All right, thanks everybody. We're sort of approaching the end of the day, but I'm really thrilled to have MBX Biosciences here with us. We have Kent Hawryluk, who is the President and CEO, and Sam Azoulay, who is the Chief Medical Officer. You know, Kent is to my immediate left, and Sam is to my far left. And again, I'm just going to say thank you so much for joining us. It's an absolute pleasure to have MBX here with us today. So Kent, you know, maybe just big picture, just give us a brief overview of MBX, including just the path to the public market and now where you're headed.
Great. So MBX Biosciences is a clinical stage biopharmaceutical company that's founded by global leaders in peptide drug design and development. And we're pioneering a platform technology we call precision endocrine peptide, or PEP. And PEPs are engineered to have optimized pharmaceutical properties, including extended time action and consistent drug exposure, as well as more convenient, infrequent dosing regimens. And this platform technology is now validated in humans. And it's an exciting point for the company following our Series C and IPO, which occurred last quarter, which brought in about $250 million into the company and gross proceeds from really premier biopharma investors. And so now in our lead program, MBX 2109, we're conducting a phase two clinical trial called AVAIL in healthy, excuse me, in adults with hypoparathyroidism, or HP. And MBX 2109 is an investigational parathyroid hormone, or PTH, peptide prodrug with intended once weekly dosing.
We have orphan drug designation in the U.S. Now, our second program, MBX 1416, is a long-acting GLP-1 antagonist versus agonist and a potential therapy for post-bariatric hypoglycemia. We're completing a phase one clinical trial and are planning to present top line results in early January of 2025. Lastly, we have an obesity portfolio, which includes MBX 4291. That's our first development candidate that we believe has the potential for once monthly dosing, as well as better GI tolerability and potentially greater weight loss compared to current market leaders. It's a GLP-1 GIP coagonist prodrug. You know, with this, with these financings, with these coming catalysts, it's just a lot of momentum and excitement heading into 2025.
Great. So maybe we can just talk about what you're particularly excited about for 2025. I think you kind of hit on the catalyst briefly, but maybe give a little bit of background on the individual product opportunities.
Right. Well, again, just at a high level, thank you for referencing our IPO. And this is really a means to an end. It really helps us to pursue our goal toward a fully integrated biopharma company. So with these proceeds, which now bring our total amount raised to $400 million, we announced recently we had cash on the balance sheet of $277.1 million approximately, which provides runway we estimate out to mid-2027. So a lot of value creation potential. And, you know, it's the idea that we can accelerate our current product candidate development. We can plan for the next stage of development, also potentially expand our pipeline and grow our organization to support the ongoing development and potential commercialization.
I mentioned the major catalyst in our lead program, phase 2 top line results planned in Q3 of 2025 and 1416 early January phase 1 top line results. And the IND submission for 4291 is planned for the second quarter of 2025. So kind of stacking up some interesting catalysts. I would say beyond that, it's really the idea of looking at our PEP platform and how we can expand our obesity portfolio. And as you know, Seamus, our members of our team have a long history in obesity. And I think that's an area, given the overall market opportunity, the heterogeneous nature of this disease, and the need for a variety of treatment regimens. It plays to our strength, and we're looking forward to pursuing that in the coming year.
Great. So let's talk about the lead program. You know, MBX 2109, weekly PTH replacement therapy. You know, I think the best way to start here is to talk about the unmet need and hypoparathyroidism as just a starting point.
Yeah, yeah, thank you. So as you know, this hypoparathyroidism is related to surgery, thyroid surgery. And when inadvertently you take away the parathyroid, which are just behind the thyroid gland. So it has a high burden on the patients because it's impacting the calcium. And the calcium is critical for many tissues, especially muscles, nerves, et cetera. And so the patients have a lot of symptoms related to this hypocalcemia. And there is no more homeostasis, right? It has disappeared. And so in order to compensate, because until recently there was not that much treatment except calcium and vitamin D, and they have to take a lot of calcium and vitamin D up to one of the patients was referring to 60 pills a day, including at night, putting the alarm at nine to wake up and take the pill. So high burden.
And the risk is that they have symptoms and the symptoms are related to involuntary muscle contraction. You know, the brain, which is like foggy, and you don't know you have impact on cognitive function. And it has also an, also the treatment itself has an impact on the patient because you can go easily on the hypercalcemic side. And the hypercalcemic side has an impact on the kidney. So you have also, in addition, the risk of chronic kidney disease in addition to cardiovascular disease, et cetera. So high burden. And so recently Yorvipath was approved, and we see it as very favorable. But it's a once daily. And we think that our PTH replacement therapy, MBX 2109, has a potential really to be game changing with a weekly administration.
Other rationale that I will give you, especially its PK that avoid excursion, which has a potential to avoid excursion in the hyper- and hypocalcemic range and potential again to protect the patient in the long run.
So feedback that we've gotten from thought leaders on Yorvipath is that it is a dramatic improvement over what was previously available, Natpara. You know, how do you look at your development opportunity, you know, the similarities and differences to Yorvipath that are, you know, kind of where you can improve upon Yorvipath or even match it, but deliver a once weekly of those two, you know, where do you think we should be most focused?
I'm going to start with how this product was developed. It's a prodrug, right? In addition, it has fatty acylation, which gives a very long half-life. Most importantly, or more importantly, is the peak to trough ratio in terms of concentration, which is within the same range than Yorvipath. Yorvipath is a 1.4-1.5 ratio over 24 hours, where our ratio is 1.5-1.8, but over seven days. Less, more stability. We think that over time it will be translated in better efficacy and better safety. That's what we are aiming for. We designed also our phase 2 study with some differences with Yorvipath. I like to say that our clinical trial, which is of a 12-week period, is entirely placebo controlled. If you refer to Yorvipath, only four weeks, the first week were placebo controlled.
That's a difference in terms of quality because what's happening after the four weeks, you know what treatment you have. So it has also an impact on the patient. So that's a difference. And if you refer to the clinical trial per se, you have these four weeks fixed dose, and then we have an additional eight weeks. So it's where during these weeks we can titrate up the treatment to get the patient at the right dose level and the right calcium into normal calcium, serum calcium range. That's the goal. And again, differences with Yorvipath. Yorvipath looked at 26 weeks in terms of open-label extension when we would be looking at 12 weeks in our total result.
Again, we will be defining our responder as a composite endpoint, which is similar to Yorvipath, except that it was at four weeks, and our primary endpoint will be at 12 weeks.
Great.
Maybe I can just add another difference. When we look at the SBA that the FDA came out with recently upon the approval of Yorvipath, and they looked at their device and that they noticed that with this, they observed that with this insulin pen, if you will, where you have three doses that you can dial, there is some overlap such that above 30-60 micrograms, they did not get approval in the U.S. So what we're looking at is a different approach and a device with a once weekly single dose strength, use it, dispose of it, and a pen-like injector. And so, you know, we think that there is opportunity for differentiation there as well.
One area of questions that we've gotten has also been around this ability to fluctuate the dose or titrate the dose on a daily basis. But I believe the label actually comments that the measurements are taken every seven days roughly. I believe FDA actually agreed in your trial that it's seven days. So what would be the value of doing daily measurements or being able to variabilize your dosing on a daily basis? Is there much upside to that from Yorvipath versus your weekly dosing?
Yorvipath doesn't change a dose every day. Just to be clear, they cannot change a dose, and the patient cannot change a dose himself or herself without a serum calcium level. So in fact, in the label, if you refer to the label, the dose is recommended to be changed if needed every week, seven days, and except in case of hypocalcemia, and they said a minimum of three days. So it's very well defined in terms of how you can change a dose and who can change a dose. To be clear, it's a physician, it's not the patient. So in our study today, in our phase two study, we change the dose we allow to titrate up every two weeks. And we measure the serum calcium every week. And when it's time to potentially change the dose, we have serum calcium level in the morning.
If it's good, we don't change the dose. If it's not, if it's on the hypo side, you can titrate up if needed again, or you can reduce the calcium supplement or the vitamin D. Remember, in the phase two trial, we want to get the patient completely independent from active vitamin D and calcium supplements will be within the 600 milligrams per 24 hours.
Okay, great. That's super helpful. And as you think about the other, some of the other questions that we've gotten from investors have been around, you know, orphan drug designation and the ability to pursue, you know, the opportunity in the United States as well as overseas. Any issues in that regard from your perspective?
I think we already have the ODD in the U.S., and we think that we have all the elements to get it in Europe, and it's based on a number of factors. First, chemical and physical properties. We think we have improved this. So that with our design, we are a prodrug, right? We have fatty acylation, and that's led to a PK, which is flat, which is infusion-like PK, which is also a great advantage, which gives this weekly administration, so another advantage, and the peak to trough ratio, which is within the 1.5-1.79, which is again another differentiation after a week. And if everything goes fine, in addition, we will have clinical data that will show that the maintenance therapy will be easier due to this low peak to trough ratio.
In addition, I think I'm not going to say it again, but we have this device, which is what I like to say, reliable. We know exactly what the patient will get. It's one single use, one dose.
Great. Okay. That's super helpful. You know, maybe you can just kind of draw parallels and differences between other areas where we've gone from, you know, twice a day or daily to a weekly asset and how you see this market either being similar or different. What do you think is kind of most comparable to?
That is very much the playbook that we were looking at in founding this company and seeing the opportunity in particular in hypoparathyroidism, and you know, you look from Natpara, which maybe had the PK profile that would lend itself to BID versus daily. You have now TransCon with a once daily and potentially others, once daily, and once weekly is really differentiated, and so we have seen in, for example, the GLP-1 market when you went from, you know, BID, QD, weekly, there was a dramatic market shift to the once weeklies, and it isn't only the convenience factor, although certainly patients and prescribers prefer that, but you tended to also see improved clinical outcomes, you know, better adherence, compliance, potentially, you know, more consistent drug exposure, and we would see applying that here.
And this is perhaps akin to GLP-1 has a narrow therapeutic window where you really want to maintain that drug exposure while reducing variability or continuous infusion-like profile. And so we're very excited about that in 2109. And by the way, with 4291 and obesity too, although with a longer acting compound.
You know, other questions that we've gotten from investors along the way have been, you know, okay, well, how do you see this pricing that Yorvipath chose to move forward with? Do you see it as a risk or more of an opportunity from your perspective? Do you think it, are you concerned at all about how that impacts the market?
First of all, Seamus, we see it as an opportunity. We noted the guidance of $285,000 annual price and the WAC price in the U.S. market. We think that gives us pricing flexibility. You know, you combine that with a superior product profile, which we believe we have. That just gives us a lot of optionality. We would anticipate a favorable reimbursement dynamic, which should afford us a rapid launch. You know, really think that we're well positioned to follow with a once weekly. I mentioned the playbook before. I think we really focused on the long-term unmet need and market opportunity. I mean, we're really close with the patient population and the community like the Hypopara Association.
We just continue to hear that there is a very compromised quality of life and this risk of not only symptoms, but the long-term complications. We know that this kind of continuous infusion-like PTH replacement therapy is the appropriate treatment. We just see long-term major opportunity sort of regardless of what other product performance looks like.
Okay, great. Recruitment and kind of recruiting the trials. Can you? I know you have a very specific target in terms of when you hope to achieve it. Maybe you can just give us a sense of the enthusiasm for participation in the clinical trial.
Right. So we just shared in our quarterly earnings announcement that we are on track to complete phase 2 enrollment in the first quarter of 2025, which sets us up for expected top line results in the third quarter of 2025, and it's just really an attractive program. The AVAIL phase 2 trial, you not only have a 12-week randomized placebo-controlled trial, but that's followed by a two-year extension study where all of the patients who enroll in AVAIL are able to receive MBX 2109, and that's really attractive, and then the recognition that this is once weekly, so maybe Sam can share some feedback from the recent.
Yeah, I just attended the Hypoparathyroidism Association 10 days ago. And I was the last one to present. And they said, well, maybe there will be nobody in the room, right? And it was packed. It was packed. And I learned that there are at least twice as many people on the phone. And in fact, it generated a lot of interest from the audience. I got a lot of questions. But in addition, they asked us whether we're psyched because they wanted to participate. And they were very interested in the weekly administration. So we continue even to get phone calls as we speak, in fact, from some patients. It's anecdotal, obviously, but for me, it's meaningful.
It's really consistent with our mission to help people with endocrine and metabolic disorders live fuller and healthier lives. We want to relieve the pill burden and having to just think about your disease every day or multiple times a day. So really excited about what we can do for this community.
So that brings us to MBX 1416. So, you know, not a lot of folks are familiar with post-bariatric hypoglycemia. There's a lot of, you know, sort of questions around, geez, why would you approach that in an era of GLP-1? So Kent, maybe you can answer both of those questions.
We've long been interested in this indication, and it fits our profile. It's clinically validated target. There is significant unmet need. This is a chronic, severe orphan condition, which by the way, our market estimates from our research, we estimate a U.S. prevalence in excess of 90,000, and, you know, an established pathway to regulatory approval, established regulatory endpoint, so we're very interested in pursuing this, and I think there's growing recognition that this is a problem, and bariatric surgery is the gold standard for the severe obese population. You look at a BMI in excess of 40, and we don't think that's going away.
GLP-1s we found from our research, first of all, could become a gateway to allow patients to get to a safer weight to undergo the bariatric surgery, or they could start on a GLP-1 or incretin and decide it's not going kind of meeting their needs going quickly enough, and they want to go to the most, you know, reliable and gold standard treatment for greatly reducing the weight. You know, I think that following the COVID pandemic, when elective surgeries kind of came back in vogue, there was a spike and probably we're looking at a normalization to the curve, but we're seeing kind of steady growth. We're not, you know, projecting shoot the lights out growth, but we think it's steady, and importantly, you have this core base of population that's meaningful.
Great. And then just in terms of the treatment, you know, can you talk about the disease, the treatment? What are you correcting? And, you know, equally importantly, how is this a validated mechanism? I think we have at least one other asset out there with some data.
Yeah. So the disease is following surgery, bariatric surgery. It happens roughly six months to a few years after the surgery. So, and imagine that you cannot go to a dinner or to a party because you may get a hypoglycemic symptom, which can be so severe that you can pass out. You cannot drive. This patient cannot drive. So it can be very severe. And the most important is you cannot predict it. It's completely unpredictable. So what's happening is when you eat, this patient eats, the food gets too fast from the stomach to the small intestine. There's a secretion of GLP-1, so inadequate secretion, overexpression of the GLP-1. In return, secretion of insulin and the glucose goes down. And so the patient might pass out. So that's a very severe disease, in fact. And today, there's not that many treatments. In fact, there is no treatment.
You change a meal, you take multiple meals instead of small meals, but there is no treatment. You have to take the glucagon pen with you in case something happens. Someone else has to give it to you. So nothing, so strong unmet medical need, and as you said, there is one company which is ahead of us, and avexitide is a product that is being developed. It's in phase two right now. In fact, it's moving to phase three, and it's paving the way for us, but it's given once a day again, and we are going to be given our product, which is a GLP-1 antagonist, right, will be given every week, so big change again, because we are going to cover the night, we're going to cover the week, potentially give the life back to the patient, so that's a big, big change.
So again, from a regulatory standpoint, avexitide is paving the way for us because we know what we need to do in order to get the regulatory through the regulatory path and we'll be following this and having a, we are now in phase one, and we will move to phase two as soon as possible because we think that we need to get data in patient and that the patient will get the benefit of it too.
And, you know, Kent, can you just talk about the importance of that phase one data in terms of platform validation from your perspective? And when we see it, what you'll be looking for?
I think importantly, we'll be looking at safety and tolerability as a phase one study and PK, so we were able to share from the SAD portion of the study a 90-hour half-life for MBX 1416, which is supportive of once weekly, and we will be providing with the phase one data, the PK from the SAD and MAD. You know, I think PD markers want to see more in actual PBH patients. We know that the 1416 molecule is very active, a very active antagonist, very potent antagonist, so we would project that if we have the PK, that would translate to clinical benefit in patients based on the proof of concept that we had with avexitide, which was a GLP-1 antagonist, albeit shorter acting.
Great. Well, with that, unfortunately, we have.