Great. Good afternoon, everyone. Welcome. My name's Jessica Fye. I'm a biotech analyst at JPMorgan, and we're continuing our 44th Annual Healthcare Conference today with MBX. First, you're going to hear a presentation from the company, and then we're going to go into some Q&A. So if you're in the room here and you have a question, just raise your hand. Someone will come over with a microphone, or alternatively, you can also submit questions online, and I can read them off the iPad up here. But with that, let me turn it over to MBX's CEO, Kent Hawryluk.
I'd like to thank Jess and the JPMorgan team for the invitation to present at the JPMorgan Healthcare Conference now for our fourth year. MBX is an Indiana-based company, so we're very thrilled right now with the success of our IU football team. I brought my hat, but maybe no one more thrilled than a VIP guest. We have Richard DiMarchi, Distinguished Professor of Biochemistry at IU, and frankly, a legend, as one investor in our last meeting pointed out, inventor of Humalog, the first GLP-1/GIP co-agonist, and first GLP-1/GIP/glucagon triple agonist, the precursors to Mounjaro, Zepbound, and retatrutide, and I would just say that as exciting as football is, appearing in a national championship, more important is the impact that Richard's discoveries have had on millions of patients with metabolic diseases.
It's really an honor that he's here because he and I have been partners for the last 20 years and more. He's a co-founder of MBX. He's a key architect of our Precision Endocrine Peptide, or PEP, platform technology that's clinically validated and producing some potential best-in-class therapeutics. Today, I'm going to be presenting for the first time preclinical data on our newest next-generation PEP candidates in obesity, underscoring our commitment to addressing the full spectrum of the disease. I'll be making forward-looking statements. I encourage everyone to review our risk factors and other disclosures in our SEC filings. MBX is pioneering PEP therapeutics with a passion to give patients their freedom through convenient and tailored treatments for endocrine and metabolic diseases. We have a pipeline of potential best-in-class therapeutics addressing proven markets and significant unmet need. We have our most catalyst-rich year in our company's history.
In terms of our lead program, canvuparatide, we have a number of major milestones this year, most importantly, initiation of our confirmatory phase III trial in Q3. Building on the phase II successful data release, which clinically validated our PEP platform technology, and also the encouraging preclinical data on our first obesity candidate, MBX 4291, a GLP-1/GIP co-agonist with potential once-monthly dosing and better tolerability. And we're now tripling our obesity portfolio this year with the finalization and selection of an amycretin and a GG G agonist in the second quarter and third quarter of this year. In the fourth quarter, we will be releasing the MAD 12-week data from our phase I study that's underway. And that study is designed to demonstrate once-monthly dosing and better tolerability. We have, for imapextide, a phase II- A proof of concept study readout in Q2.
MBX is in a strong financial position, especially following the successful $200 million public offering on the heels of our positive phase II data last September, which left us with around $375 million in cash at year close. This supports all of the clinical studies that I've described and more, completion of the phase III, 2- phase I proof of concept studies in our two newest obesity candidates as well. So we believe that we have a tremendous opportunity to demonstrate benefit for patients in 2026 and beyond. Now I'm going to take you briefly through our Precision Endocrine Peptide, PEP technology, starting on the left with innovative peptides that are designed to optimize for potency, including multiple mechanisms of action in a single peptide, dose volume, shelf life, and other properties to enhance the patient experience.
Next is our programmable prodrug technology, which provides slow release of the active peptide in the bloodstream without needing any enzymes. It's through a natural chemical process. The purpose of this is to improve tolerability through a slow rise and steady exposure. We often talk about infusion-like exposure without the inconvenience of a mechanical pump, then fatty acylation to extend the time in the bloodstream, and this is to provide extended exposure and more convenient, less frequent dosing, so we synergistically combine these technologies to provide potential best-in-class therapeutics with convenience and personalization. There's a lot of enthusiasm building in the hypoparathyroidism HP community for canvuparatide. Patients point out that they really are excited to regain their freedom from the daily burden of their disease, and they specifically say that once weekly will make a big difference in their quality of life. And this is a pretty sizable population.
We estimate a U.S. and E.U. prevalence of over 250,000. The standard of care is antiquated. It does not address the root cause of disease, PTH deficiency, and it's a steep burden. Think of taking large doses of active vitamin D and calcium throughout the day and night. And for some, it's setting your alarm clock for the middle of the night to wake up and take a handful of pills. The symptoms are devastating, from cramps to brain fog to seizures, and the long-term complications are even more serious: kidney stones, chronic kidney disease, and cardiovascular issues, but there's reason for hope. New treatment guidelines stress the importance of PTH replacement therapies, and our competitor is establishing the market through once-daily Yorvipath.
And with our recent positive phase II data, we believe it supports best-in-class and a new standard of care and an opportunity to get more patients on a PTH therapy. Our AVAIL phase II study, very successful. We saw a 63% responder rate at 12 weeks. That was highly clinically significant, clinically meaningful, and statistically significant. That rate improved to 79% at six months. Importantly, 94% of the patients who completed the 12-week study chose to enter a two-year open-label extension study. One KOL remarked that that was one of the strongest indications he saw of our drug's efficacy. We had excellent safety and tolerability. There were no discontinuations. We had no treatment-related SAEs. 96% of responders at 12 weeks remained responders at six months, pointing to the excellent durability of effect. And well, I think you can see why we're very excited to advance to phase III.
It's been great to see the translation from the original PEP design from Richard through the preclinical and phase I results, and then last September, the phase II. Once weekly drives preference in HCPs and HP patients. These are new primary market research data that I'm presenting, and you can see that over on the right, 100% of patients said they would choose a weekly over a daily, and the vast majority of healthcare professionals. Importantly, looking down below, 80% of the docs said they would intend to switch their patients from a once-daily to a once-weekly. This isn't surprising. It's been consistent with what we've been saying and our conviction that we would become the category leader, and it's what we see in other indications when you switch from a once-daily to a once-weekly.
You see rapid adoption of the once-weekly and an expansion of the number of patients on therapy. It's a big year ahead for the program. We are, again, really excited to start enrollment. We expect in the third quarter of this year and to continue updating with data from our open-label extension, with one-year data expected in the second quarter at a major medical meeting. Based on our confidence in having a successful phase III study, we don't want to lose any time on commercialization. So we've already begun the pre-commercial activities and intend to recruit a chief commercial officer this year. Well, in the 20+ years that I've been in obesity, I would say I've witnessed nothing short of a revolution. Just think back to 2005.
We were talking about obesity being a result of lifestyle choices and that it was virtually impossible to treat the disease safely and effectively and how far we've come. And yet there's still more work to do. And I think there's now a recognition that we're entering a phase of looking at the individual needs of patients and bringing to them sophisticated next-generation therapies. And it's really our goal to become a leader in the obesity field and address the full spectrum of the disease. So how are we addressing the unmet need? Let's start from the pharmacokinetic or PK perspective. We know that some major needs for patients, when we talk to KOLs, when we talk to industry partners, is tolerability. And think about it. What good is a drug, even if it's effective in lowering weight, if the patients feel lousy? They're not going to stay on it.
Also, dosing frequency. This is a chronic disease. We realize it takes lifetime treatment. And so patients want less frequent dosing. This graph is a concentration curve designed to kind of show you how we differentiate, starting with the red curves, which is representing Zepbound or tirzepatide. So if you look at that on the left, you see the steep rise in exposure, and then it's kind of trailing off. And then that repeats every week. This is a once-weekly therapy. And the KOLs tell us it's that steep rise to Cmax exposure in the fluctuations that's causing the GI distress. So nausea, vomiting, leading to discontinuations, poor adherence. Now let's look at the green curve. This represents our target product profile based on translational modeling. Instead, you see this slow rise and then steady exposure.
One endocrinologist who looked at our data described it as almost peakless or without peak. And we think that's a great way to look at it. Again, infusion-like exposure without the pump. And we believe we'll have a long exposure to support once-monthly dosing, but with tolerability. I mentioned the full spectrum of needs, and I'll start with 4291, our obesity candidate in the clinic. This uses the gold standard of GLP-1 and GIP mechanisms proven in Zepbound, but like I shared, with better tolerability and once-monthly dosing. Next, one of our newest next-gen PEP candidates, an amycretin. Significant weight loss through a synergy of the incretins and also this complementary mechanism, amylin, which is thought to not only suppress appetite and lower weight, but potentially preserve muscle. It's a recurring theme, but once-monthly and better tolerability as well is our expectation for our amycretin.
And then our triple G, introducing glucagon to turbocharge weight lowering, as we saw with retatrutide, with nearly 30% weight loss last December in their phase III, but with tolerability issues where we think we can improve. So MBX is developing a robust obesity portfolio with the potential to give patients choices. Now we'll kind of look behind the scenes at how we get to that green curve of the target product profile. This is 4291, invented by Richard. In the illustration in the lower left, we depict our 4291 in red because it's a prodrug. It's designed to be biologically inactive. However, in circulation, note the red zigzag at the left, that slowly releases the active peptide. So on the right side of the left panel, you see it's now in neon purple, indicating it's active. And note the yellow tail as well.
That is the fatty acylation, which associates with the heart-shaped molecule albumin. So over on the right, this shows the mechanism of action at work. The active peptide is able to release from albumin and bind to either GLP-1 or the GIP receptors, which are known mechanisms to drive weight loss. I'm going to present some proof of concept data supporting the tolerability hypothesis that I gave. Let's look at the left in this concentration curve. After a single administration in non-human primates, we see that slow rise in exposure, and it's dose proportional. After the fourth once-weekly dose, we see flat as a board exposure and some accumulation, as expected. So this is very representative of that infusion-like exposure. As well, we did see good tolerability here in this four-week study. The NHPs did not show nausea or vomiting while losing almost 20% of their weight.
Note in NHPs, they turn over albumin three times faster than in humans. So we tend to see a shift for longer activity in humans, in fact. This is where we are today. We have a phase I study underway, and we are on track to present top-line results for our 12-week MAD study in the target population, BMI 30 and above, and it's designed to show once-monthly dosing and better tolerability. We have the potential for multiple cohorts to try different dosing regimens as well. If there's one slide to remember from the presentation, I would say this is it. This is our big reveal for JPMorgan this year, and we're showing how we're, like I said, tripling our obesity portfolio. On the left, this is our amycretin where we're finalizing our development candidate selection. Now you're used to concentration curves.
I'm comparing the Novo Amycretin in blue, where you see that steep rise, and then the exposure is falling off, to our amycretin prodrug active peptide following release from prodrug. There in green, you see the slower rise and steady exposure out, supporting, we believe, monthly dosing. Now, over on the right, we see a very similar profile for our triple agonist program. In green, in this case, it's not retatrutide, but our proprietary triple agonist, but it has very similar PK characteristics, and again, the steep rise and the falling off, and yet, the triple agonist prodrug active peptide has the slower rise and steady exposure. We can't wait to see this translate and look forward to sharing updates on our development candidate selections and clinical plans later in the year.
In our effort to treat the full obesity spectrum, we recognize that patients experience post-bariatric hypoglycemia or PBH after undergoing bariatric surgery. Itself, a mainstay obesity treatment. It's a pretty sizable population as well, frankly similar in size to hypoparathyroidism. By our primary market research, over 125,000 patients in the U.S. are affected. And the impact on quality of life is devastating, particularly due to the unpredictable timing of the severe hypoglycemia, which can lead to loss of consciousness, even death. So there's a fear factor. Imapextide is designed to be a potential best-in-class treatment for PBH as a GLP-1 antagonist with intended once-weekly dosing. It's fatty acylated GLP-1 antagonist. And the idea here is to give patients their life back through giving them peace of mind, days and nights without crashes or interventions. And we have phase II- A proof of concept data expected in Q2.
Similar to the response we saw from our market research in HP, again, once-weekly dosing really drives preference. We saw that almost all of the patients would choose, based on our profile, looking at our data, our once-weekly versus a once-daily, and a majority of the HCPs as well. So it's very encouraging. And with that, I would say we have a great setup for this year. We are unique, I believe, in having three clinical stage programs, two new obesity programs that will be on their way to the clinic, a track record in innovation in obesity, I would say perhaps second to none in biotech companies of our size, and cash to give us a lot of optionality in how we advance these programs to patients. So I'm very excited to share throughout the year updates on our progress and data. Thank you.
I think we now have questions.
Great. So as a reminder, if you do have a question in the room, just raise your hand so someone can bring you a microphone. This one here.
Thank you. Firstly, I have a question about your amylin analog program. Have you disclosed if this is highly selective on amylin receptor over calcitonin receptor or not?
We have not disclosed that.
Thank you.
Stay tuned.
Thank you, and the next question is, can you adjust the speed of the project's cyclization? I mean, are you using the same end-terminal design for each molecule, or are you trying different combos?
We call it a programmable prodrug because we can tune it for different release times.
Yeah. I mean, if you are using different ones, why don't you choose the slowest one for all the molecules?
One aspect is our molecules are fatty acylated. Albumin has a 21-day turnover in humans. We pay attention to that as well. You don't want sort of wasted drug on board due to the albumin turnover.
Thank you. The last question about your long-acting design, except the prodrug design. Is there any special design of the active drug?
The active drug is the starting point. And that's where I referred on, if you recall, the slide on the left, the innovative peptides. And there's a lot of protein engineering that goes into that to increase the potency, dial in multiple mechanisms, and pay attention to stability, solubility, etc. And that's where I go back to just having exceptional expertise in MBX.
Yeah. Thank you.
Great. So maybe just at a high level, while we're talking about the platform, can you talk about your framework for selecting targets and potential drug candidates?
Staged, evidence-based. We look at our protein engineering strengths, where we can apply that, the unmet need, and certainly market size.
All right. Maybe starting with canvuparatide, can you talk a little bit more about how the design and mechanism of canvu compares to Yorvipath or abaloparatide?
Yes. It's very different. Remember, we have this slow release through our prodrug, which cyclizes under physiologic pH and temperature at a controlled rate. Importantly, the active peptide is fatty acylated. So it has a long half-life, a la semaglutide/tirzepatide, which are fatty acylated. It's the combination of these two technologies, I want to stress, that creates this infusion-like profile, PK profile. And that's very differentiated. In terms of similarities, it's replacing the missing hormone, PTH. And our active peptide is a full agonist at the PTH1 receptor, as is Ascendis's Yorvipath's active peptide. So one of the features is we had a peak to trough over a week. We showed in our phase I data. In healthy volunteers, that was the same as Yorvipath's over a day, which we believe is more infusion-like.
I guess if we look to the phase II available data, what are the specific kind of metrics or endpoints that you think best support the differentiation of your drug?
Sam?
We had very positive results at 12 weeks after the double-blind placebo-controlled period with 63%, statistically significant and certainly clinically meaningful. We got the 79% at six months during the open-label extension. I think that's really a really good number in terms of responder rate. Also, the number of the percentage of patients moving from the double-blind placebo-controlled to the open-label extension, we had 94% of the patients moving to the open-label extension. All these characteristics, I think, are extremely valuable results and can also be good signs for our phase III program.
How should we think about the higher-than-expected placebo response in phase II?
I'm going to start again by saying that we got statistically significant results versus placebo, which was not only significant but also meaningful. Our placebo response rate is not surprising. It's very similar, in fact, to what Yorvipath observed at the end of their double-blind placebo-controlled at four weeks in their phase II, which was in the ITT population, was 27%. We got 31%. Not that very much a difference there. However, what is the most important thing is that what will be the placebo response at six months? We do believe that in alignment with what Yorvipath observed with 5% placebo response rate at six months, we would expect to see the same thing. It's very simple to explain. It's very unlikely that a patient with hypoparathyroidism who needs treatment can stay six months with a placebo.
So we are expecting to see also in our phase III program a low placebo rate at six months.
When we look ahead to the one-year open-label extension data coming up, what would you orient folks to watch for in terms of efficacy and safety? And should we expect to see any new metrics with that update? And can you remind us of the competitive benchmark at the one-year mark?
So at one year, what you would expect to see is, first, the retention rate. Again, we got 94%. So it will be important also to see how many patients are still in the study. We'll be looking at the durability of effect, right, the response rate at one year. But if you remember, we looked at the bone biomarkers. They were moving to the right direction. And even some expert, especially Willard Dere, who is the one who developed Forteo, was very enthusiastic about the bone biomarker. So that's great. But most importantly, the biomarker is the BMD. So that will be new data that we'll be releasing. And what we want to see in these populations, the BMD is pretty high. They have a dense bone. There's no turnover. So we showed that the turnover is back through the bone biomarkers.
But the BMD will be an important measure. We'll be also looking at urine calcium, and we'll be looking at safety and tolerability.
You mentioned the dense bone. So do you want to see it kind of start to normalize?
Yeah, exactly. So what you would expect to see on the bone biomarker increase is normal when you reestablish a PTH condition. So that's what you would expect. But after a certain period, you would expect to see a plateau. BMD should go down, but within the normal value, the same things that Yorvipath observed within the normal value when matched in terms of gender, age, and ethnicity.
Okay. How many patients are still ongoing in the phase II OLE?
So you will have to wait a little bit when we'll be releasing the data.
All right. And what about I think you mentioned you've got an end-of-phase II meeting coming up here? What do you intend to discuss as it relates to trial design? And is there any possibility of an outcome that would enable you to get urinary calcium data in the U.S. label?
So the end of phase II is a normal process with the FDA. So we meet with the FDA at the end of the phase II before initiating a phase III program, which is a normal pass. And so we'll be discussing with the FDA the design, the study design. And again, we are not going to recreate the wheel. We are going to follow the path for this type of product for PTH replacement therapy, which we'd expect to be a double-blind placebo-controlled study for six months, followed by an open-label extension. The endpoint, the good thing is the endpoint that we chose in phase II, we're going to use something very similar in phase III, in fact, the same composite endpoint. In addition, the FDA is likely to require. I'm not speaking on behalf of them. We'll see.
But it's likely to require a stable dose during the last weeks. And we will be discussing also with the FDA what are the conditions for urine calcium and other parameters that would help us being how can I say highlighted in the label or elsewhere. But really, that will be a condition to be discussed with the FDA.
From an enrollment perspective, would you still expect to enroll kind of patients who had normal urine calcium even if it wasn't elevated?
So we are going to select a population of hypoparathyroidism. But we are going to stratify and to make sure that we have enough patients with elevated urine calcium that will help us also to show and demonstrate the reduction in this population.
Okay. How do you think about phase III enrollment timelines in light of Yorvipath's commercial availability?
It's a global study. We had really strong enrollment. Remember, in our phase II, when Yorvi was on the market, we exceeded our original enrollment target. We have a lot of enthusiasm from patients and PIs, and Sam, you want to elaborate?
Oh, sure. So I have a number of anecdotal stories. I'm not going to tell you all of them. But just we went to Hypopara Association, which was, I believe, in October last year. And we got a lot of enthusiasm, not only from the physician, but also from the patient. You know that this population know very, very well their disease. They were enthusiastic about the potential for weekly administration. So we are not concerned by the recruitment, even in the U.S., to be honest. In fact, our phase II was also concomitant. The recruitment was concomitant with Yorvipath. And the population is large. So we are not concerned.
But I have other anecdotal stories, as I said, one of them being that the physician wanted to be a site for phase III and put their patient in the study.
We view the launch of the daily Yorvipath as going well. There's still a vast majority of patients who are not on a PTH replacement therapy, let's be clear. And then in our market research, we had Centerview provide our blinded profile to endos treating HP patients. And they came back to us that this would be their drug of choice and drive switching. So combined with the enthusiasm we're hearing from the PIs, we think we'll be in a real strong position to enroll the trial. We, by the way, are currently looking at approximately four quarters for enrollment, kind of in line with other studies, other types of phase III studies. As we understand the enrollment rate, we'll provide updates.
So maybe this will get you to share some more anecdotes. But what are you hearing from KOLs on the back of your phase II data about their reaction to the clinical profile? And where do they see canvu fitting into the market?
Yeah. I already gave you the feedback from Will Dere, who has developed Forteo. So he knows very well the field. And when he saw our bone biomarker increase and the drug effect, he was really enthusiastic about the potential that this drug has. And again, when we meet with our investigators, but also with other experts and at the Hypopara Association, as an example, we find this similar enthusiasm. And it's aligned with the market research that Kent just discussed, completely aligned that the weekly administration is a driver.
So what market share do you think Canvu could ultimately capture?
We aim to be the number one prescribed PTH replacement therapy, and we believe we can back that up with our clinical profile, which continues to improve, and with the market research that we've conducted.
Any PTH questions in the room? We'll shift to obesity. So you're heading into a phase I readout in the fourth quarter. What do you want to see both in terms of weight loss and tolerability? And what's the right competitive benchmark that we should hold this data up against?
Yeah. So this phase I, which is in the target population, so we even could speak about phase II almost, target population of patients with BMI above 30. So this study is divided in three parts. And each part informs the next. So the first one is the SAD, when we'll be evaluating different doses. And we'll have already a good idea about the tolerability, GI effect, like nausea, vomiting, diarrhea, et cetera, but also a good idea about the PK. Then we'll be moving to the MAD. The drug will be given weekly for four weeks. And again, good idea about tolerability and PK. But the most important part will be the last one, the 12-week portion of the study, where, again, we will be evaluating potentially different treatment algorithms in order to optimize the tolerability.
One of them being, as an example, to administer MBX 4291 on a weekly basis for four weeks, then monthly. So at the end, we will have a tolerability profile, right? If we are right in terms of what the PK we discussed, we will have the confirmation about the monthly PK because it will be a real monthly administration. And the last one will be an idea about weight loss. And if everything is combined, then it opens a path to the phase II, the next step of development.
And I would just emphasize the tolerability. I think they're fair to say there are a number of parties out there that are pursuing longer-acting incretins, for example. But they're focused on the tail, in other words, the exposure duration. But they're less focused on the burst effect that we continue to hear from KOLs is actually driving the intolerability. So we believe that our pro-drug approach is a novelty that can give us some confidence that we'll see that better tolerability show up in our 12-week study.
So what's the benchmark that you want to beat on nausea or vomiting, whatever tolerability metric you want to look at?
We want to compare to other once-monthlies. That's important, assuming that we can indeed dose once monthly in our 12-week study as we intend to. There, we've seen some challenges with other monthlies that employ different technologies, such as antibodies or antibody derivatives. Think of Fc fusions, where you get that steep rise to Cmax, and then you're having to lower the dose, titrate, et cetera. We just have a very different approach. Really can't wait to see the data. I think it's going to be 12-week data is really currency in the field.
Okay. So 4291, let's say you're kind of starting to see what you want to see. Where does this fit in the market, which seems to be evolving, right, among not just injectables but also orals?
The beauty of the monthly incretin injectable subQ that we're developing is that it can be better tolerated and also drive better adherence with convenient once-monthly dosing and durable effect. And with orals, there are some questions. If you lack adherence and you get back on, you can get some spikes in exposure and the GI issues similar that I talked about earlier. So I think we're in a sweet spot. And if you poll patients whether they would prefer to remember to take a pill every day versus once a month, I don't know, maybe when they're paying their mortgage or rent, take a subQ injection easy, and you don't have to think about it. I like our positioning. But I go back to this is now in the field of or in the time of individual needs, addressing individual needs.
There's no question how large the obesity market is, the unmet need is, and I think there's a role for different treatment approaches.
All right. Well, with that, we're out of time. So we'll stop there. Thank you.
Thank you.
Thank you.