Okay, well, good afternoon, everyone, and thank you for joining us on our next session. I have the pleasure of introducing the CEO of MBX Biosciences, Mr. Kent Hawryluk, and he has a recent IPO, which has been quite successful, and without further due, he's going to give a presentation and overview, and if you have any questions, hopefully we'll have some time at the end.
I want to thank you all for attending and for Mike and the Jefferies team for hosting this wonderful event. Just to point out, this presentation will contain forward-looking statements, so I encourage you to refer to our public disclosures in the SEC filings, which are available on our website. MBX Biosciences is a clinical stage biopharmaceutical company founded by global leaders in peptide drug design and development. We're pioneering a platform technology called Precision Endocrine Peptide, or PEP, which was created by Dr. Richard DiMarchi, who is a world-class innovator and well-known for inventing Humalog, as well as the first GLP-1 GIP coagonist. PEPs are engineered to have optimized pharmaceutical properties, including extended time action and consistent drug exposure, as well as more convenient, less frequent dosing. Our lead program, MBX 2109, is an investigational parathyroid hormone, or PTH, peptide pro-drug therapy for hypoparathyroidism.
We have orphan drug designation in the U.S. and a phase II clinical trial underway. Our second program, MBX 1416, is a long-acting GLP-1 antagonist and potential treatment for post-bariatric hypoglycemia, or PBH. We're completing a phase I clinical trial and are set to report top-line results in early January of 2025. MBX also has an obesity portfolio, including MBX 4291, which we believe has the potential for once-monthly dosing, as well as improved GI tolerability and greater weight loss compared to current market leaders. It's a GLP-1 GIP coagonist pro-drug. We have other programs in lead optimization for obesity and comorbidities. The company has raised a total of $400 million to date from premier biopharma investors. This includes proceeds of around $251 million from our Series C financing and upsized IPO, both of which occurred last quarter.
And our cash at the end of September was approximately $277.1 million. And that provides operating runway through to mid-2027, we estimate. So MBX has a lot of momentum and important value-creating milestones in 2025 and beyond. So they're summarized here, and I will be addressing these as I update you on all of our programs. MBX is well-positioned to execute. Our leadership team brings together exceptional expertise from large pharma and smaller biotech. And members of our team have collaborated over several decades on the discovery, development, and commercialization of first-in-class endocrine therapeutics, including Forteo, Byetta, and Humalog. And previously at Marcadia Biotech and MB2, Dr. DiMarchi and I advanced multiple GLP-1 and glucagon-based programs through clinical development with strategic collaborations with Lilly, Merck, Novo Nordisk, and Roche. We'll continue to build our team to support the ongoing development and commercialization of our product candidates.
I'll share a high-level summary of our pipeline. Our lead investigational drug, MBX 2109, is a potential long-acting PTH replacement therapy, which is designed to provide consistent exposure to PTH with convenient once-weekly dosing. We presented positive phase I data last year and have our AVAIL phase II trial underway. We are projecting to complete enrollment in this study in the first quarter of 2025 and to present top-line results in the third quarter of 2025. Our second compound, MBX 1416, is a potential treatment for post-bariatric hypoglycemia PBH, which utilizes a clinically validated mechanism of action, GLP-1 antagonism. We announced earlier this week that we completed the patient visits. As I mentioned, expect to present top-line results very soon. In our obesity portfolio, our first development candidate is MBX 4291, a potential once-monthly GLP-1 coagonist pro-drug.
We are in the process of completing IND-enabling activities in order to submit an IND in the second quarter of 2025. In parallel, we'll continue the discovery and development of other obesity programs, applying our PEP platform technology. As background and sharing a little bit more under the hood of our PEP platform, I'll just kind of remind everyone that peptides have been a very important drug modality for a century. However, existing peptide therapeutics have some limitations. You think of sometimes a shorter half-life requiring frequent dosing of super physiologic dose levels and daily fluctuations that can lead to deleterious effects for patients. Our central thesis is providing continuous infusion-like PK profiles. We do this through several means. We start with a really very innovative peptide design, and it's engineered to have optimized potency, stability, and solubility.
We apply a proprietary prodrug technology, which is precisely controlling the rate of activation of the drug, which serves to flatten the PK profile. And then fatty acylation. This is a state-of-the-art, pretty well-established technique for increasing duration of action, and it's used in Semaglutide and Tirzepatide. And so we combine our know-how in these proprietary tools to create what we believe are transformative peptides. This technology is now validated in humans in our two clinical stage programs. So let me share some more background on our lead program, MBX 2109. And hypoparathyroidism is a serious disease affecting 250,000 people in the U.S. and EU. And there's a high burden of illness. It is caused by a deficiency in PTH. And PTH is very important for the maintenance of calcium homeostasis in nerves and muscle, which rely on calcium for proper functioning.
Patients with HP can experience hypocalcemia, which has really negative effects, including tetany, seizures, brain fog, and they can also experience hypercalcemia, and this is largely due to the standard of care, and not only are there symptoms associated with acute hypercalcemia, such as weakness and GI issues, but more importantly, there's the risk of long-term complications affecting multiple organs, including the kidney, so the standard of care is very burdensome. It consists largely of taking active vitamin D and calcium on average seven or eight times throughout the day, and sometimes a handful of pills at a time, and as I mentioned, this can lead to fluctuations in calcium and risk of long-term complications. There are two PTH agonists that are requiring daily administration. TransCon PTH was approved in U.S. and EU as YORVIPATH, and eneboparatide is in phase III development by AstraZeneca.
Where we believe we have differentiation is in a once-weekly PTH replacement therapy with a flat or continuous infusion-like profile and opportunities to reduce the calcium excursion, leading to reduced symptomology, risk of long-term complications, and overall quality of life improvements. I mentioned that we presented positive phase I data last year. This was a randomized placebo-controlled SAD-MAD study, and the primary endpoint was safety and tolerability. We were also in secondary endpoints exploring the PK profile, as well as change in PD markers, importantly serum calcium and endogenous PTH, which is a signal for calcium change. So first of all, MBX 2109 was shown in the phase I study to be overall safe and well-tolerated. We showed a PK profile supportive of once weekly and by design with our PEP approach.
So there was a half-life of MBX 2109 active drug of eight or nine days, and a peak to trough over a seven-day period that was comparable to what's seen daily with the other PTH therapies. Additionally, we saw a dose dependency, which is very helpful in selecting doses. So we saw a dose proportional increase in calcium and corresponding decrease in endogenous PTH. Again, these are healthy volunteers, so they have intact PTH signaling, negative feedback loop. So here's where we are today. We are conducting our AVAIL phase II trial in adults with hypoparathyroidism. We are targeting randomizing 48 patients into one of four treatment groups: 400, 600, and 800 micrograms of MBX 2109 once weekly or to placebo.
There is a 12-week treatment period, first a four-week fixed dose period, followed by an eight-week dose adjustment period, where study investigators will be able to adjust the dose of the patients in 200 microgram increments every two weeks based on the serum calcium values, and so for a total of four potential dose adjustments. The primary endpoint is at 12 weeks. The percentage of responders is defined by normalization of albumin-adjusted serum calcium while independent of active vitamin D and reducing their calcium levels. We will also be looking at secondary endpoints, including safety and tolerability, certain other PD markers, and patient-reported outcomes. Importantly, every patient who enrolls in AVAIL and completes the study will have an opportunity to enroll in an open-label extension, which is two years, which is an attractive feature of this study, we believe, for patients participating.
We are, as I said, enrolling and expect to complete enrollment in the first quarter of 2025 and to present top-line results in the third quarter. So now I'll turn to our second program, MBX 1416, in post-bariatric hypoglycemia. And PBH is a serious, rare, and chronic complication from bariatric surgery, typically occurring six months to up to three years following Roux-en-Y and vertical sleeve gastric bypass surgery. And the result is occurrence of severe hypoglycemia. And what happens is anatomical changes from these procedures cause the rapid transit of nutrients from the stomach to the small intestine, such that following a meal, you have a dramatic overexpression of GLP-1, causing an increase in insulin and decrease in blood glucose. So this can result in really serious neuroglycopenic symptoms, including confusion, seizures, and loss of consciousness. The patient impact is great, right? Because you don't know when this could occur.
Typically, severe hypoglycemia requires an intervention, including a potential injection of glucagon, often by a third party. It can lead to social isolation. There's no approved pharmacotherapies. The standard of care focuses on dietary interventions, small frequent meals, avoidance of high glycemic index foods. This is hard to adhere to and does not always work. There are some off-label use of medicines, but they are not clinically validated in PBH, and they can have serious toxicities. Reversal of the bariatric surgery is a last resort and not often effective and not widely used. We see a real potential unmet need here. The goal with MBX 1416 is to have a once-weekly GLP-1 antagonist to prevent severe hypoglycemia and reduce this burden of illness, reduce the need for a glucagon rescue or these other more serious interventions.
So we are wrapping up our phase I trial, completed the patient visits, and we'll be evaluating the top-line results to present in early January. This is a SAD-MAD study in healthy volunteers with the primary endpoint safety and tolerability. And also, we'll be looking at PK. Preliminary PK data support once-weekly dosing with a half-life of 90 hours, dose dependency, dose-dependent increases in exposure, CMAX area under the curve. So we'll be looking for that in the MAD as well. And we did a mixed meal tolerance test in the MAD portion. The caveat is another GLP-1 antagonist, Avexitide, that is once daily. It did not see meaningful PD effects in the healthy volunteers and only saw that when they moved to PBH patients. But with Avexitide, there was demonstration in a phase II trial that a GLP-1 antagonist can greatly decrease the frequency of these severe hypo episodes.
So the third area of our company, we have an obesity portfolio. Pardon me. And I think we all know that obesity is a global epidemic that has created a very large and growing market opportunity. Based on the success of Zepbound, a number of pharma companies have entered the space or are looking at it. And where we believe we are differentiated is in our scientific leadership in obesity and in our PEP platform technology. The current obesity agents, incretins, require once-weekly administration, and they're associated with pretty significant GI intolerability or side effects, nausea, vomiting. And this leads to quite a bit of discontinuation or issues around adherence. So where we see an opportunity applying our PEP platform technology is to create a very flat PK profile with extended duration of action supportive of less frequent dosing.
And so what we did is take as a starting point that GLP co-agonism is very well established. Tirzepatide is a market leader and kind of a gold standard for weight loss. However, it is, as others in the class, associated with the GI side effects and discontinuation. So we have, as you see on the right, applied all of our PEP platform tools to MBX 4291. As illustrated at the top by green and blue, this indicates that the MBX 4291 active drug can bind both the GLP-1 and GIP receptors for both of those activities synergistically. Additionally, you'll note these sort of sticks on both ends of the molecule. And those are fatty acids or lipids. So this molecule is fatty acylated multiple places. The red zigzag represents our proprietary PEP platform technology, which is specifically designed in this case to support once-monthly dosing in humans.
So following the conversion in circulation, which, by the way, requires no enzymes or exogenous factors, it is purely based on the pH and temperature in circulation. And once it's converted, you can see then that it has activity at both receptors. And the binding activity of both receptors is very similar to Tirzepatide. And also, as a result, the weight lowering and lower food intake in the DIO models corresponds quite well to Tirzepatide. And where we have real market differentiation is in the PK profile. So let's start with Tirzepatide. So following a single subcutaneous administration in cynomolgus monkeys, you're going to have a pretty rapid rise to CMAX, as shown in the black solid triangles. And then you're going to have a pretty marked decrease in drug exposure, such that Tirzepatide needs to be dosed once weekly.
Now let's look below that at the empty blue squares representing MBX 4291 active drug. What you see instead, in contrast, is a slow, steady rise to CMAX in a prolonged portion of the curve, representing a flatter PK profile than tirzepatide. When you consider that albumin has three times longer half-life in humans than in cynomolgus monkeys, we believe that we have a PK profile supportive of once-monthly dosing, as well as multiple ways to win, we feel, with this asset. Because while this molecule kind of self-titrates, if you look at the ramp-up to CMAX, we can also explore potentially dosing strategies with more frequent dosing to reduce the peak to trough further, reduce GI side effects potentially, and get to greater exposures and weight loss potentially more rapidly than the titration that occurs five or six months with tirzepatide.
So we're very excited to complete our IND-enabling activities, as I shared, to file an IND in the second quarter, and then to follow that in a phase I study that can really investigate many of these hypotheses about our differentiation. So I'll return to our milestones. You can see that we have a pretty catalyst-rich year ahead and very focused on execution and delighted in the remaining time to answer your questions about our pipeline.
That was fantastic. Maybe first, as you execute on the phase II study, I know that people are looking at the currently approved PTH drug and also the AstraZeneca drug to be an example of, obviously, an approved agent with efficacy and safety. How do you expect your phase II results to show efficacy and safety, and how do you expect them to compare, and is that a reasonable bar that we should be looking at?
Thank you. So we, again, believe that what you want to achieve with a PTH replacement therapy is this continuous infusion-like profile. And that's not only us saying that, but our competitors like Ascendis would say that too. So the way we go about achieving that with our prodrug and fatty acylation, we think can translate to really strong efficacy. So I want to point out that what we're conducting is a 12-week treatment period, placebo-controlled for the entire 12 weeks, and that Ascendis in their phase II had a four-week placebo-controlled treatment period. So that's a difference right off the bat.
And so we think that, focused on hitting our primary endpoint and showing that we have a significant ability for patients to get off of the pills, the supplements, and to have normalized serum calcium. And so that's our main goal. There are other things in the phase II we'll be looking for and I'm sure reporting on, but that's the main ability. And we will be getting to a steady state with this molecule after the third or fourth dose. So after the 12-week treatment period, we will have had an opportunity to dose titrate and get doses that will inform the phase III.
Fantastic. Okay. Secondly, I know that there was a recent IPO of another company, and they claim to be starting a daily oral therapy for PTH. There were questions around how the competitive landscape might look and what the bars might be. Do you have any comments about how that may fit in? Are there other examples in the markets where a weekly injectable or much more convenient drug, presumably also efficacy could be better too, versus the potential of a daily oral?
I think the question refers to a daily mimetic GPCR mimetic. And with small molecules, first of all, you have to look at the bioavailability and the PK profile. Does it provide that kind of continuous infusion-like profile? And my understanding is that the once-daily from Septerna is being evaluated in 180 volunteers in a phase 1, both BID and QD. So that's quite a difference. And I think when you look at the obesity space, plenty would say that a weekly injectable is quite competitive with a once-daily or even twice-daily pill. And again, the goal for these patients is moving away from the pill burden and not having to think about their disease every day or multiple times a day.
And I think as we've learned also in obesity, but also other classes as well, there's countless, the hurdle for an oral is not easy. And you have a direct injection of the actual peptide. So that is significantly more de-risked. So these patients need high efficacy and convenience, and the bar remains fairly high for that drug. Good. If there's no further questions, thank you very much, Kent, for that. And we look forward to the data next year.
Thank you.