Right. Thanks, everybody, and thank you for joining us here this afternoon at Guggenheim's SMID Cap Biotech Conference. I'm Seamus Fernandez, one of the senior biopharma analysts here at Guggenheim, and I'm really pleased to be joined by MBX Biosciences CEO Kent Hawryluk, who is here to my right. Kent, thanks so much for joining us. Maybe as investors are trying to get more familiar with the MBX story, this is a great opportunity to kind of give folks a brief overview of MBX, where you guys came from, and also what you're bringing in terms of opportunities and catalysts this year.
Terrific. Thank you, Seamus, for hosting. Appreciate the opportunity to update you all. MBX Biosciences is a clinical-stage biopharmaceutical company founded by global leaders in peptide drug design and development. We're pioneering a new platform technology called Precision Endocrine Peptide, or PEP. You can think of peptides or PEPs as engineered to have optimized pharmaceutical properties, including extended time action, consistent drug exposures, and more convenient, less frequent dosing regimens. Our lead program, canvuparatide, is an investigational parathyroid hormone, or PTH, peptide prodrug therapy for hypoparathyroidism. We have orphan drug designation in the U.S. We are currently conducting a phase II clinical trial called AVAIL, with enrollment completion expected this quarter and top-line results in the third quarter of 2025. Our second program is MBX 1416, a GLP-1 antagonist and potential treatment for post-bariatric hypoglycemia, or PBH.
And we presented positive phase I results of our phase I study in MBX 1416 in early January and plan to move that program into phase II in the second half of this year. And MBX also has an obesity portfolio of differentiated PEP candidates. And this includes MBX 4291, our first obesity candidate, which we believe has the potential for once-monthly exposure to GLP-1/GIP co-agonism, and also potential for better GI tolerability and greater weight loss than key competitors. Other programs in lead optimization for obesity and other comorbidities, which we will be sharing developments on. And with MBX 4291, we are on track for an IND submission next quarter, which would be followed by a phase I study in the target population. So I think that MBX is really unique in having a proven platform technology, as well as multiple clinical stage programs in areas of unmet need.
Great. And let's talk a little bit about what you see as the sort of opportunity for MBX to create value for investors this year. We saw the 1416 phase I data early this year. But I think the big event is coming up in the third quarter. So let's drill down into the hypoparathyroidism opportunity as you see it.
Fantastic. Yeah, certainly a transformational milestone for MBX in 2025 is our expected top line results for the AVAIL study in the third quarter. This is really important for the company in terms of our first phase II readout. Also just canvuparatide, we are super excited about this program. Unlike the products and candidates in hypoparathyroidism, canvuparatide is a potential first once-weekly parathyroid or PTH replacement therapy with consistent drug exposure or flat infusion-like PK profile, and a potential to reduce the excursions into hypercalcemia and hypocalcemia and the symptoms and long-term complications those cause while eliminating the pill burden for patients and improving their quality of life. Where I think this is really significant is when we talk to patients with hypoparathyroidism or HP, they really want it to be understood that the disease is really about a PTH deficiency, right?
And this arises typically from inadvertent removal of parathyroid glands during neck surgery. And they want to distinguish that from calcium deficiency because sometimes it can get a little confusing. And even patients with HP who are fortunate enough to be able to maintain their calcium in a fairly normal range with fewer excursions due to taking this quite enormous amount of pill supplements, they don't feel stable typically or feel well. So I think this boon in terms of PTH replacement therapies is going to be quite revolutionary. And we feel we're really part of the natural progression of that coming after a once daily with a once weekly. I mean, we've seen what this has happened in type two diabetes going from Victoza to Trulicity and Ozempic. It's pretty stark.
You, of course, start with patient and prescriber preference for a once weekly, the convenience, but then you also typically see better clinical outcomes follow, better adherence, compliance, and perhaps more consistent drug exposure. That's kind of where I see HP now. It's a really exciting transition point. We're really rooting for the first U.S.-approved true PTH replacement therapy and kind of creating the market and helping patients.
Great. So talk a little bit about the differentiation opportunities of your weekly versus the on-market daily, Yorvipath, and sort of the potential of AstraZeneca's eneboparatide, which is also a daily asset.
Right. So what we're really excited about with canvuparatide is it was designed with our proprietary prodrug technology, which was invented by Dr. Richard DiMarchi, who's just one of the foremost peptide chemists. He invented Humalog. He was involved with the discovery development of Forteo, Eli Lilly. And famously now, he invented the first GLP-1 GIP coagonist at one of our previous companies together, Marcadia Biotech. And really in understanding in endocrinology, you want to keep this kind of narrow window or consistent drug exposure. We saw that our prodrug technology would really find an optimal application in hypoparathyroidism, where you want to keep PTH in a pretty steady range. So what we have here is a prodrug. The active drug of canvuparatide is a PTH 1 to 32 plus a lysine and fatty acid for extended time action.
And then we have this really elegant two amino acid prodrug extension, which is designed to make the prodrug biologically inactive, but in circulation under physiologic pH and temperature without any need of enzymatic intervention. That two amino acid prodrug extension forms a ring at a precisely controlled rate, thereby breaking the amide bond and releasing active drug, which in itself is fatty acylated, as I mentioned.
So you really have two contributors to this flat pharmacokinetic or PK profile that we were able to demonstrate in our phase I study in healthy volunteers with an eight- or nine-day half-life and a peak to trough of about 1.4-1.7 over a seven-day period, which is comparable to what was seen with Yorvipath around 1.4-1.5, but over a 24-hour period. So we believe ours is more infusion-like. We think that, again, that can help in terms of minimizing excursions, making patients perhaps feel better, which could come through in the patient-reported outcomes with that consistent PTH replacement.
Great. And in terms of the endpoints that will be sort of revealed when the phase III trial completes, maybe you can help us understand the difference between what you're looking for at 4 weeks and then prospectively at 12 weeks.
Maybe I could just start with discussing our AVAIL study in case you haven't been following it. What we're looking to do with AVAIL, it's a randomized double-blind placebo-controlled study where we intend to recruit around 48 patients to be evenly randomized into three treatment groups, 400, 600, and 800 microgram doses of canvuparatide once weekly or to placebo for a four-week fixed dose treatment period. That's followed by an eight-week dose adjustment period where the study investigators can increase or decrease the dose in 200 microgram increments every two weeks for a total of four potential dose adjustments.
This is to reduce calcium and vitamin D supplements according to a well-established algorithm and get patients to ideally their optimized dose by the week 12. We'll be looking at pooled treatment cohorts to placebo. Our primary endpoint is the portion of patients who are maintained in the normal calcium range while eliminating active vitamin D and reducing their calcium supplements to 600 milligrams or below. So based on a 90% powering, we believe success, a successful outcome in this phase II trial would be 55% improvement in the pooled treatment groups versus 7% placebo or a 48% overall improvement.
Great. So that is really detailed. As we kind of look at the dynamics around the relative target product profile, is it a long-acting Yorvipath? Are there opportunities to improve upon what Yorvipath achieved? And if there are opportunities to improve upon what Yorvipath achieved, what do you think they might be?
Okay. So I think it's important to look at where we'll be with a 12-week endpoint. This is different from the study designs of Yorvipath and eneboparatide. So recall Yorvipath had a four-week fixed dose placebo-controlled study that was followed by an open label extension. And by the way, AVAIL, our 12-week study will be followed by a two-year extension study where everyone in the extension study will receive treatment of canvuparatide. And the study investigators will be able to optimize further the dosing. So after the four-week Yorvipath data release, they then provided 26-week data, including the four weeks and then the open label extension, which was sort of pooled. They don't have anything in between. So that's one caveat. And then eneboparatide was a four-week phase II open label.
So, I think it would be really. We would guide investigators to really look at the improvements we're able to show. Of course, hitting the top line, the primary endpoint, we would also look for some secondary endpoints around the bone biomarkers, for example, the PK profile, which I think we fully believe will carry over from the healthy volunteers to the patients. There's no reason it should be different. And the fact that this is a once weekly compared to a daily is not to be overlooked as a tremendous benefit for patients.
Great. Let's talk about the tolerability and the safety profile that's, I think, potentially uniquely important here. The sort of frequency of injection site reactions, the data that you would say is kind of proof positive that canvuparatide is sort of starting off on a very robust footing as it relates to both safety and tolerability.
Sure. So what we saw in the randomized placebo-controlled phase I was really overall well-tolerated, safe compound, no SAEs. The most common AEs was injection site reactions. These were mild redness, not dose proportional, resolved on their own within a few days. And as a reference, in our phase I in the treated groups, we saw 31% ISRs, as I described it, this erythema or redness. And when we looked at, say, the Yorvipath label, they have a 39% ISR rate. Eneboparatide in phase II, 46%. And this is a great safety profile, which in 76-subject phase I, we don't see why it would be different in our phase II. So I think that's for one thing and none of the other measures, lab measures, no imbalances. Again, really safe and well-tolerated compound.
We had expectedly asymptomatic hypercalcemia in the 600-microgram cohort and two asymptomatic hypercalcemia in the 900- or top cohort, 900-microgram highest cohort. This was expected in a phase I study, healthy volunteers with intact PTH and also intact homeostatic response system. You're pushing doses where you're already having high calcium to see kind of how high you can go. Not surprisingly, at the higher doses, we kind of put people into lab value hypercalcemia that had no symptoms, resolved very quickly without intervention. Yorvipath had some hypercalcemia in the phase I as well. I think looking at a similar kind of safety profile, now in HP patients are going to have lower calcium going into it. Look for less excursions. We'll look for these other secondary endpoints I mentioned and certainly look forward to providing the data package in Q3.
Sounds great. Any comments on the Yorvipath launch so far just in the U.S. and Europe?
Yeah. It's early days, but we're encouraged by what we see. I think it certainly demonstrates that there's uptake for a PTH replacement therapy. We'll continue to watch the U.S. very closely, but I think so far so good. We really are staying focused on the long-term opportunity. We know that the unmet need is there. There's been this burning need for a PTH replacement therapy. And what we see with once weeklies is you typically not only get the switching, but you tend to grow the market when you have a well-tolerated, safe, easy to titrate treatment option. So we would look for switching. We would look for a portion of looking ahead to a potential approval and launch. We would be looking for switching.
Also, a portion of HP patients who would require a dose of Yorvipath above 30 micrograms, which is not available in the U.S. due to restrictions on the label. And then, of course, treatment-naive patients. And this is a $250,000 prevalence in U.S. and EU. And so we think it's throw in rare disease pricing, a large multi-billion-dollar opportunity, we believe, where there are multiple players that can compete successfully.
Great. Let's shift gears a little bit to your second asset, 1416 and PBH. Maybe just describe for us the data that you showed so far, what it proves out about the platform from your perspective, and then also what you see as the opportunity in post-bariatric hypoglycemia.
Great. Well, just first, an observation that we were again able to reproducibly demonstrate we could deliver using our PEP technology, a long-acting molecule that translates to PD effects in healthy volunteers, and to set the stage in post-bariatric hypoglycemia, this is a serious chronic rare disease with a high burden of illness, and it's an estimated 90,000 U.S. prevalence alone, so not too dissimilar in size from hypoparathyroidism. We've even seen larger prevalence estimates, and there's no approved pharmacotherapy. Sort of the fear factor with this disease of not knowing when you could have an episode of severe hypoglycemia that could render you unconscious or require a rescue injection of glucagon really wreaks havoc on your life, and there's a big unmet need that we believe could be addressed with 1416.
So what we showed with our phase I results in early January was, first of all, we had a well-tolerated molecule with an overall favorable safety profile. And so there were no SAEs. The majority of the AEs were mild to moderate. And the most common was ISRs. And we also demonstrated that we had a half-life of 90 hours and accumulation of drug concentration, steady state between two or three doses. So we believe covering the whole week, providing a weekly therapeutic option. And nice dose proportionality in both the SAD and the MAD. And kind of a bonus was in the mixed meal tolerance test, within 60 minutes, we saw an increase in GLP-1 with statistical significance. And that was both at the 10- and 30-microgram dose level. So we see a path forward to investigating this candidate in PBH patients next half of this year.
Great. In terms of what you would like to see in a PBH population, this was sort of healthy volunteers, but in a PBH patient population, what would you hope to actually see in terms of the clinical data? And maybe talk a little bit about the competitor asset that's advancing currently of avexitide.
Sure. So what was great to see, not only the 90-hour half-life compared to ave xitide's two-hour half-life as a once daily, potential once daily, is this GLP-1 effect at both the lower and higher dose levels. Because what we saw with avexitide when they were in healthy volunteers is a similar signal. So when you think about MBX 1416 being a competitive antagonist, it's a GLP-1 sequence that's chemically modified to act as a highly potent antagonist. And it's fatty acylated for long-time action. And we've demonstrated in vitro that we have tenfold greater potency as an antagonist than avexitide. So where we see success is in getting into PBH that we would have not only the GLP-1 antagonism, but the predicted effect on insulin and on a glucose nadir. Because ultimately, what we're trying to do is reduce, prevent these episodes of severe hypoglycemia.
The perturbation in this disease is you have this really excessive GLP-1 excretion due to the changed anatomy in the bariatric surgery population that present with this complication. So the nutrients passing more rapidly to the small intestines creates this bolus of GLP-1. That's why you want a GLP-1 antagonist. It's a clinically validated target. So avexitide is now in phase III. And they have shown in PBH patients this mechanism can reduce the frequency and severity of hypo.
Great. And when you think about the size of the market opportunity, there are GLP-1s out there. But there's also a high prevalence of post-bariatric surgery patients, not necessarily PBH patients. But how do you sort of scale the market opportunity? And I know you guys have done a lot of market research on this.
We have. And we feel the 90,000 U.S. prevalence is pretty solid. And this is a chronic disease. I want to emphasize that. So you have it for life, unfortunately. And we see a steady, not large growth in bariatric surgery, but steady single-digit CAGR in our estimates by speaking to bariatric surgeons and endocrinologists. We see that persisting because it remains the gold standard for significant and sustained weight reduction in this quite obese, severely obese population. And we just aren't there yet with medicines that can bring 40%, 50% of your weight off.
And in fact, if anything, we heard feedback from the surgeons in endos that the Incretins can become a gateway for patients that are currently too large to undergo the bariatric surgery safely. And this provides a means for them to get to a healthier weight to undergo the surgery. We think bariatric surgery is here to stay for its sort of niche and will continue to, unfortunately, add PBH patients to the base that we currently see.
Great. Maybe just lastly, any updates to share on your obesity pipeline efforts? Obviously, you talked about the opportunity for 4291 to advance the IND stage. Anything else that you would point out relative to that opportunity or other products in development?
Thanks for the question. We're really excited about our obesity portfolio. Again, from the inventor of the first GLP-1/GIP co-agonist himself, Dr. DiMarchi, I think our candidates are very special. 4291 is on track for an IND submission next quarter. We will be excited to share more about our plans with a very efficient phase I trial in the target obese population and what we hope to garner from that. I would just say that we are aware of the competitive landscape, particularly that people are emulating what we do and Dr. DiMarchi. This is clear. We've been a little mum about our ongoing lead optimization, but we have some really exciting preclinical development that we'll continue on this year. I'm sure more developments to come there as well.
Obviously, the IPO completed sort of the second half of last year. Just remind us your cash and cash runway?
Right. Yeah. So we had two successful financings in 2024, more than $250 million in proceeds. And we ended 2024 with approximately $262 million in cash, which we believe will fund our operations into mid-2027. So just a lot of milestones that we can accomplish in that period. And we're really excited for the value creation for shareholders.
Super. Well, thank you so much, Kent, and thanks to MBX.