Morning, everybody, and happy Monday. I'm Serge Belanger, one of the healthcare analysts at Needham. I want to welcome you to Needham's 24th Annual Healthcare Conference. To kick off the conference this morning, we have MBX Biosciences and the company's CEO, Kent Hawryluk, who will give us an overview of the company. We do have the ability to take Q&A, so for those listening online, you can submit questions via the portal, and we'll take them as they come in. With that being said, Kent, thanks for joining us this morning, and I'll hand it over to you so you can tell us about MBX.
Good morning. I want to thank each of you for attending, and Serge and the Needham team for hosting us at this virtual event. I'm delighted to share an update on MBX Biosciences as 2025 is off to an exciting start, and we have a number of important value-creating milestones in the months ahead. I would like to remind everyone that this presentation contains forward-looking statements and encourage you to review our risk factors and other disclosures in our most recent SEC filings, all of which are available on our website. For those of you new to the story, MBX Biosciences is a clinical-stage biopharmaceutical company founded by global leaders in peptide drug design and development. We are pioneering a novel precision endocrine peptide platform technology, or PEP. PEPs are engineered to have optimized pharmaceutical properties, including extended time action, consistent drug exposures, and convenient, infrequent dosing regimens.
Our lead product candidate, Canvuparatide, formerly MBX 2109, is an investigational parathyroid hormone, or PTH, peptide pro-drug therapy for hypoparathyroidism, or HP. We have orphan drug designation in the U.S. and are conducting a phase II clinical trial called Avail. Last month, we reported that Avail has completed full enrollment and reconfirmed that we expect to report 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. We reported positive phase I results in January and plan to advance this program to a phase II in the second half of this year. We are also advancing a portfolio of obesity 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 have additional programs and lead optimization for the treatment of obesity and comorbidities and look forward to sharing more about those programs later in the year. We have raised over $400 million to date, including over $250 million in gross proceeds in our financings last year. We had a year-end cash balance in 2024 of approximately $262 million, which we expect to support our operations into mid-2027. We have considerable momentum and important value-creating milestones in 2025 and beyond. Our team of seasoned executives brings exceptional expertise from large pharma and clinical-stage development 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 continued development and intended commercialization of our product candidates.
I mentioned earlier that our expanding pipeline of product candidates is based on our PEP platform. This proprietary platform technology is designed to overcome the key limitations of unmodified and modified peptide therapeutics to improve clinical outcomes and simplify disease management. It is based on three main components. First, we start with innovative peptides that are designed to have optimized pharmaceutical properties, such as increased potency, stability, and solubility. We can engineer multiple mechanisms of action in a single peptide, such as our GLP-1 GIP co-agonist, MBX 4291. We can apply a programmable pro-drug to provide controlled gradual release of active drug through an internal chemical reaction, which can reduce peak-to-trough concentration ratios and can improve clinical outcomes. Canvuparatide and MBX 4291 are pro-drugs. All of our product candidates are fatty-acylated to extend duration of action and reduce dosing frequency.
This is through facilitating binding to circulating albumin. This approach is used in tirzepatide and semaglutide and is compatible with non-injectable formulations such as oral. I will provide an overview of our pipeline. Our lead investigational drug, Canvuparatide, is a potential best-in-class drug candidate for the treatment of HP, which is designed to provide continuous infusion-like exposure to PTH and convenient once-weekly dosing. Our positive phase I results were published last December. As I mentioned, we have fully completed enrollment in this phase II trial and are on track to present top-line results in the third quarter. Our second program, MBX 1416, is a potential therapy for PBH, employing a clinically validated mechanism of action, GLP-1 antagonism. We have completed recently our phase I and reported top-line results, and we plan to initiate a phase II trial in PBH patients in the second half of this year.
Our lead candidate from our obesity portfolio is MBX 4291, a GLP-1 GIP co-agonist pro-drug with the potential for once-monthly administration. We have completed IND-enabling studies and are preparing an IND to submit this quarter. We have other obesity programs in development and look forward to sharing more about these additional candidates later in the year. We estimate the market opportunity for each of our rare disease programs exceeds $1 billion annually, with considerable upside potential with our obesity portfolio. Now, I will take you through our lead program, Canvuparatide and hypoparathyroidism. Chronic HP is a serious condition that, while rare, affects over 250,000 people in the U.S. and EU combined. It is 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 in tissues such as muscles and nerves, which rely on calcium to function properly. HP can cause hypocalcemia, which has significant harmful effects on patients, including tetany, seizures, and brain fog. The complications mentioned on the right side of the slide are due to both PTH deficiency and to the standard of care, which can also create acute hypercalcemic symptoms, including GI issues and weakness. The current standard of care in HP is onerous for patients, consisting of large doses of active vitamin D and calcium supplements, on average seven or eight doses throughout the day and night. Importantly, they do not address the underlying cause of disease. Patients with HP can experience significant fluctuations in their serum calcium and symptomatology of hyper and hypocalcemia, along with long-term complications affecting multiple organs, particularly the kidneys.
I believe you can see why there is a significant unmet need for PTH replacement therapies. Unlike other products and candidates that are administered once daily, Canvuparatide is a potential first once-weekly PTH replacement therapy with a flat pharmacokinetic or PK profile. We believe that Canvuparatide can reduce the hyper and hypocalcemia fluctuations in the symptoms and complications they cause while eliminating pill burden and improving quality of life for patients. In addition to patient preference for less frequent dosing, we know that, as we've seen in other indications like obesity, the patients and prescribers quickly adopt the weekly option when transitioning from daily to weekly. We believe that Canvuparatide can improve both adherence and efficacy. Our phase I trial, I mentioned the data were published last year. This is a single and multiple ascending dose placebo-controlled study.
The primary endpoint was to assess safety and tolerability in healthy volunteers. The secondary endpoints were to explore the PK and pharmacodynamic effects, such as increased serum calcium and reduced endogenous PTH, which is a marker for increased calcium. The results demonstrated that we have a half-life of eight to nine days with a flat peak-to-trough ratio over seven days that is comparable to what has been observed over one day with the competitors. We also saw a dose-dependent PD response, which was helpful in selecting our doses for our phase II trial. Lastly, the results indicated that Canvuparatide is generally well tolerated with a favorable safety profile. In addition to supporting once-weekly dosing, these results are a powerful indication that we can apply our PEP technology to create novel peptides with continuous infusion-like PK profiles. This is where we are today.
Our Avail trial is now fully enrolled. In fact, we exceeded our original enrollment target based on strong demand from patients and study investigators. It is a randomized double-blind placebo-controlled study. We have enrolled 64 patients with HP who are randomized to one of four treatments: 400, 600, or 800 micrograms of Canvuparatide given once weekly or to placebo. During the 12-week dose period, there is a four-week fixed dose period followed by an eight-week titration period where study investigators may adjust the patient's dose every two weeks by 200 micrograms. The primary endpoint is the proportion of patients who are able to eliminate active vitamin D and reduce calcium supplements after 12 weeks of treatment while maintaining normal serum calcium levels. We will also be exploring safety, tolerability, PK, other PD markers, and patient-reported outcomes.
Every patient who completes Avail has an opportunity to enter a two-year extension study where everybody is treated with Canvuparatide on an open-label basis. We are very excited about the potential for Canvuparatide and believe that if approved, it could be a game changer for HP patients. Now, I will turn to our second program, MBX 1416. PBH is a rare, serious, and chronic complication of bariatric surgery. We estimate a U.S. prevalence of over 90,000, and there are currently no approved pharmacotherapies for this disease. Therefore, we see a significant unmet need. Even with recent advances in obesity medicines, bariatric surgery remains the gold standard for significant and sustained weight loss in the severely obese population. We see this need and market opportunity continuing. PBH typically presents six months to three years following Roux-en-Y and vertical sleeve gastric bypass procedures.
Anatomical changes from these surgeries cause nutrients to rapidly leave the stomach and enter the small intestines. When PBH patients eat, excessive GLP-1 release occurs, which increases insulin and reduces glucose in circulation. Severe hypoglycemia can result, leading to serious neuroglycopenic symptoms, including confusion, seizures, and loss of consciousness. This disease can be very debilitating for PBH patients because the timing of hypoglycemia is unpredictable, can occur multiple times throughout the day and night, and may require an injection of glucagon as a rescue. GLP-1 inhibition has been clinically validated as a potential therapy to reduce the frequency and severity of hypoglycemia in PBH patients. MBX 1416 is designed to be a long-acting, highly potent GLP-1 inhibitor. We see this as a real advance because the current standard of care really focuses on dietary intervention, such as small, frequent meals and the avoidance of high glycemic index foods.
There are off-label medicines with very limited clinical data, and these are often poorly tolerated. Surgery is a last resort, but it's highly invasive, and the results are unpredictable. As I mentioned, GLP-1 inhibition has been clinically validated. With MBX 1416, our goal is to be the first once-weekly approved therapy for PBH. We do this with a molecule that is based on the human GLP-1 sequence, with structural modifications to increase the potency, stability, and solubility. It is fatty-acylated to provide convenient once-weekly dosing and full coverage day and night. Our goal is that by eliminating or by inhibiting GLP-1, we can prevent severe hypoglycemia from occurring and thereby drastically improve the patient's quality of life. I mentioned that in January, we presented positive top-line results from our phase I study.
This was a randomized double-blind placebo-controlled single and multiple ascending dose trial. It was designed to explore the safety, tolerability, PK, and PD of MBX 1416 in healthy volunteers. We're very pleased with the results and believe that they support this as a potential meaningful therapy for this chronic disease. First, the results showed that MBX 1416 was generally well tolerated with a favorable safety profile. There were no serious adverse events. The treatment emergent adverse events, the majority were mild to moderate injection site reactions, mainly redness. We also saw and confirmed a 90-hour half-life, which is supportive of once-weekly dosing. Lastly, we saw a PD signal in these healthy volunteers that we believe may translate to a clinical benefit in PBH patients.
We are very excited about these results and look forward to initiating a phase II trial in PBH patients following an end of phase I meeting and alignment on the study design. Now I will turn to our obesity portfolio. When you consider that obesity is now a global epidemic, and given the blockbuster success of Zepbound and Wegovy, many pharmaceutical companies have entered the obesity space. However, current obesity treatments require weekly injections, and they are encumbered by pretty significant GI side effects. This limits the dose escalation and ultimately impacts the efficacy. The GI intolerability also contributes to the reduced adherence and quite high discontinuation rate, 65%, according to JAMA in these GLP-1s. We see an opportunity for improved therapeutics.
Our approach is to look at multiple mechanisms of action and unique PK profiles that are designed specifically to improve efficacy, tolerability, convenience, and compliance. As the obesity landscape matures, we believe a variety of treatment options will be needed to manage this disease in a heterogeneous population. Our first obesity candidate is a GLP-1 GIP co-agonist pro-drug, MBX 4291. We selected these two mechanisms because tirzepatide or Zepbound, which is an FDA-approved GLP-1 GIP co-agonist, is currently the market leader and also has demonstrated head-to-head superiority versus the leading mono-agonist, semaglutide. MBX 4291 is a pro-drug, so it is designed to provide gradual controlled release of active drug. This is to avoid the rapid and frequent fluctuations observed by the GLP-1s, which the experts tell us contribute to their GI side effects.
As you can see from the illustration on the right, MBX 4291 active drug exposure over one month and binding at the GLP-1 and GIP receptors is enabled by the strategic combination of our PEP technologies. We are very excited about this opportunity to have a differentiated product candidate in obesity and particularly see it as well positioned as a monthly treatment option in a chronic use. We have completed our IND studies and are finalizing the IND, which we plan to submit this quarter, and then to initiate a phase I study in the high BMI adults later this year. In 2024, we demonstrated that we could reproducibly apply our PEP technology to deliver long-acting peptides with consistent drug exposure that translates to PD effects in healthy volunteers.
Now, in 2025, we have a potentially transformational milestone with the release of phase II data in HP patients for the first once-weekly PTH agent, Canvuparatide. We have other important milestones as well as we advance each of our clinical stage programs in development, including initiation of a phase II in PBH patients for MBX 1416 and initiation of a phase I study in the high BMI adults for MBX 4291. We anticipate having other development candidates in obesity too. I think that MBX is unique in having a proven platform technology and multiple clinical stage programs in diseases where there's substantial unmet need. We believe we're well positioned to create exceptional value in 2025 and look forward to keeping you apprised of our progress. Let me thank you once again for your interest in MBX and to Serge and the Needham team for hosting us.
I'll now turn it over to Serge for questions.
Sure. Thanks, Kent. Like I said earlier, for those listening online, you can submit questions via the portal. Kent, on the Canvuparatide program, for the phase II trial design, I think you mentioned there was a fixed dose period followed by a titration period. Just curious where you expect patients—obviously, it's going to be a personalized dose—but will patients all end up at the highest? Do you expect them to end up at the highest dose or to be the lower dose possible?
I think you hit the nail on the head in describing HP as personalized medicine. I believe that the phase I results really set us up nicely to select the dose range for our phase II . One thing to orient you, if you look at our 900 microgram dose in our phase I study, that produced a maximal change in serum calcium of about 1.1 milligram per deciliter. That kind of corresponds with the 24 microgram dose of Yorvipath, which is given once daily in their phase I in healthy volunteers. That is roughly equivalent to our 800 micrograms in our phase II trial. The starting dose for Yorvipath in the phase III and in the label is 18 micrograms. I think we are kind of bracketing the range very nicely.
Now, in the titration period, we can go up to 1,600 micrograms in 200 micrograms times four potential dose adjustments. I think this is a very nice range for us to explore in these very heterogeneous HP patients, and again, to be able to select doses for our phase I II.
You mentioned the Avail trial is set to read out in the third quarter later this year. Just curious if you can highlight expectations for results here and what you would consider a success to move forward to phase III development.
Right. The Avail study design was originally powered at 90% to show a response of the pooled treatment groups of 55% versus 7% for the placebo or a 48% placebo-adjusted response. When we consulted with KOLs, they believed this was clinically meaningful and would help us select the doses for the phase III as we move forward. We are happy that we were able to kind of over-enroll the trial or increase the enrollment to 64 patients versus the original 48. Now we would have 97% powering for that same effect of 48%. We think we are well positioned for success and very much look forward to Q3 to presenting the results.
Taking ahead to a phase III program, would it also have kind of a fixed dose initial dosing period followed by titration? Just curious what you're thinking in terms of the design.
Of course, it's subject to our end of phase II meeting and alignment with the FDA. Generally, we're not looking to reinvent the wheel and would expect something that pretty closely resembles the phase III for Yorvipath, noting that we are a once-weekly drug candidate versus once daily.
Yeah. On the PTH market opportunity, I guess first on Yorvipath, how much uptake has that product had? Has there been any payer pushback as a branded product so far? What is a new market opportunity?
It's pretty early in the game, but we would say that we're pretty impressed and pleased with the initial launch of Yorvipath in the United States. We're not surprised. We're pretty close to the hypopara community and know that there's significant need for a PTH replacement therapy. We're pleased that there is one, albeit once daily. I think the way we're taking a long-term view and know that there is a large market opportunity that's potentially being underestimated at present. I'll explain why. When we talk to the HP patients, we realize that even those whose calcium may be fairly well managed on the calcium supplements and active vitamin D, they tell us they don't really feel normal or well controlled and would like to have a PTH replacement therapy.
I think we're potentially looking at expanding the market, particularly when you have a convenient once-weekly offering. We've seen in other indications, again, like obesity, the once-weekly option is quickly adopted, and it tends to expand the market.
Okay. I guess just to follow up on that, what do you expect the PTH market opportunity to look like when Canvuparatide makes it to market? Should we expect additional once-daily treatment options, or is somebody else also working on a more extended duration product?
I don't have a crystal ball, but I do believe that, again, Yorvipath will create a nice market. We will have the opportunity as a once-weekly to, first of all, have switching. That's often seen when you transition from a once-daily to a once-weekly option. There will also be treatment-naive patients that we believe we can serve. There could be the portion of the U.S. market that Yorvipath is not able to serve. For example, in Europe, it's approved up to 60 micrograms, but in the United States, only up to 30 micrograms. We think there's a pretty meaningful population there that won't be able to benefit from Yorvipath, whether it's 8%-10% of the market. We'll see. I think that's also low-hanging fruit for us.
I guess, one question on the obesity program that's getting underway. I think you highlighted the various ways new obesity products could differentiate themselves, dosing, a more favorable AE profile. Curious what now is kind of the minimum weight loss bar in order to be relevant and successful in this market.
We have designed our phase I study to explore the many different ways that we believe MBX 4291 can win, or that is to say, be successful as a viable obesity candidate. For example, our phase I study does have a 12-week component that we would hope to execute. I think there are some benchmarks out there for what success looks like at 12 weeks. I would say that we really are hoping to demonstrate once-monthly dosing frequency and weight lowering. I think that has a different bar. This can be for switching and monthly maintenance once the weight lowering has been achieved through more frequent dosing. I would also say that we will be exploring more frequent dosing with MBX 4291 because there is already an established precedent for a titration period.
What's unique about MBX 4291, it has such a flat peak-to-trough ratio over one month. We project that's comparable to the peak-to-trough over a week with the current therapies. When you would dose MBX 4291 more frequently, say, during a dosing titration period, that really flattens the peak-to-trough further. We think that can allow us to have much better tolerability and potentially get to higher concentrations and thus greater weight lowering. Again, multiple ways to win with this molecule.
I think one of the last slides in your presentation was highlighting the various catalysts for each of your programs. Can you talk maybe about what kind of updates or data from potential competitors you're watching for in 2025 that could be relevant for investors?
What stands tallest is our phase II Avail data for Canvuparatide in Q3. This program is our highest corporate focus. We're very excited about that milestone. I think as we share more about our obesity portfolio, not only more details on our MBX 4291 phase I trial, but the other programs that are advancing in discovery and preclinical development, I think there will be quite a bit of interest in our obesity portfolio as well.
Okay. Maybe just to wrap up here, anything you find that is misunderstood or underappreciated by investors about the company or one of your programs?
There is one thing I would really want investors to consider that is if you like Ascendis, you should really love MBX because we have a potential once-weekly PTH replacement therapy pro-drug with this very flat continuous infusion-like PK profile, which we think can be a market leader and build on the market success of the once daily. I think there is just an extraordinary amount of value that we can create with this program. Like I alluded to, I think with obesity, that is pretty early now, and we by design have not shared much information given the competitive environment that exists. As we begin to reveal more, I am really excited about the investor interest for that set of programs. Consider that the inventor is Richard DiMarchi, who invented the first GLP-1 GIP co-agonist at our previous company together, Marcadia Biotech.
We are not new to this field. We have a long history. We know what success or what good looks like in obesity. I believe truly that we have created some novel peptides that should allow us to be major players in the obesity field as well.
All right. Kent, thank you for joining us this morning and kicking us off with a great presentation on MBX.
Thank you again. I appreciate the opportunity.