcium supplements after 12 weeks of treatment while maintaining normal calcium levels. We'll also be examining safety, tolerability, PK, other PD markers, and patient-reported outcomes. All patients who complete the study will be able to enroll in a two-year extension study where everybody will be treated with canvuparatide on an open-label basis. Now I will turn to our second program, MBX 1416. PBH is a rare, chronic, and serious complication of bariatric surgery. We estimate that there's a U.S. prevalence of over 90,000 patients.
There's currently no approved pharmacotherapy for PBH. Therefore, we see a meaningful opportunity for a treatment for PBH. PBH presents typically three months or six months to three years following Roux-en-Y or vertical sleeve gastric bypass procedures. Anatomical changes from these surgeries cause nutrients to quickly leave the stomach and enter the small intestine. When PBH patients eat, an excessive GLP-1 release occurs, which stimulates insulin secretion and reduces glucose in circulation. Severe hypoglycemia can result, leading to serious neuroglycopenic symptoms, including confusion, seizures, and loss of consciousness. PBH is very disruptive to the patient's lives because the timing of hypoglycemia is unpredictable, can occur multiple times a day, and may require an injection of glucagon as a rescue. GLP-1 approach has been used and clinically validated. Right now, the standard of care for PBH is focused on dietary intervention.
So, let's look at small frequent or frequent small meals, avoidance of high glycemic index foods. And this is very difficult to manage for patients. Compliance is an issue. There are off-label medications with limited clinical data, and they can be poorly tolerated oftentimes. So, this approach with GLP-1 agonism clinically validated, and the idea is to inhibit GLP-1 at the GLP-1 receptor, curbing this kind of influx that is occurring with these patients, this pathophysiology. So, our goal with MBX 1416 is to be the first once-weekly drug approved to treat PBH. It is designed as a long-acting, high-potency GLP-1 antagonist. It's based on the human GLP-1 sequence with structural modifications to enhance potency, stability, and solubility. It's fatty acylated to extend the time action, thus supporting once-weekly dosing.
We believe that by blocking GLP-1, we can prevent the severe hypoglycemia from occurring and vastly improve these patients' quality of life. We were pleased to report last week positive data from our phase I study. The study was a single and multiple ascending dose, randomized, double-blind, placebo-controlled study. It was designed to look at the safety and tolerability, the pharmacokinetics, and pharmacodynamics of MBX 1416 in healthy adult subjects. We're pleased with the results. It supported our belief that MBX 1416 can be an important treatment for PBH available to patients and their doctors. First, we determined that MBX 1416 was well tolerated with a favorable safety profile. There were no serious adverse events. The majority of treatment-emergent adverse events were injection site reactions, mild to moderate, mainly erythema or redness.
Second, we demonstrated a half-life of 90 hours, which fully supports once-weekly dosing. And lastly, we saw a favorable PD signal in GLP-1 in these healthy volunteers that we believe will translate to a therapeutic benefit in PBH patients. So very excited to have made this announcement and are intending to take a phase II forward in the second half of this year to further optimize dosing. So now I'll turn to our obesity portfolio. I believe everyone's aware that obesity is a global epidemic. It's created a very large market opportunity that's only growing. And many pharmaceutical companies have recently entered the field following the blockbuster success of Zepbound and Wegovy. However, current obesity treatments require weekly injections. And they're associated with pretty significant GI side effects, which reduce adherence and increase discontinuation, thereby limiting the effectiveness of the drugs and maximal weight-lowering potential.
Thus, we see an opportunity for improved obesity treatments, and further, we believe that we can use our PEP platform to, first of all, discover novel peptides that have extended time action and also utilize flexible dosing to improve tolerability and effectiveness, and we believe that just given the heterogeneity of the patient population as the obesity landscape matures, a variety of treatment options are going to be needed. And we selected this first candidate, MBX 4291, as a GLP-1 GIP coagonist prodrug based on the fact that tirzepatide is the current market leader for achieving weight loss. In fact, recently, tirzepatide demonstrated superiority against the monoagonist semaglutide in a head-to-head study, so if you look at the illustration on the right, you can see that MBX 4291 takes advantage of all the key parts of our PEP technology or tools in our toolbox, so to speak.
So if you can see the illustration there, the yellow tails at each end of the molecule in the upper left of the illustration, these represent fatty acylations. So this facilitates binding to albumin and circulation and extending time action. The red zigzag at the N-terminus represents our proprietary prodrug moiety. And this is designed to activate under physiologic conditions, pH, temperature, requiring no enzymatic intervention. And it's at a precisely controlled rate. And this was tuned specifically to support a once-monthly target product profile. So now you see the conversion. And when you consider the active drug exposure over one month and the binding at the GLP-1 and GIP receptors, you see that we've strategically combined several elements of our PEP technology to enable this. So we're very excited that we have completed our IND- enabling studies.
The team is preparing an IND submission to take place next month and very interested in taking this forward into the target population with a phase I study. And we'll continue to share more on our progress on this program and our other obesity programs throughout the year. We think that this asset is really differentiated not only against current obesity drugs on the market, but also those in development. Well, 2024 was a transformational year. And what it did was show, I believe, that we could reproducibly apply our PEP platform to create peptides that deliver long-time action, consistent drug exposure, which translates to a PD effect in healthy volunteers.
So now, as we look ahead to 2025, we're very closely anticipating what we think will be a transformational milestone for the company: the release of our AVAIL phase II data in PTH patients of the first once-weekly PTH agent, canvuparatide. We also have other important milestones this year as we advance each of our PEP candidates through clinical development, including the initiation of a phase 2 trial in PBH patients with MBX 1416 and initiation of a phase I study in the target population with MBX 4291. I think MBX is unique in having a proven platform technology as well as multiple rare endocrine disease programs with significant unmet need and large market opportunities. I think we're positioned for a really exciting year and an opportunity to create significant value for shareholders. These conclude my remarks.
I want to thank you again for your interest in MBX and, again, the J.P. Morgan team. And as Jess mentioned, we now have some time for questions.
Great. Thanks for the presentation. You spent some time talking about your PEP platform. But can you also walk through how it's different from other long-acting technologies we hear about?
Absolutely. Well, first, I mentioned that we really start with world-class peptide designers, medicinal chemists. These include Dr. Richard DiMarchi, who's our scientific co-founder. He's the inventor of Humalog, also famously the first GLP-1 GIP coagonist, and he's really been working on this PEP platform for quite a few years, creating the design rules and optimizing it, and so we start, first of all, with just an innovative peptide to begin with. Now, in terms of extending the time action, we do use fatty acylation, which, as I mentioned, has been used in tirzepatide, semaglutide. I would say it's more elegant versus, say, other techniques that have been used in the past, a little more dated, like pegylation, for example, so that's one distinction. What's really quite special and differentiated is our prodrug, and this adds another dimension to creating that flat peak-to-trough, that really infusion-like profile that we achieve.
It's really efficient. You think about it as a couple of amino acid extensions with chemical modifications that tune it to cyclize at a controlled rate under physiologic conditions. It breaks the amide bond, releases the active drug to have its intended pharmacologic effect. And so that kind of delayed release effect is not easy in peptides. It's something we've been able to demonstrate reproducibly and, again, I think really quite differentiated.
With that technology, what's your method for selecting targets and potential drug candidates?
We start with significant unmet need in endocrinology and metabolism, large market opportunities where you have standard of care that can be improved, opportunities to get better efficacy, and simplify disease management. That's sort of the baseline. Beyond that, we really want to see clinically validated targets based on where we are. In endocrinology, there are quite a few of those, but also well-established endpoints for regulatory approval.
Makes sense. So maybe digging into canvuparatide, can you talk about how the design of that product, maybe compare and contrast it with other products we've heard of, like Ascendis's Yorvipath or Astra's eneboparatide?
I'm going to invite Sam Azoulay, our CMO, to answer that one.
Thank you. Thank you, Kent. Yeah. So our PEP platform was very useful to design MBX 2109. MBX 2109 combined two technologies: the first one, which is a prodrug technology, and the second one, the fatty acylation technology. And Kent spoke about that the fatty acylation was already proven and being used with semaglutide and tirzepatide. But let's back to how it works, how the drug works. So when you inject MBX 2109 into the bloodstream, it's inactive by design. The prodrug is still a prodrug. When you inject it, it gets through because of the pH and temperature physiological condition, right? No enzymatic intervention. The prodrug gets transformed into an active drug. And one of the at the N-terminal, there is two amino acids and the fatty acylation, a fatty acyl, which is cleaved, and it's cleared. So then these drugs become active, right?
It is going to the PTH receptor and activates it. However, there is this fatty acylation on the C-terminal. Remember, there were two fatty acylations. The one left on the C-terminal helps binding with albumin. And albumin is being used as, I like to say, a reservoir, if you want. And so there is this slow release coming from the pro-drug and also albumin, which is also acting as a reservoir for the drug, right? That's how it works. So it's a very nice technology, which is unique to MBX. And I think I like to say it's an elegant technology, right, as compared to maybe others such as Yorvipath, which is using a pegylated classical linker technology. And eneboparatide has a different mode of action. It acts on the R0 receptor conformation and has a long signaling, but has a very short half-life.
So in both cases, Yorvipath and eneboparatide, despite some differences in mode of action, are both once-daily dosage when MBX 2109 is weekly, given it will be administered weekly. So it's a big difference, not only on technology, long half-life, right? But also back to the technology itself, this long half-life also has a very short, very small, sorry, peak-to-trough ratio, which thinks that maintain the concentration over time, over the week. And the peak-to-trough ratio is around 1.5-1.7. So it's a very, very elegant technology, which was developed by MBX with regard to PTH replacement.
What are the aspects of the phase I data for this product that you think kind of best highlight the differentiation?
So clearly, the product has a very good safety profile, is being shown to be well tolerated. But also, what's very, very important is the PK. The PK shows that it has a half-life of eight to nine days, the Tmax, which is around two to three days. As I said, the peak-to-trough ratio is around 1.5-1.7, low inter-individual variability. So a very nice PK profile that in the population of PTH of a hypoparathyroid patient, patient with hypoparathyroidism, sorry, would be a very good PTH replacement and could maintain the concentration of calcium over time in a stable range. So in our phase I study, we also proved that we had a pharmacodynamic effect you were expecting, as well as this subject, healthy subject, have endogenous PTH. And so you see a very nice decrease in the endogenous PTH due to the negative feedback.
So a good tolerability, good safety profile, confirmation of the PD effect, and certainly a PK profile, which is by design exactly the one we expected.
Got it. So you reiterated your target to complete enrollment in the phase II AVAIL trial this quarter. Anything you want to share on how far along it is today?
I'll just show that I'm really pleased with our progress and very confident that we're on track to complete that enrollment, which sets us up for very nice, like I said, a major data release in the third quarter, our top-line results.
When we look at that data in the third quarter, what are you looking for when the study reads out? What's the win scenario?
Can I let our CMO address that?
So we have a study design that is planned to show a difference with placebo. And back to the study design, it's a placebo-controlled study, double-blind, all along the study. So it's worth 12 weeks of double-blind placebo-controlled. The first four weeks are dose which is fixed. So that means the physician and the patient could not change the dose. But the following eight weeks, we can adjust the dose according to the need. And so that's, at the end, we will be evaluating the proportion of patients that will reach their target of serum calcium within the normal value, completely independent from vitamin D, and with calcium supplement, which will be at a low level of 600 mg a day or lower. And we expect to see positive results against placebo.
We calculated the number of subjects, and we expect at least to see 55% responder as compared to placebo, 7%, so that's a design which will allow us to go to phase III when we will get the result and if we confirm this good result, and again, in phase III, what we would expect is to see the calcium to be maintained with a normal value over time with no excursion in the hyper and hypo due to the good PK profiles that I described previously. So that will be a good control of serum calcium, but also good safety profile, which we're aiming for. Obviously, we will be confirming this in phase II and III.
Great.
Anything to add?
No.
Just to confirm, you said you're looking for a 55% responder rate on active. And what do you expect for the control?
So that's a sample size calculation. So the sample size calculation is 55 versus 7%. But that's the minimum that we should be observing. We can obviously observe more than this. That's the minimum treatment effect that you could expect to see a significant value.
Okay.
Significant value.
Let's fast forward and assume this product gets approved. What kind of types of hypoparathyroidism patients do you envision going on this product? Is it going to be treatment experienced? Are you going to pick up naive patients? How do you think about peak market share and what could be a market that has multiple players?
I believe it's both. We certainly could expect to pick up some treatment-naive patients. Again, there's 250,000 HP patients in the US and Europe combined. And so we see an opportunity for multiple players and blockbuster potential. And switching is certainly something we think a lot about. And as I mentioned, when you look at the endocrinology field, and it's kind of usual to start with a once-daily product to establish the market. And then when a once-weekly comes along, there's a pretty quick migration to it. And it's not only for convenience, but also history shows better clinical outcomes. You can think about better adherence, more consistent drug exposure. And there's special attributes of our product candidate, canvuparatide, that Sam described. So we're really excited to continue the development and hopefully the approval and commercial launch of this.
Great. Maybe we can switch gears and talk about MBX 1416 for post-bariatric hypoglycemia. You flagged a result last week when you gave us that MAD data that I believe was an increase in GLP-1 in the subjects who had their mixed meal tolerance test. How do we interpret that finding?
Great. Sam, go ahead.
Yeah. So we're in the healthy volunteers, right? So these patients do not present a disease. They don't have surgery. But so we were very happy to see a signal of GLP-1 increase. We were looking also at other parameters such as insulin, C-peptide, and other PD such as glucose nadir. So we didn't see it in health, but again, it was in healthy volunteers.
Seeing this GLP-1, which was significant at two time points on two different days, sorry, D9 and D23, that was the two times where we performed the mixed meal tolerance test, was a good signal that we had an increase in GLP-1, which was reproducible, statistically significant at 45 minutes on D9 and at 30 minutes on D23 for both 30 mg and 10 mg, 10 and 30. But to be completely transparent that on D23, it was borderline for the 30 mg, very close to be significant.
And the effect on GLP-1 was observed in healthy volunteers with the first-generation GLP-1 antagonist avexitide. And just pointing out something about that program, that has a two-hour half-life. So when you contrast that with our 90-hour half-life, what we think we have is the full week coverage. So we can prevent hopefully severe hypoglycemia both day and night. And severe hypoglycemia can occur. It's unpredictable. It isn't only right after the meal. It's something you really need to watch for. So really pleased, it's an encouraging signal. Demonstrates, I believe, the competitive antagonism. So we're occupying the receptor, and therefore you see a rise in GLP-1. There can be some sort of feedback loop effect too. But again, an encouraging signal that we would predict could translate to a therapeutic benefit in the PBH patients.
I know the team is very excited to advance to phase II later this year.
Great. And maybe just the last one. I'll skip the phase II design because I doubt you'll tell me right now. But on ISRs, I know you saw some of those in the subjects in phase I. How do you mitigate that or reduce the rate in phase II?
Go ahead, Sam.
Yeah. So first, we observed some ISR, which were really type erythema, which was redness. So, we are planning to address with very simple measures such as cold compress, such as a steroid cream. And in some cases, you can even add some antihistaminic drugs. So simple measures that we hope and we are aiming to see as the ISR being reduced.
Great. Thank you.