10:30, so we'll get going. Good morning, everyone. Thank you for making the time to be with us here today. My name is Cabrel Happi, and I am here with TD Cowen, and I have the honor of introducing Kent over here, Kent Hawryluk, and he'll be introducing the presentation with MBX Biosciences. Without further ado, I would like to welcome him over here to the stage so he can lead the presentation. Thank you.
I'd like to thank each of you for attending today and to Cabrel and the TD Cowen team for hosting us at this wonderful event. I'm really excited to provide an update on MBX Biosciences as 2025 is off to an exciting start, and it's shaping up to be a really transformational year for the company. I'd like to remind everyone that this presentation contains forward-looking statements, and I encourage everyone to review our risk factors and other disclosures outlined in our recent SEC filings, all of 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 are pioneering a precision endocrine peptide platform technology, or PEP. PEPs are engineered to have optimized pharmaceutical properties, including extended time action and consistent drug concentrations, as well as convenient, less frequent dosing.
We recently unveiled the non-proprietary name of our lead candidate, canvuparatide, formerly MBX 2109. Canvuparatide 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. I'm pleased to report that this morning we announced full enrollment in this Avail phase II trial and that we exceeded our original target based on a great deal of enthusiasm for the study and the number of patients that were in screening. We also reconfirmed that we intend to announce our top-line results in the third quarter. Our second program, MBX 1416, is a long-acting GLP-1 antagonist and potential therapy for post-bariatric hypoglycemia, or PBH. In January, we announced positive phase I data and plan to advance this program to phase II in patients with PBH later this year.
We also have an obesity portfolio of differentiated PEP candidates, including MBX 4291, a GLP-1 GIP co-agonist pro-drug, which we believe has the potential for once-monthly dosing, improved GI tolerability, and greater weight loss than current market leaders. We are preparing an IND, which we intend to file next quarter, and to initiate a phase I study later this year. In addition, we have other obesity programs in lead optimization and look forward to sharing more about those developments later in the year. The company has raised over $400 million, including over $250 million in our finance and gross proceeds in our financings last year. Our 2024 year-end cash balance was approximately $262 million, which we expect to fund our operations into mid-2027. We have tremendous momentum and a number of important value-creating milestones in 2025 and beyond.
Our team of seasoned executives brings exceptional experience from large pharma and clinical development stage companies. Members of our team have collaborated successfully over several decades on the discovery, development, and commercialization of first-in-class endocrine therapeutics, including Forteo, Humalog, and Byetta. We plan to continue to grow our team to support the ongoing development and intended commercialization of our product candidates. I mentioned that our expanding pipeline of candidates is based on our proprietary PEP platform. This PEP platform is really designed to overcome the key limitations of unmodified and modified peptide therapeutics and to improve clinical outcomes and, importantly, simplify disease management for patients. It is based on, first, innovative peptide design to optimize pharmaceutical properties, including enhanced potency, stability, and solubility. We can engineer multiple mechanisms of action in a single peptide, like our GLP-1 GIP co-agonist, MBX 4291.
Second, a programmable pro-drug that provides gradual controlled release of the active drug at a precise rate through an internal chemical reaction, which reduces peak-to-trough concentration ratios and can improve clinical outcomes. Canvuparatide and MBX 4291 are pro-drugs. Third, fatty acylation to extend time in circulation, thereby reducing dosing frequency. This approach is used in tirzepatide and semaglutide and is also compatible with non-injectable formulations such as oral. It is incorporated into each of our current PEP candidates. Now, I will provide an overview of our pipeline, and our lead investigational drug, MBX 4291, or canvuparatide, is a potential best-in-class drug candidate for hypoparathyroidism, or HP, which is designed to provide continuous infusion-like exposure to PTH and convenient once-weekly dosing. We had our phase I data published last December.
As I mentioned this morning, we were very pleased to announce the completion of enrollment in our Avail phase II trial. In fact, we exceeded our target due to this very strong patient interest in this trial. We are on track to provide top-line results in the third quarter. Our second compound, MBX 1416, is a potential treatment for PBH, which is utilizing a clinically validated mechanism of action, GLP-1 antagonism. We provided positive phase I results in January, and are excited to advance this to phase II in PBH patients later in the year, as I mentioned. Also, the first candidate from our obesity portfolio is MBX 4291 with potential once-monthly dosing.
We have completed the IND enabling studies and are preparing an IND to submit in the second quarter of this year and to follow that with a phase I study, along with other programs in our obesity portfolio that we'll continue to advance and share more about later in the year. We estimate that the market opportunity for each of our rare disease programs exceeds $1 billion annually, with considerable upside potential with our obesity portfolio. Let me take you through our lead program, canvuparatide in hypoparathyroidism. Chronic HP is a serious condition that, while rare, affects over 250,000 people in the U.S. and EU combined, and it carries a high burden of illness. It's caused by a deficiency in PTH, typically due to the inadvertent removal of the parathyroid glands during neck surgery.
PTH is responsible for maintaining calcium homeostasis in the blood and tissues, such as muscles and nerves, that require calcium for proper functioning. It can, hypoparathyroidism can cause hypocalcemia, which has serious harmful effects on patients, including tetany, seizures, and brain fog. The complications mentioned on the right are due to both PTH deficiency and to standard of care, which can also cause symptoms of hypercalcemia, such as GI issues and weakness. The standard of care today is very onerous for patients. It consists of taking a lot, taking large doses of active vitamin D and calcium, on average, at least seven or eight times throughout the day and night. Importantly, this does not address the underlying cause of disease.
Patients with HP can experience large fluctuations in their serum calcium levels, along with the symptomology of hyper and hypocalcemia and long-term complications affecting multiple organs, particularly the kidneys. In contrast to other products or candidates to treat HP, canvuparatide has the potential to be the first once-weekly dosed PTH replacement therapy with a flat pharmacokinetic or PK profile. We believe that canvuparatide can reduce the excursions in hyper and hypocalcemia, the symptoms and complications those cause, and eliminate the pill burden while improving quality of life.
In addition to the patient preference for less frequent injections, we believe that, you know, what we see with other indications like obesity or type 2 diabetes, when there is a transition from daily to weekly treatment options, patients and physicians quickly adopt weekly dosing based not only on increased convenience, but also they tend to have improved efficacy. We conducted a phase I trial, and as I said, we reported those data and published those last December. It was a single and multiple ascending dose placebo-controlled trial. The primary endpoint was to evaluate safety and tolerability.
We also had secondary endpoints to look at PK and other PD markers, and what we found here is that canvuparatide had a half-life of eight to nine days with a flat peak-to-trough ratio over seven days that was comparable to what has been observed over one day with the other PTH. Thus, we think more continuous infusion-like. We also saw a dose-responsive PD response, which was very helpful in selecting our phase II doses. Lastly, we observed that canvuparatide was generally well tolerated with a favorable safety profile. This is where we are today. Canvuparatide is now in a phase II trial, and this is a randomized double-blind placebo-controlled trial. We have enrolled 64 patients who are randomized to one of four treatment groups: 400, 600, or 800 µg of canvuparatide dosed weekly or to placebo.
During the 12-week treatment period, there is a four-week fixed dose period followed by an eight-week titration period where study investigators can adjust the dose of canvuparatide by 200 µg every two weeks. The primary endpoint is the proportion of patients who are able to eliminate active vitamin D and reduce calcium supplements while maintaining normal calcium levels, serum calcium levels. This is at 12 weeks of treatment. We'll be looking at other secondary endpoints: safety, tolerability, PD markers, and also patient-reported outcomes. Each patient who enrolls and completes the Avail phase II trial will be able to enter a two-year extension study where everybody will be treated with canvuparatide on an open-label basis. We are very excited about this program and believe that if approved, canvuparatide can be a game changer for HP patients.
Let me take you through our second program, MBX 1416. PBH is a serious, rare, and chronic condition, a complication of bariatric surgery. We estimate a 90,000 U.S. prevalence, and there are no approved pharmacotherapies to treat it. Therefore, we see a tremendous unmet need. PBH typically presents six months to three years following Roux-en-Y or vertical sleeve gastric bypass surgery. Anatomical changes from these procedures cause nutrients to rapidly leave the stomach and enter the small intestine. When PBH patients eat, there is a secretion of excess GLP-1, which increases insulin and decreases glucose in circulation. Severe hypoglycemia can occur, leading to serious neuroglycopenic symptoms, including confusion, seizures, and even loss of consciousness. Currently, the standard of care consists of dietary intervention.
Small, frequent meals, avoidance of high glycemic index foods, and this is really hard for patients to maintain and remain compliant with. There are some off-label medicines with limited clinical data, and they tend to have significant side effects. Surgery is a last resort. However, it's highly invasive, and the outcomes may be unpredictable. GLP-1 inhibition has been clinically validated as a therapeutic approach to prevent the frequency and severity of hypoglycemic episodes in patients with PBH. Our goal is for MBX 1416 to be the first once-weekly drug approved to treat PBH. It is based on a highly potent GLP-1 antagonist. We started with the human GLP-1 sequence and made structural modifications to improve the potency, stability, and solubility. We fatty acylated it to extend time action and provide full day and night coverage.
We believe that with 1416, we can prevent the hypoglycemic episodes that occur and really just create havoc on these patients' lives because the timing is unpredictable. They can occur multiple times per day, and they may require an injection of glucagon as a rescue. Given the chronic nature of this disease and the severity, the lack of any approved pharmacotherapies to treat it, we see a tremendous opportunity. We are very pleased then that our phase I results, which we released in January, were supportive. First, I will mention this was a single and multiple ascending dose trial, randomized, double-blind. We found, first of all, that MBX 1416 was generally well tolerated with a favorable safety profile. There were no serious adverse events. The most common treatment adverse event, the majority, were injection site reactions, mainly redness.
We also saw that there was a 90-hour half-life for MBX 1416, which is supportive of once-weekly dosing administration. We saw a favorable PD signal in GLP-1 in healthy volunteers that we believe will translate to a therapeutic benefit in patients with PBH. We are very pleased with these results and believe they support taking the program into phase II in PBH patients and following an end of phase I meeting mid-year. We intend to do that. Let me give you a brief look at our obesity portfolio. As we know, obesity is now a global epidemic, Zepbound and Wegovy are blockbuster successes, and now multiple biopharmaceutical companies have entered the obesity field. However, current obesity treatments require weekly injections and are burdened by very significant GI side effects. This limits dose escalation and ultimately impacts the efficacy.
GI intolerability also is seen to contribute to the reduced adherence and very high rates of discontinuation for the GLP-1 therapies, 65% according to JAMA. Thus we see a route, an opportunity for improved therapies. We believe that we will be able to create differentiated candidates through the discovery of peptides that have multiple mechanisms of action and unique PK profiles that specifically are designed to improve efficacy, tolerability, convenience, and compliance. MBX 4291 is our first obesity candidate. It is a GLP-1 GIP co-agonist pro-drug. We selected these two mechanisms because we know that Zepbound or tirzepatide is the market leader currently, and it demonstrated superior weight lowering compared to semaglutide in a head-to-head study.
MBX 4291 is a pro-drug because we wanted to provide this gradual controlled release of active drug to eliminate the frequent and rapid fluctuations in concentrations in the GLP-1s that the experts say contributes to the GI side effects. As demonstrated by the illustration on the right, the exposure to MBX 4291 active drug over a month and the binding at the GLP-1 and GIP receptors is enabled by the strategic combination of our PEP technologies. If you can see there on the upper right-hand side in the cartoon with the red molecule, the yellow tails at both ends represent fatty acylations. See they're binding to albumin. The red zigzag at the end terminus is representing our pro-drug moiety. This provides that gradual controlled release of the active drug under physiologic conditions in circulation and without requiring enzymatic intervention.
We are very excited to see differentiation with this molecule, and particularly in terms of thinking about once-monthly maintenance dosing and chronic use. We have completed the IND enabling activities on this program and are preparing an IND to submit next quarter. We very much look forward to initiating a phase I study in high BMI adults later in the year. Really to summarize, in 2024, we were able to reproducibly demonstrate an ability to apply our PEP technology to deliver long-acting peptides with consistent drug exposures that translated to PD effects in healthy volunteers. As we look ahead to this year, we anticipate achieving a transformational milestone for MBX with the Q3 release of our top-line results in Avail for the first once-weekly PTH replacement therapy candidate.
We see an opportunity to achieve additional important milestones this year, as we advance each of our programs through clinical development, including the phase II study with MBX 1416 in PBH patients and the initiation of our phase I study for our first obesity candidate, MBX 4291, a GLP-1 GIP coagonist with potential once-monthly dosing. We think we're unique in having both a proven platform technology as well as multiple clinical stage programs in disease areas with tremendous unmet need. We see a great deal of opportunity to create value in 2025, and we look forward to updating you on our programs throughout the year. I would just thank you again for your interest in MBX and to our host at TD Cowen. I believe we have some time left over for questions.
[Hello] .
Hello.
There's a couple of data sets ahead of you, right? The TransCon and enebo. What are we looking for in phase II that will tell you you're on the right track given the precedence?
Thank you for the question. Enebo paratide is reading out a phase III. They had a phase II study that was not placebo controlled. It was open label. We will see how that translates to the phase III. With TransCon PTH, that has been recently approved, and the uptake has been pretty strong with their launch. That was a 26-week phase III, randomized placebo controlled. We have thought about our phase II as follows. We originally powered it at 90% based on 48 patients to show a 55% pooled treatment group effect compared to 7% for placebo or a 48% overall improvement. When we talk to KOLs for 12 weeks, with a randomized placebo controlled study, we think that is a great achievement and will show that we really have an efficacious product candidate to take forward.
W hat? The primary employee being?
The proportion of patients who are able to eliminate active vitamin D and reduce their calcium, while maintaining serum calcium in the normal range.
If yours was 155 versus 7, what were the benchmarks ahead of you? What did those guys do?
We don't think you can really compare directly. YORVIPATH and their phase II did not show 12-week data. They did show 26 weeks, mostly from the open label. Theirs was, their phase II was a four-week randomized placebo controlled trial followed by an open label extension. Ours is 12 weeks randomized double-blind placebo controlled for the entire 12 weeks, and then we have a two-year open label extension. In addition to this 12-week readout, we do anticipate later sharing comparable time points and data, which would provide better comparison. Again, for now, we're very focused on our primary endpoint and clearly demonstrating that we are able to help reduce the pill burden for these patients and keep them in the normal range.
What did they show it for?
35% placebo-adjusted rate.
Okay. Thank you.
Sure. Yes.
Quick question on the PBH program.
Yes.
Have you seen any trends, related to the numbers of surgeries that are still being performed today given the increment of taking over?
Yeah, it's a great question. We hear this with the advances in the obesity medicines. Will bariatric surgery go away? We don't see that in the numbers or when we talk to bariatric surgeons and endocrinologists, and we have done our own primary research in this area. Really, when you think about it, bariatric surgery is the gold standard for significant and sustained weight loss in these severely obese patients. We don't really think where the obesity medicines are today, you can get to that 40-50% reduction you need. We think they will continue. We're not, you know, estimating, you know, shoot the lights out increases, but steady growth. Again, that's supported by what we're seeing in the numbers to date. This is a chronic condition. You have this 90,000 or more U.S.
Prevalence that unfortunately is going to have this for life. We are only adding to that with more procedures. Yes.
Are you guys thinking about your obesity strategy when you think about other people looking for once-monthly injections, but also other targets within obesity like a GLP-1? I know that's a big deal today. Earlier stage molecules. How are you guys thinking about leveraging your technology within the constraints of your balance sheet to make sure you maximize value there?
Absolutely. First of all, we see very few candidates out there that have a GLP-1 GIP co-agonist with potential once-monthly dosing. We think this is a great place to start. We have a lot of experience with these particular targets. I'll just point out that our scientific founder and the inventor of MBX 4291 is Dr. Richard DiMarchi, who invented the first GLP-1/GIP co-agonist at our previous company, Marcadia Biotech. We believe in these mechanisms. Again, they're very proven today. We see the opportunity with other mechanisms as well. We like clinically validated mechanisms where possible. We're continuing to advance a full portfolio of assets. We have the means to do that given our ability in the past to raise financing. We are continuing to advance these preclinical programs.
I think in terms of how we think about them strategically, while we are, our vision is to build a fully integrated biopharmaceutical company and the rare disease programs really suit that ability of a smaller biotech to commercialize. Clearly, in obesity, we see an opportunity to recruit a pharma partner. I would say based on prior experience with multiple companies in obesity, that with proof of concept data, that's the strongest time to do that.
With any of your programs, are you looking at a potential loading dose?
In obesity, it's interesting because you have a pretty standard titration period, excuse me, with the incretins. We have this interesting profile, this unique PK profile where we have a peak to trough over one month that we estimate would be the same as over one week for tirzepatide. If we were to give MBX 4291 more frequently in the beginning, the question is, could we have even better GI tolerability, get patients to a higher overall dose level, and create better weight lowering? These are the kinds of hypotheses that we can explore in a phase I study and intend to.