Thanks for sticking with us for the last couple of sessions at the Citizens Life Sciences Conference. My name is John Waldman, Senior Analyst here. We're pleased to have MBX Biosciences and CEO Kent Hawryluk joining us. This is actually a company we recently initiated coverage on, one of the more recent IPOs in the biotech space. Doing something that's very difficult to do, but we think a really interesting story with a competitive, compelling pipeline of assets. Kent's going to share a couple of slides, then we'll jump into a Q&A. If we have time, maybe a couple of questions in the room.
Thank you, John, for hosting us at this event. Really delighted to provide an update on MBX and what I believe is our most important year in our history. I will remind everyone that I'll be making forward-looking statements and ask you to refer to our risk factors and our recent SEC filings. For those of you new to the story, MBX is a public clinical stage biopharmaceutical company. It's a continuation of a more than 20-year relationship with Richard DiMarchi, our scientific co-founder. Richard is the inventor of Humalog and the first GLP-1/ GIP coagonist. When you think of peptides like hormones, they have short half-lives. Typically, it requires frequent injection or infusion with a pump, both inconvenient for patients, even impractical.
With Richard's decades of innovation in peptides, we've created this precision endocrine peptide or PEP platform technology with the goal to unlock the potential of peptide therapeutics focused on continuous infusion-like drug exposure with convenient, infrequent dosing regimens. This PEP platform has already produced two clinical stage programs, and soon we expect a third. These are with significant unmet need, two rare endocrine disease indications, hypoparathyroidism or HP, and post-bariatric hypoglycemia, PBH. We also have a potential once-monthly obesity treatment we're very excited about, as well as other programs in obesity we're developing. We're in a strong financial position with cash to support our operations into mid-2027, supporting a number of value-creating milestones in each of our programs. These are shown on the right side of this pipeline slide. I'll note that each of our product candidates have the potential to be category leaders with significant revenue.
We estimate more than $1 billion in revenue for each of our rare disease programs with considerable upside for our obesity portfolio. Our lead investigational drug, Canvuparatide, is the potential first once-weekly PTH replacement therapy. We had orphan drug designation in the U.S. We published positive phase one results last year, and we have a phase two trial fully enrolled on set or on target to report data in the third quarter. Our second compound, MBX 1416, is a high-potency, long-acting GLP-1 antagonist for PBH. We presented positive phase one data earlier this year. We plan to advance to a phase two in PBH patients in the second half of this year. I mentioned we have an obesity portfolio. The first obesity candidate is MBX 4291. It's a GLP-1/GIP co-agonist prodrug.
We're intending to file an IND this quarter, and we're on track to do that, followed by a phase one in high BMI adults with a phase 1C that's 12 weeks in length. We think that's really important to show potential once-monthly dosing, as well as other potential benefits, including better GI tolerability, even better weight lowering. We will be excited to continue developing candidates, and we plan to report more about that later in the year. If you note, we will be in the target population in each of our programs in the second half of 2025, with POC in 2025 and 2026, so some near-term milestones. We designed our lead program, Canvuparatide, to overcome the limitations of current standard of care and current product and candidates in development, PTH replacement therapies. As a reminder, there's a large unmet need here.
HP, though rare, more than 250,000 prevalence in the U.S. and EU combined. The standard of care is subpar. Large doses of active vitamin D supplements, which do not address the underlying cause of disease, which is parathyroid hormone, PTH deficiency. Not surprisingly, on standard of care, these patients have fluctuations in their serum calcium, which has short-term and long-term adverse effects, harmful effects. Yorvipath recently launched in the U.S. once daily, and Canvuparatide once daily in phase three development. Canvuparatide is very unique. It is once weekly, and it has continuous infusion-like profile drug exposure. The magic of that is applying our PEP technology, and I'm sure we'll talk more about that in the Q&A.
What's important to remember is that we believe we could have superiority to Yorvipath based on three areas: the potential for greater adherence, compliance with a once-weekly, homeostasis or stability, so fewer fluctuations in hyper and hypocalcemia, and overall patients feeling better. We demonstrated in our phase one that Canvuparatide performed as we predicted. First of all, once weekly, supported by eight to nine-day half-life, continuous infusion-like profile, peak to trough concentration ratio over a week, comparable to Yorvipath over a day. The expected PD effect, dose-dependent, helped us select the doses for the phase two and established safety and tolerability. What's great is we are now fully enrolled in our AVEIL. In fact, in March, we announced full enrollment and that we exceeded the original target with 64 patients randomized. AVEIL, our phase two trial, is the first 12-week randomized double-blind placebo-controlled trial.
We designed this study with the end goal in mind, which is we want to have a differentiated label. We also wanted to create a study designed to support dose selection for our phase three. We have an open-label extension following the 12-week placebo-controlled period, which enables us to report data at later time points like six months, one year, which is comparable to Yorvipath data release for phase two. Our goal in phase in Q3 is to provide the most comprehensive data set possible so that investors can compare us to our peers. We're on track to do so. If I could leave you with anything in this fireside chat, it's that MBX has a clinically validated platform technology, multiple high-value clinical programs with significant unmet need, and near-term de-risking milestones.
I think we're set up exceptionally well to create value, and it's, in my view, an attractive entry point. We'll be excited to have the Q&A and to keep you apprised as we progress this year.
Yeah. One thing that strikes me on kind of your evaluation, you guys, again, were one of the few IPOs that flew high, pulled back with no real fundamental change. You put out some of your PBH data, but I think that was phase one data within expectations, and you're moving the program forward. You're going to have de-risking proof of concept from three indications for clinically validated targets with differentiated mechanisms in the next 18 months. It's like shocking that I think.
An opportunity, perhaps.
Yeah. I think, I mean, obviously, everything's a show-me story these days, but this setup, I think, is unparalleled at this valuation. I want to talk a little bit about each of the programs over the next 15 minutes or so. Hypoparathyroidism, tell us about the unmet need, the difficulty of standard of care, and then how Yorvipath, Ascendis drug, can change that. That can set the table for kind of your differentiation down the road.
Right. This is a new era, and we're really excited for patients with HP to finally have a true PTH replacement therapy. I mean, this standard of care, I said subpar, but think about having to set your alarm clock for the middle of the night to wake up and take a handful of pills. And it's still not really making you feel normal or stable. That's what they tell us. Even if their serum calcium levels appear in the normal range. So they need this PTH function replaced. What we've seen with Yorvipath is that this mechanism does work. We see also an opportunity for improvement. Already in one quarter, Ascendis, with the launch of Yorvipath, has 2,000 HP patients on drug. That's just the tip of the iceberg, we believe, and foresee great adoption.
We have seen this story in other weekly indications like in obesity. When you go from a once daily to a once weekly, you have really rapid uptake of a once weekly. Initially for convenience, but you typically also see improved clinical outcomes as a result. I mentioned a few specific to Canvuparatide where I think we can differentiate, and that's what we're focused on.
With Yorvipath, you see excursions both with high and low calcium. What's the clinical consequence? Are those the poor symptoms that patients experience? How difficult is that for people to manage? Can you talk a little bit about the monitoring requirements that docs are setting?
Sure. The standard of care creates these large swings, right? Because the supplements are so short-acting, you're just chasing sort of the effects of having PTH deficiency. The thesis that continuous infusion-like PTH replacement should reduce those excursions holds. We think we are more infusion-like, if you will, than the once daily. Overall, we really support this approach with the PTH replacement. I think there's some interesting things when you dive into the label for Yorvipath and where we talk about room for improvement. There is the fact that in the United States, Yorvipath is only approved to half the dose range as in Europe on account of variability with drug delivery with the pen. In the label, the FDA is emphatic about not giving multiple injections with the pen, which would be required to dose above 30 mcg.
I think that's an opportunity for us with our pen approach, single use, single dose strength, once a week disposable, minimizing the room for error and variability. Just looking at the development of Yorvipath and some of the claims that I'm sure Ascendis would have liked to have had in the label for Yorvipath and to be thoughtful about how we design our study, engage with the FDA to try to get some of those in claims around PRO, urine calcium, et cetera.
I've gotten a little bit of pushback from folks that turns out to be investors in some of your competitive companies. Talking about your PK data and saying that you have broader peak to trough ratios, can you talk a little bit about what you've seen? I've asked for clarity on that. What I guess what they're probably saying is you have a higher peak and a higher trough over a week versus Yorvipath, which is higher daily fluctuations. What do you say when someone talks about your PK profile not being an improvement?
We disagree. We see a very comparable peak to trough over a seven-day period to what they see over a day period. We think that is more fluid or more continuous infusion-like. Our KOLs have this point of view, share this point of view as well. We will be able to look at in the HP, the AVEIL study at calcium at a peak concentration and at trough, and I think put that to rest. When we look at the healthy volunteers, with the caveat that the healthy volunteers have endogenous PTH, so they have the homeostasis, so they can adjust various pathways to keep their calcium in the normal range. When we are pushing calcium through this PTH replacement therapy and we look at the peak increase or maximal increase in serum calcium, we can see something interesting.
At the 900 mcg, we have about a 1.1 mg per deciliter EMAX or rise in calcium. That corresponds to the 24 mcg dose level of Yorvipath. Their starting dose in the label and in the phase three is 18 mcg, just to anchor that a bit. If you look at our trough concentration of Canvuparatide active drug for the 900 cohort in the MAD in phase one, we saw an equivalent concentration as the peak for the 600 mcg cohort. When we look at the PD response or the EMAX for the 600 mcg, we saw a 0.8 mg per deciliter EMAX or rise in calcium. That is a 0.3 mg per deciliter delta. That is a very tight range, very normal. We have even read some KOLs in these analysts' report validating that. We will look at it in HP patients.
We have high conviction that we'll see that parallel or that correlation, that PK to PD type of correlation.
Can you talk about the response endpoint in phase two? The other thing that we like particularly is that essentially the phase three is going to repeat what you do in phase two. Can you talk about the responder endpoint and what you want to see there?
It's interesting. When you look at the Yorvipath label in the U.S., they were credited with a 64% placebo-adjusted treatment response. That may be a little bit lower than people have in their minds about where Yorvipath came out in terms of the primary endpoint. What we've done with our phase two is our primary endpoint is based on the phase three endpoint for Yorvipath. It's the proportion of patients who have eliminated active vitamin D supplements, reduced their calcium supplements to 600 mg or less while maintaining serum calcium in the normal range, right? Almost exactly the Yorvipath phase three endpoint. How we've powered our study with 64 patients enrolled is 97% power to show a 55% pool treatment response versus 7% placebo response or a 48% placebo-adjusted treatment response. I mentioned that we're the only 12-week randomized placebo-adjusted or placebo-controlled study.
What Yorvipath has is four-week fixed dose in the phase two followed by 26-week open label. There is some need to set the stage in terms of what we expect to see. I think that when we talk to KOLs, about a 50% placebo-adjusted treatment response is very clinically meaningful at 12 weeks. It will allow us to select doses for phase three and be in a good position to expect a great response in the phase three pivotal.
Can you talk about that four-week and then you have the ability to titrate and optimize dose? What kind of triggers that? How much can you fluctuate? How does that change interpretation of the data, if at all?
This is a common approach. When you think about HP, this is personalized medicine. Each patient's a little different. They have different degrees of PTH deficiency. Also, our molecule reaches steady state after about third or fourth doses by design. It's a prodrug. It's fatty acylated. That's the combination of the PEP technologies that I was sharing. We have this gradual controlled release through the prodrug. We use fatty acylation similar to semaglutide and Tirzepatide to extend time in circulation. We have four weeks to get to steady state. Don't change the dose of Canvuparatide, but you're bringing down supplements according to an established treatment algorithm that's based on Yorvipath. Now, you're bringing first down active vitamin D, then calcium.
After four weeks, and you're at steady state, you look at your serum calcium and you decide, do you want to adjust the dose of Canvuparatide while still bringing down supplements? Because again, the goal is you get the patients off supplements while staying in the normal range. We think it's really well designed. The phase one data that I referenced gives us confidence that we'll have the desired outcome in the phase two.
You mentioned KOLs tell you 50% delta on the response endpoint is clinically meaningful. We've seen this in other indications that I think even if you were comparable or even a little bit with a less optimal profile than Yorvipath, you'd still see commercial uptake given the convenience of weekly dosing. How do you think that trade-off and balance will play out? Do you think you have wiggle room? You talk about potential advantages on top of just dosing. What's kind of your internal base case assumption for your target profile? How low do you think that could go to still have a drug?
Convenience does matter. I think the uptake we've had in the AVEIL study is a testament to that. There's a lot of interest from patients and the prescribers in a once weekly. I don't think it's either/or. I think there are opportunities and advantages to showing differentiation beyond convenience. I don't see why we wouldn't be well positioned to do that given our profile.
That'd be very exciting to see. Can we move to post-bariatric hypoglycemia? Can you talk a little bit about that opportunity as far as prevalence? I guess an obvious question would be if we're having all these anti-obesity medications, do we have bariatric surgery going away or lessening? Does that diminish your market? What else is in development for that indication?
I appreciate the question. I think PBH, fair to say, is less well understood than hypopara. Interestingly, when we do the market research, primary research, we come up with a prevalence in the U.S. that's pretty comparable. There's no approved pharmacotherapy today. Thus, we see a lot of unmet need and a role for MBX 1416 as a highly potent long-acting GLP-1 antagonist. The mechanism is clinically validated. There was a once-daily Avexitide that's now in a phase three. It has a very short half-life, two, two and a half hours, and it's going for once-daily. We established in our phase one a 90-hour half-life. That supports full day and night coverage throughout the week. That's important because the timing of the severe hypoglycemia is unpredictable. It doesn't have to occur just after a meal.
It could be in the middle of the night, and that's particularly dangerous. We're very excited to advance into patients with PBH in a phase two study in the second half of this year.
Can you talk a little bit? I don't think.
I'm sorry. You asked about the bariatric surgery. I mentioned our primary research. We asked a very question of the endocrinologists and the bariatric surgeons. There are puts and takes. One sort of tailwind is that currently there are some patients who are too large to undergo bariatric surgery safely. These GLP-1s can bring them to an operable weight. Some start on a GLP-1, but you know there's a high discontinuation rate today with the GLP-1s. I'm sure we'll get to that in talking about MBX 4291. That means that some just don't go back on drug and are looking for an alternative, which bariatric surgery can provide. We think it remains the gold standard and has staying power. This is a chronic disease too. You think about continuing to grow.
Unfortunately, these patients, once diagnosed, will have it for the rest of their lives.
Have you talked about your phase two trial design? I think the previous Avexitide study was 14-week crossover, so four weeks in total, but you're going for longer dosing. Would you need a longer study? Like big picture-wise, what kind of trial design would make sense?
We have a measured approach with this program. It's not our lead indication. It's not our lead program. We want to, in the phase two, optimize dose. So we're going to look at the experience that Avexitide has had in the clinic and design our drug or our development path accordingly, not reinventing the wheel, being very measured and methodical about it to get to the best outcome.
Jumping to your GLP-1, GIP agonist, Dr. DiMarchi is instrumental in developing a lot of these incretins. Can you talk a little bit about what we know about the potency of the drug, how it compares to Tirzepatide? I know you've shown some preclinical data, but digging into the molecule, how does this stack up?
Stacks up very well in the sense that if you look at MBX 4291 active drug, so after it has been released from the prodrug form, it performs very similar to Tirzepatide in vitro at each of the receptors, GLP-1 and GIP, in terms of binding potency and in the balance. Also in terms of in vivo, like the gold standard DIO rodent model. Where it differs is in the PK. That is the secret sauce here. This too is a prodrug. You can think of similar technology that has been clinically validated with Canvu and now designed or tuned for once monthly dosing. We estimate, and we are going off of non-human primate data, so that is the caveat. When we model it for humans, we project a peak to trough over a month that would be similar to Tirzepatide over a week.
Again, kind of analogous to Canvuparatide type of product profile. Why does that matter? We know that the GI side effects that come from the GLP-1s today that cause that like 65% discontinuation rate largely is due to not only the CMAX or the maximum concentration, but the rate of rise to get there. There is a certain self-titration that's built into our prodrug, MBX 4291. In our phase one, I mentioned we plan to have a 12-week study in high BMI adults. That's an opportunity to try different dosing regimens. You have a precedent with these GLP-1s for a titration period.
We could think about starting at a more frequent dosing than once monthly, adjusting the dose accordingly so that we flatten the peak to trough and have better tolerability potentially, or get people to a higher tolerated maximum dose and see greater weight lowering, then switch to once monthly. These are some exciting possibilities to explore in our phase one. I think that'll be a really transformative milestone. Of course, the biggest transformative milestone, I'd be remiss in not reminding you, is the AVEIL phase two data in the third quarter.
We got AVEIL, hypoparathyroid data, 3Q. We're going to be kicking off two trials second half of the year, data from both of those next year. One question to end on, we talk about the PEP platform. Can you talk about the reproducibility for Canvu from your modeling PK to your phase one and then also in PBH? And should that give investors confidence that you can keep doing the same thing and you will be able to do the same thing with 4291?
Yes, yes, and yes. It was spot on. We've only continued to improve our modeling with more data. We're really excited to execute and to share the results pretty soon.
We should not even just think about these as single asset opportunities, but a platform that could be applied again and again and again.
Right. Obesity is our major discovery focus. We anticipate having additional obesity candidates that we'll be talking more about in the future.
When do you think we could hear about those?
I'm not providing any guidance on that today. It's a major effort for the company and a high priority.
Okay. We'll look forward to that. We'll be touching base soon when you guys report your first quarter results. We'll keep an ear to the ground for the data in 3Q.
Sounds good. Appreciate all your questions and interest.
Thanks, Kent. Appreciate you coming.