Morning, everyone, and welcome to Oppenheimer's 35th Annual Healthcare Conference. I'm Trevor Allred, one of the biotech analysts here at Oppenheimer. We have MBX Biosciences CEO Kent Hawryluk here with us today to tell us about the company. As always, feel free to submit questions, and we'll have a few minutes for Q&A at the end. Kent, take it away.
Good morning. I'd like to thank each of you for attending, as well as Trevor Allred, Leland Gershell, and the Oppenheimer team for hosting us at this event. I am delighted to provide an update on MBX Biosciences as 2025 promises to be a transformational year for the company. I'd like to remind everyone that this presentation contains forward-looking statements. I encourage you 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 novel precision endocrine peptide, or PEP, platform technology. PEPs are engineered to have optimized pharmaceutical properties, including increased time action and consistent drug exposure, as well as convenient, less frequent dosing.
We recently unveiled the non-proprietary name for our lead product candidate, canvuparatide, formerly MBX 2109. Canvuparatide is an investigational parathyroid hormone, or PTH, peptide prodrug therapy for hypoparathyroidism. We have orphan drug designation in the U.S. and are conducting a phase II clinical trial. Our second program, MBX 1416, is a long-acting GLP-1 antagonist and a potential therapy for post-bariatric hypoglycemia, or PBH. We reported positive top-line results from our phase I study last month and plan to advance it to phase II in the second half of this year. MBX is also developing an obesity portfolio of differentiated PEP candidates, including MBX 4291, a GLP-1/ GIP co-agonist prodrug, which we believe has the potential for once-monthly dosing, improved GI tolerability, and greater weight loss than current market leaders.
We have multiple programs in lead optimization for the treatment of obesity and comorbidities and look forward to sharing more about these developments later in the year. We have raised over $400 million from premier biopharma investors, including over $250 million from our financings last year, and our 2024 year-end cash balance was approximately $262 million, which we believe will support our operations into mid-2027. We have considerable momentum and a number of key 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 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.
As I mentioned previously, our expanding pipeline of product candidates is based on our novel PEP platform. This proprietary platform is designed to overcome key limitations of unmodified and modified peptide therapies and improve clinical outcomes and simplify disease management for patients. It is based on innovative peptide design to improve pharmaceutical properties, including increased stability, potency, and solubility. As well, we can engineer multiple mechanisms into a single peptide, for example, our GLP-1/GIP co-agonist prodrug, MBX 4291, and second, a programmable prodrug that provides drug activation at a precisely controlled rate through an internal chemical reaction, which can reduce peak to trough and improve clinical outcomes, and canvuparatide and MBX 4291 are prodrugs, and third, fatty acylation to extend time action and reduce dosing frequency by facilitating binding to circulating albumin.
This approach has been used in tirzepatide and semaglutide and is compatible with non-injectable formulations such as oral. It is designed into all of our current PEP candidates. Now I will provide an overview of our pipeline. Our lead investigational drug, canvuparatide, is a potential best-in-class drug candidate for hypoparathyroidism, or HP, which is designed to provide continuous infusion-like exposure to PTH with convenient once-weekly dosing. We published positive phase I results last year, and our Avail phase II trial is currently underway with patient enrollment completion expected this quarter and top-line results expected in the third quarter of this year. Our second compound, MBX 1416, is a potential therapy for PBH employing a clinically validated mechanism of action, GLP-1 antagonism. We recently completed our phase I trial and reported positive top-line results.
We are planning to initiate a phase II study in PBH patients in the second half of this year. Our lead candidate from our obesity portfolio is MBX 4291, a GLP-1/GIP coagonist prodrug with potential once-monthly dosing, and we have additional programs in lead optimization and plan to share more about these additional obesity candidates later in the year. We estimate the market opportunity for each of our rare disease programs exceeds $1 billion annually, with significant upside potential for our obesity portfolio. Now let me take you through our lead product candidate, canvuparatide, for hypoparathyroidism. Chronic HP is a condition that, while rare, affects over 250,000 patients in the U.S. and Europe and has a high burden of illness. It is caused by a deficiency in PTH, generally due to inadvertent removal of parathyroid glands during neck surgery.
PTH is responsible for maintaining calcium homeostasis in the blood and tissues such as nerves and muscles, which rely on calcium for proper functioning. PTH can cause hypocalcemia, which has really significant 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. This can also cause symptoms of hypercalcemia, and these include GI issues and weakness. The standard of care today consists of large doses of calcium and active vitamin D, on average at least seven or eight doses spread throughout the day and night. Importantly, these supplements do not address the underlying cause of disease. HP patients can experience large fluctuations in their serum calcium and associated symptomatology of hyper and hypocalcemia, as well as long-term complications affecting multiple organs, particularly the kidneys.
In contrast to other products or candidates that are administered daily, canvuparatide is a potential once-weekly dose PTH replacement therapy with flat infusion-like pharmacokinetic or PK profile. And we believe our therapy could reduce hyper- and hypocalcemia excursions, the symptoms and complications they cause, while eliminating the pill burden and improving quality of life. In addition to patient preference for less frequent injections, we believe that once-weekly administration of canvuparatide will improve both convenience, compliance, and effectiveness. As seen when transitioning from daily to weekly treatment options and other indications such as obesity, patients and physicians quickly adopt weekly dosing based on improved convenience and improved clinical outcomes. Our phase I trial was a single- and multiple-ascending-dose placebo-controlled study in healthy subjects. The primary endpoint of the study was safety and tolerability.
The secondary endpoints were to evaluate PK and to examine PD or pharmacodynamic effects, increases in serum calcium, and autogenous PTH secretion, which is a marker for increased serum calcium. Results from the phase I trial demonstrated a half-life of 8-9 days with a flat peak to trough over one month, comparable to what has been observed over one day with other PTH therapies. We also saw a dose-dependent PD response, which helped us to select phase II doses. Lastly, the phase I trial showed that MBX 2109, or canvuparatide, was generally well- tolerated with a favorable safety profile. In addition to supporting weekly dosing, these results are a strong indication that using our PEP technology, we can design peptides with a flat PK profile consistent with infusion-like profile. Now, this is where we are today.
Our Avail phase II clinical trial is ongoing and on track to complete patient enrollment this quarter and report top-line results in the third quarter of this year. It is a randomized double-blind placebo-controlled study in approximately 48 patients who are randomized to one of four treatments: 400, 600, or 800 microgram doses of canvuparatide given once weekly or to placebo. During the 12-week treatment period, there is a four-week fixed dose period followed by an eight-week dose titration period. There, the study investigators can adjust the dose by 200 µg every two weeks. The primary endpoint is the proportion of patients who can discontinue active vitamin D and reduce calcium supplements after 12 weeks of treatment while maintaining normal serum calcium levels. We'll also be examining safety and tolerability, PK, other PD markers, and patient-reported outcomes.
All patients who complete the study will be able to enter a two-year dose extension study where everybody will be treated with canvuparatide on an open-label basis. We're very excited about the potential for canvuparatide and believe that if approved, canvuparatide could be a game changer for HP patients. Now, I will turn to our second program, MBX 1416 and PBH. PBH is a rare, chronic, and serious complication of bariatric surgery. It has a high burden of illness. We estimate a U.S. prevalence of over 90,000, and there are currently no approved pharmacotherapies representing a significant unmet need. PBH typically presents six months to three years following Roux-en-Y or vertical sleeve gastric bypass procedures. Anatomical changes from these surgeries cause nutrients to rapidly leave the stomach and enter the small intestine.
When PBH patients eat, an excessive GLP-1 release can occur, stimulating insulin release and decreasing glucose in circulation. Severe hypoglycemia can result, leading to serious neuroglycopenic symptoms, including seizures, confusion, and loss of consciousness, and PBH is extremely disruptive to PBH patients' lives because the occurrence of hypoglycemia is unpredictable. It can occur multiple times a day and may require an injection of glucagon as a rescue, and even with recent advancements in obesity treatments, bariatric surgery remains the gold standard for significant and sustained weight loss in severely obese patients, and given the nature or chronic nature of this disease and absence of approved pharmacotherapies, we believe there is a significant need for an effective treatment for PBH. The standard of care mostly involves dietary intervention, frequent small meals, or avoidance of high glycemic index foods. Compliance with this regimen is challenging for patients.
There are off-label medicines with limited clinical data, and these are often poorly tolerated. Surgery is a last resort, but it's highly invasive, and the outcomes may be unpredictable. Use of a GLP-1 inhibition-based mechanism has been clinically validated as a potential therapy to prevent and reduce the frequency and severity of hypoglycemia in PBH patients. Our goal is for MBX 1416 to be the first once-weekly drug approved for PBH. It is designed to be a highly potent, long-acting GLP-1 antagonist. It is based on the human GLP-1 sequence with structural modifications to increase potency, stability, and solubility. It's fatty acylated to reduce dosing frequency and to provide day and night coverage. We believe by inhibiting GLP-1, we will be able to prevent severe hypoglycemia from occurring, thereby vastly improving patients' quality of life.
In early January, we were pleased to announce positive top-line results from our phase I trial, a single and multiple ascending dose study. The trial was a randomized double-blind placebo-controlled study designed to evaluate the safety, tolerability, PK, and PD of MBX 1416 in healthy adult volunteers. These results support our belief that MBX 1416 can offer an attractive therapeutic option for this chronic disease. And first, the phase I results showed that MBX 1416 was generally well tolerated with a favorable safety profile. There were no serious adverse events. The majority of the treatment emergent adverse events were mild to moderate injection site reactions, mainly redness. Second, we confirmed a 90-hour half-life, which supports once-weekly dosing. And lastly, we observed a favorable PD signal in GLP-1 in healthy volunteers, which we believe may translate to a therapeutic benefit in PBH patients. Excuse me.
Overall, we are very pleased with these results and are intending to initiate a phase II trial in PBH patients in the second half of this year to further optimize dosing. Now, let's turn to our obesity portfolio. Everyone is aware that obesity is a global epidemic that creates a very large market opportunity, and many pharmaceutical companies have recently entered the obesity field following the blockbuster success of Zepbound and tirzepatide or Wegovy, and however, current obesity treatments require weekly injections and are associated with significant GI side effects, which often lead to reduced adherence and increased discontinuation, thereby limiting their effectiveness and maximal weight lowering. Thus, there is an opportunity for improved obesity treatments. We believe using our PEP platform, we can overcome these shortcomings with the discovery of peptides that are long-acting and have the flexibility to dose to optimize tolerability and efficacy.
As the obesity landscape changes, we expect that a variety of treatment options will be required to help manage this disease in a heterogeneous population. MBX 4291 is our first obesity candidate. It is, as I mentioned, a GLP-1/GIP co-agonist pro drug. We selected these two mechanisms based on the fact that tirzepatide or Zepbound is currently the market leader for achieving weight loss. In fact, recently, tirzepatide demonstrated superiority against semaglutide in a head-to-head study. Looking at the illustration on the right, you can see that MBX 4291 utilizes all the key tools in our PEP toolbox. The yellow tails at each end of the molecule represent fatty acylations and to facilitate binding to albumin.
The red zigzag at the end terminus of the molecule represents our prodrug moiety, which activates the drug at a precise rate through a cyclization under physiological conditions without need for enzymatic intervention, so active drug exposure over one month and binding at both the GLP-1 and GIP receptors is enabled by the strategic combination of our PEP technologies, and we believe that our candidate is significantly differentiated from therapies currently on the market and in development. We're excited to have finished our IND-enabling studies and look forward to filing an IND in the second quarter of this year, proceeding to a phase I later in the year pending IND approval, so in 2024, we demonstrated that we could reproducibly apply our PEP technology to deliver peptides with consistent drug exposure and PD effects in healthy volunteers.
Now, as we look ahead to 2025, we anticipate achieving a transformational milestone for the company with the release of phase II data in the third quarter for in PBH patients for the first once-weekly dose PTH replacement therapy, canvuparatide. Additionally, we anticipate achieving other important milestones as we advance each of our programs in clinical development, including dosing PBH patients in a phase II clinical trial of MBX 1416 and initiating a phase I study in high BMI adults for MBX 4291. And MBX is unique in that we have a proven technology platform and multiple clinical stage programs in diseases with high unmet need. So we believe MBX is well positioned to create significant value in 2025 and look forward to providing updates on our programs throughout the year. So thank you for your interest in MBX.
I want to thank our host at Oppenheimer once again.
Thanks, Kent. I have a few questions for you here. I guess first, can you discuss some aspects of your phase II PTH design? How are you powering and what advantages does this have over other PTH phase II trials?
Okay, great. First, let me just say that we are developing canvuparatide as a potential once-weekly dose PTH replacement therapy. The goal of the study is to demonstrate that we can effectively and safely replace the heavy treatment pill burden that I described with calcium supplements and active vitamin D that the HP patients are taking and replacing that with a weekly administration of canvuparatide while maintaining normal serum calcium levels. Consider that every HP patient's a little different based on different levels of endogenous PTH.
So the phase II trial is double-blind, placebo-controlled, as I said, 12 weeks in total duration. And in the first four weeks, the patients will be randomized in the three treatment groups into placebo. And this is really important because this is how we establish steady state for this long-acting PTH, and it will help us determine the phase III starting dose. And then during the next eight weeks, the physician will progressively eliminate active vitamin D and calcium supplements down to a level less or equal to 600 mg per week. And I want to point out this titration is guided by a medical algorithm that's in the protocol and pretty well established in the development of PTH replacement therapies. So the range of MBX 2109 tested in the study is between 400 and 1,600 micrograms.
So a successful titration will be achieving the right personalized dose of canvuparatide, allowing the patient to be completely off of active vitamin D and reduce to 600 mg or less of calcium. And to your question, the Avail trial is powered at 90% to show a 55% improvement in the pooled treatment group versus 7% in placebo for a 48% overall improvement at 12 weeks. And we think this would be a successful outcome based on the trial design. It's rigorous, again, placebo-controlled out to 12 weeks. And I think that would show a clear and meaningful improvement.
Okay, great. And can you tell us a little bit about the flexibility in dosing titration?
I mean, I think you mentioned kind of the range there, but how does the titration portion of the trial work and what is the total range week to week that can really happen there?
Right, right. So it was important for us, given the kind of personalized nature or precision medicine approach here, that we be able to explore a full dose range because really what we're looking for, assuming this drug is approved, is to be able to replace, be able to have patients switch from a once-daily, be able to treat patients who currently would require a dose of YORVIPATH, a once-daily approved drug that's currently not available in the U.S., namely over 30 mg, or treatment naive patients. So we, as I said, are looking at a potential dose range of 400-1,600 µg.
But this would come into play in the eight-week dose titration period if, say, a patient had a real PTH deficiency and needed to explore that range. And this follows this very well-established treatment algorithm that I mentioned.
Okay, great. And one question on obesity as well. Can you highlight the unmet need here for a long-acting GLP-1? And are there any advantages that you guys expect to see beyond dosing frequency?
Well, exactly. GLP-1 has really been transformative in weight loss and particularly tirzepatide, which I mentioned is currently the gold standard. But we believe that our prodrug approach could be one of the next generation in obesity treatments that kind of goes beyond the current class and addresses some of the shortcomings.
So, specifically, knowing that the GI side effects is caused not only by Cmax or the peak concentration or drug exposure, but the rate at which you achieve that Cmax. And so, can we use our PEP technology to reshape the PK curve, right, and to provide a slow, steady rise to Cmax in a prolonged steady exposure such that we can dose once monthly and potentially reduce the GI side effects? This can have a dual benefit, right? We can improve adherence, reduce discontinuations. But can we actually reach higher dose levels due to better tolerability? So, I think multiple ways to win.
Okay, great. Well, we have no other questions. So, with that, thank you all for joining us, and we will see you at the next.