Thanks for joining the MBX Biosciences presentation. It's our pleasure to have Kent Hawryluk, CEO of MBX and recent IPO winner, I suppose. MBX is developing Precision Endocrine Peptides, and I will let you do the honor of presenting your own company for a little bit, and then we'll go into Q&A.
First of all, thank you, Annabel, for the opportunity to provide an update. I will be making some forward-looking statements, so please refer to our disclosures in the SEC filings. MBX Biosciences is a clinical stage biopharmaceutical company. It was founded by global leaders in peptide drug design and development. We're advancing a platform technology called Precision Endocrine Peptides, or PEPs. PEPs are engineered to have optimized pharmaceutical properties, including extended time action and consistent drug exposure, as well as convenient dosing regimens. It was invented by our scientific founder, Dr. Richard DiMarchi, who's a world-class peptide chemist. He's well known as the inventor of Humalog, as well as the first GLP-1/GIP co-agonist. Our first program, MBX 2109, our lead program, is a parathyroid hormone, or PTH peptide pro drug, with, we believe, potential for differentiation.
We have a phase II clinical trial that's enrolling patients in hypoparathyroidism. Excuse me. We have orphan drug designation in the U.S. Our second program, MBX 1416, is a GLP-1 antagonist and potential therapy for post-bariatric hypoglycemia, or PBH. We have completed subject visits in a phase I clinical trial. Additionally, MBX has an obesity portfolio, including our first obesity development candidate, MBX 4291, which we believe has the potential for once-monthly dosing, as well as potential improvements in GI tolerability and greater weight lowering compared to current market leaders. It is a GLP-1/GIP co-agonist pro drug. We have other programs in obesity that are in lead optimization at this stage. The company has raised $400 million to date, and quite a bit of it came last quarter in our Series C and IPO, which garnered $251 million, approximately, in gross proceeds.
At the end of last quarter, we had cash and cash equivalents of $271 million, approximately, which funds our operations into mid-2027. We believe we have quite a bit of momentum and quite a bit of opportunity for value creation in 2025 and beyond. Looking at our snapshot of our pipeline, our lead investigational drug, MBX 2109, a long-acting PTH replacement therapy for HP, which is designed to provide continuous infusion-like drug exposure, along with convenient once-weekly dosing. We presented positive phase I data last year. As I mentioned, we're enrolling in a phase II study called Avail. We've communicated that we're on track to complete enrollment in the first quarter of 2025, which sets us up for top-line results in the third quarter of 2025.
With MBX 1416, our second candidate, this is a long-acting GLP-1 antagonist that's using a clinically validated mechanism in PBH, and we just this morning announced the last subject visit in this phase I trial, and we expect to report top-line results on this phase I study in early January, and in terms of our obesity portfolio, MBX 4291, this GLP-1/GIP co-agonist prodrug with potential once-monthly dosing, is working its way through the IND enabling activities, and we believe we are on track for an IND submission in the second quarter of 2025, and very excited about that once-monthly profile, and look forward to following the IND submission, going into a phase I, while we continue the lead optimization of other programs for the treatment of obesity and comorbidities using our PEP platform technology.
So just very briefly, we see differentiation with our PEP product candidates compared to the existing therapeutics in several key areas. First is this infusion-like flat PK profile. The second is more convenient, less frequent injections. And we believe the third, and importantly, this can result in greater convenience, adherence, compliance, as well as better clinical outcomes and overall improvements in quality of life. So I'll return to our pipeline so you just have a sense of what's coming. And again, we're just very excited about a quite catalyst-rich year ahead.
Before we go into the specific programs, I just want to have you maybe describe the PEP technology and how that differs from other technologies that people have been working with for peptides to extend that duration and maybe talk about the versatility. What kind of flexibility does this give you to work with different compounds?
Our PEP platform has been years in the making from Dr. Richard DiMarchi in terms of optimizing this, and we start with quite innovative PEP or innovative peptides. So these are optimized through our know-how and advanced chemical modifications to have improved potency, stability, and solubility. Additionally, we can apply a proprietary programmable pro drug technology, which provides for drug activation at a precisely controlled rate under physiologic conditions, so not requiring any enzymes. So it's very versatile and, frankly, translatable and results in lower variability. The third tool in our PEP toolbox, if you will, is fatty acylation, and this is probably well known to many folks through semaglutide and tirzepatide, which are fatty acylated peptides that are blockbuster drugs, and those have once-weekly dosing due to the fact that fatty acylation extends time in action through albumin binding. That's a plasma protein.
So it's really the combination of these techniques and proprietary tools that our experts use to create what we believe could be transformative peptides.
Okay, great. So on MBX 2109 first, that's for hypoparathyroidism. Before we go into your specific compound, we just really want to understand the market very well. There's been a product out there on the market. It was never successful for one reason or another. It was finally pulled. There is supplementation on the market. Some people believe it works. Others are like, no, it doesn't work. What is the market exactly?
We think it's significant, and the unmet need is profound. Starting with prevalence, we see a prevalence in the U.S. and E.U. combined of 250,000. As well, in terms of unmet need, what we're talking about here is a deficiency in endogenous PTH, which typically results from a thyroidectomy where the parathyroid glands are compromised or removed along with the thyroid, and you have a deficit or absence of PTH. The need is to treat the underlying pathophysiology, a PTH replacement therapy. What Natpara did, which was a PTH, a recombinant PTH, so full endogenous PTH sequence, it did not alleviate the pill burden enough for patients. The pill burden is great. We think of HP patients having to take often doses of calcium and active vitamin D seven or eight times during the day and sometimes night, right?
Setting your alarm and having to wake up and take pills. It could be a large number of actual pills. Like even anecdotally, we hear 60 or more in some cases. Really, what you want to do is alleviate the pill burden and prevent the excursions into hypercalcemia and hypocalcemia because PTH is the regulator of calcium in the body. In terms of hypercalcemia, this can result not only from therapy, but also from the supplements. What we've designed with 2109 is a long-acting PTH with a flat PK profile, where we saw in phase I that our half-life is eight to nine days. There's accumulation such that we're at steady state after the third or fourth dose. At steady state, we have a peak-to-trough over a seven-day period, similar to a once-daily competitor, Yorvipath, over one day.
So we see more of a continuous infusion-like profile that we think will be interesting. So while Natpara had a half-life of minutes, Yorvipath has a longer half-life. And what we have is this flat peak to trough. So when you think of other markets where you've had a once-daily, go to once-weekly, we've typically seen a market shift.
Okay. First, let's go to Yorvipath . Obviously, that's recently been approved. They haven't launched yet, but maybe you can talk to us about some of your clinical and regulatory learnings from their experience through the process. It was not necessarily straightforward or easy, and what gives you some comfort that you understand what the regulatory requirements are now?
Right. Well, we're pleased that the HP community, which we feel we're very close to, now has an approved PTH replacement therapy available. And we think it's a start. Do we think we could do better? Yes. And have we spent a lot of time looking at the label and the summary of basis for approval that the FDA published some weeks ago? Yes. And so fundamentally, we look at Yorvipath as a daily that the FDA pointed to potential for variability and such that there's pretty frequent monitoring of serum calcium in the patients every four to six weeks, say. And the focus is on hypercalcemia, it appears. And the FDA particularly noted the device that Ascendis used for Yorvipath was, and to use their words, "unsuitable." And that's due to the insulin pen, if you will.
It's an adapted insulin pen where the patient would select one of three doses. And the observation was there's some overlap and question of, are you getting the dose concentration that you need to get or you've been prescribed? And so thus, the need for frequent monitoring. And where we have differed there is looking at a single-use device, again, once weekly, it's a facilitated mixing and pen-like injector where the patient administers a single dose strength and then disposes of the device. And ideally, the patient only has to think about their disease once a week versus more frequently, once daily or more than that.
We think that with this combination of our different device approach and our flat PK profile, which we see as more continuous infusion-like, we would like to see less excursions into hypercalcemia and hypocalcemia and improve clinical outcomes, patient-reported outcomes, and quality of life overall.
Okay. So right now, you have primarily phase I data in healthy patients. You had a very nice dose response. So that's really good. And maybe you can talk to us about what some of the characteristics of that initial phase I study that gives you confidence that it's going to translate into a hypoparathyroid patient and some kind of clinical benefit there.
Great. And so just starting off as a phase I study, of course, great to see the overall good safety and tolerability. Of course, we were also looking at PK because we, by design, wanted to see this flat pharmacokinetic profile. And it performed exactly as designed and translating from the non-clinical work we had done. So I mentioned this long half-life of the 2109 active drug, eight or nine days, and the peak to trough over a seven-day period that was comparable to Yorvipath 's peak to trough over a 24-hour or one-day period. And we think that can lead to differentiation and better outcomes. And so just very excited now to be in a phase II trial in HP adults.
Okay. So maybe looking at this extended dosing regimen, are there any kind of, I guess some physicians have talked about there's a cycle of parathyroid in the body that maybe you want to see the cycle, but here you've got continuous dosing? So is there any concern that you could have those kinds of hypercalcemia or those things that you worry about with too much PTH? Or help us understand how you address the cycles that you might be avoiding with this continuous infusion.
I think that the basis for seeing this continuous infusion-like profile as being desirable goes all the way back to an NIH study by Gordon Cutler and Karen Winer. This used an insulin pump to infuse PTH and really established that as a gold standard for treating hypoparathyroidism, reducing risk of excursions and long-term complications. It's just cumbersome and not really practical in use. The field has been looking to design that into a molecule. Clearly, with our combination of pro drug and fatty acylation PEP, we believe we've created the desirable profile. That you kind of just want to keep it in that range. This is a narrow therapeutic window disease. The key is to kind of keep that steady PTH.
And we think the 1.5 peak to trough over a one-week, and endocrinologists we've spoken with concur that it's very continuous infusion-like and demonstrated to be what you need. I think I want to point out, sometimes we've heard speculation that maybe with a once-daily, patients could sort of adjust their dose on the fly daily. I don't know, based on how they feel or what have you. And that's just not the way Yorvipath is approved for use. So clearly, if you look at the package insert and the dosing instructions, patients are instructed that they should not adjust their dose of Yorvipath more frequently than once per week and only at the direction of their physician. So, in that it's based on monitoring their calcium, et cetera. So we think that actually sets us up very nicely in terms of our dosing frequency.
By the way, if we're successful with our molecule in reducing the amount of excursions into hypercalcemia or even hypocalcemia, it's an opportunity to have less frequent monitoring in our label.
Okay. So there's been some who've, I guess, have to talk about the questions that we had received during the whole IPO process. And one of the questions is, with daily dosing, what is the analog that you point to that you typically look to when you go from daily dosing to weekly dosing that is probably the most akin to what you might experience here?
We love the GLP-1 class because we've kind of lived through that in prior lives and saw the move from a BID to a daily to finally when you had a once-weekly. You don't only see a shift in use from the dailies to a weekly, but you see kind of an explosion in the market, tremendous growth. And beyond the convenience factor, typically you also see greater clinical benefit. You look at adherence or compliance and perhaps more consistent drug exposure that can contribute to better outcomes. And we would hope to see that apply here to us. And you can think of growth hormone. There are other examples, but I guess we're closest to GLP-1.
Okay. Yorvipath , again, to bring them up, they set the price quite high. And I just want to give you an opportunity to talk about that price, what you think that that's going to do for their ability to successfully commercialize in a market that's used to dealing with calcium, cheap calcium and vitamin D supplements. Have they priced themselves out of taking over a bulk of the market? Do they just essentially give themselves the low-hanging fruit of only the uncontrolled population rather than the symptomatic population maybe?
I believe you're referring to the $285,000 WAC pricing per annum that Ascendis has guided toward. We see that kind of in line with rare disease pricing where there's significant unmet need. We do see such very large unmet need here. I would also say that it underscores the large market opportunity given the prevalence that I mentioned. Also, you see some endocrinologists that have talked about, and you see it in some of the research that's published, prescribing two-thirds of their HP patients a PTH replacement therapy or 50% to two-thirds. We did hear just recently, we saw in a note an endocrinologist talking about kind of tempering their prescription expectations for Yorvipath in light of a potential once-weekly where they could see 80% of starts with a PTH replacement therapy choosing the once-weekly and 50% switching from a daily to weekly.
So we think there's a good opportunity for once-daily to establish the market and then for us to have an opportunity to build on that.
Is there any concern that they may, if there's any challenge in their uptake, could that potentially be a harbinger for you?
Two things. Where we are positioned, we have a lot of optionality around pricing based on where Ascendis seems to be coming out. And we would work very collaboratively with the payers as we advance our program through development and potential commercialization to really optimize our pricing model. And so I like where we are positioned and again, think there's just a lot of unmet need. We're more focused on the long-term versus sort of performance of any competitors in the nearer term.
Okay. One other question. Can you talk about the orphan drug status of Yorvipath and how that potentially does that block you? Does that call into question your orphan status?
We don't believe so. With MBX 2109, we have orphan drug designation in the United States. And keep in mind, MBX 2109 is a PTH peptide pro drug. And it combines pro drug technology and fatty acylation to create this differentiated PK profile. And it's once-weekly. And so I think the opportunity to establish meaningful difference for patients in terms of ease of use, compliance, adherence, as well as clinical benefit and quality of life exists there. And then in terms of the molecular differences. So this is a different active drug. It uses our PEP technologies. And so we think combined, there's quite a bit of merit in pursuing ODD in EU, which we would seek to do.
Okay. Great. I want to leave some time for 1416 because that's an interesting indication as well for post-bariatric hypoglycemia. So tell us a little bit about this indication. Obviously, it comes from bariatric surgery. So maybe you can talk about the market a little bit.
Maybe a larger unmet need than some are aware of. In post-bariatric hypoglycemia, we have done some market research and determined that the U.S. prevalence is in excess of 90,000. And this is people that have undergone bariatric surgery. And from anywhere from six months to three years after their Roux-en-Y or gastric sleeve surgery, they present with this PBH. And it's severe, chronic. They have it for the rest of their lives. So the consequences are it's very disturbing to their quality of life and routines. The unpredictable nature of severe hypoglycemia means that they're kind of constantly on alert for these episodes and should carry a glucagon rescue pen. And in the event of a severe hypo, could need an intervention by a caregiver, EMT, loved one, may need a glucagon or visit to ER. So large prevalence, unmet need, no approved pharmacotherapy.
They're adjusting their diet, frequent small low-carb meals, looking at off-label use of some drugs where there's no clinical validation for their use in PBH and with some significant side effect profiles, so very excited to complete our phase I. We're on track to present top-line results in January, and we hope move on to PBH patients.
What should we expect of this data? What should we be looking out for?
As a phase I study, the primary endpoint is safety and tolerability. The secondary endpoints are PK, and of course, we want to show a half-life that's supportive of the intended once-weekly use. In the SAD, the single ascending dose portion of the study, we presented preliminary data showing a 90-hour half-life. So that's fully supportive of once-weekly, and so we'll be looking at the MAD half-life, and we did a mixed meal tolerance test in this MAD portion of the phase I. I would caveat it that with the avexitide GLP-1 antagonist as short-acting, they did not see any meaningful change in the PD markers in the healthy adult subjects, and it was only when they moved into PBH patients that they saw those changes, but we will be looking at those data.
The totality of these top-line results in the phase I will inform the path forward into PBH patients.
Okay, and so you are looking at some kind of marker.
We are, but it's with the understanding that these are healthy adult subjects. These are sort of complicated redundant metabolic pathways. So the underlying disease here with PBH is that due to the anatomical changes that deposit the nutrients more rapidly from the stomach into the small intestines, you get a real spike in GLP-1 agonism, which results in increased insulin and the risk of severe hypo. So that's what we would be addressing with a competitive GLP-1 antagonist.
Okay. Maybe you can just speak about some of the worries that people have about GLP-1 agonists destroying the bariatric surgery market, which obviously this is a chronic condition, but.
Understood.
That's a primary question that people ask.
It's an understandable question in light of the success of the GLP-1s. What's interesting is when we spoke to the bariatric surgeons and endocrinologists, they do not see bariatric surgery being impacted long-term by the GLP-1s negatively, and the reason is this bariatric surgery remains the gold standard for the severe obese population like BMI over 40, and in fact, some obese patients are in fact too large to undergo the procedure and could need a GLP-1 to get to an operable weight, so that's one opportunity. Also, some patients who are severely obese could start on an incretin and not see the results quickly or sustain that they were looking for, and that creates potentially a gateway to bariatric surgery, so we saw a drastic increase right after COVID because, of course, all the elective surgeries were down, and now we're seeing a normalization to the curve.
We're not looking at shoot the lights out growth, but sustained growth with this gold standard for treating obesity.
And regardless, you have at least.
90,000.
90,000 that will never.
Population, if you will.
Right. Okay, and I guess while we're on the topic of GLP-1s and incretins and your preclinical program, so obviously there's something like 80-plus programs out there for obesity that are in development. So a lot of physicians are looking not necessarily for the same mechanisms, but maybe the next generation, the next generation after that, and maybe different mechanisms. So what can you bring to the table other than better administration?
With 4291, we have quite a differentiated profile. Of those 80 odd you mentioned, I would say how many of those have a credible once-monthly potential dosing regimen?
Maybe MariTide.
Could be, but it's an elite few, we would say. And what we have different from an antibody approach or even a fatty acylated peptide, regardless of the length of fatty acylation binding to albumin, is this pro drug that has a slow steady build to Cmax and then a sustained portion or drug exposure. And we think that that's really interesting in terms of self-titrating. We know that the GI intolerabilities with the incretin is not only a function of Cmax, but also the rate of rise. And so with our pro drug approach, which is kind of analogous to what I shared about 2109, but obviously designed for a longer profile, can we do better in tolerability?
By the way, multiple ways to win because if we dosed even more frequently than monthly, think of a loading dose or titration, which you have with the incretins anyway, can we reduce the peak to trough gut intolerability even more and get to higher tolerated dose and then switch to monthly?
And what kind of opportunities do you have to build on that, I guess, scaffold that you have? Are you going to be looking at different types of incretins outside of just GLP, GIP, what we know?
Yes, we think about MBX 4291 as being the cornerstone of our obesity portfolio, but we're very excited about other discovery activities ongoing in incretin and even other clinically validated targets in obesity to apply our PEP platform technology.
Okay. Great. We're unfortunately out of time, but.
Always a pleasure to talk to you.