Greetings, welcome to the MBX Biosciences business update call. At this time, all participants are in listen only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the call, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Mr. Kent Hawryluk, President, CEO, and co-founder of MBX Biosciences. Please go ahead, sir. Good morning, thank you for joining us to review the once-weekly canvuparatide peptide one-year data from the Phase II open- label extension study. I am Kent Hawryluk, President and CEO of MBX. I want to remind everyone that this presentation includes forward-looking statements. I encourage you to review the risk factors and other disclosures in our most recent SEC filings, available on the MBX website. I'm pleased to be joined today by esteemed colleagues, including Dr. Richard DiMarchi, MBX Scientific Co-Founder, and my business partner for the past 23 years. Richard and I started MBX with a sense of urgency to give back freedom to people with hypoparathyroidism through a PTH replacement therapy that's patient friendly and once-weekly, just as patients have today in major diseases, but not yet in HP. A product profile that frees patients from the daily burden of their disease, and which patients and HCPs tell us will be their preferred choice. MBX has expanded significantly in endocrine and metabolic diseases, while our focus remains squarely on helping transform the lives of people impacted by these diseases. We do that through novel precision peptides designed to provide consistent, steady drug exposure so important in treatment. Our one-year data demonstrates sustained benefit of once-weekly canvuparatide peptide as a potential best- in- class PTH replacement therapy in chronic HP. It's in line with our expectations, as we communicated, and includes strong safety and tolerability. It also demonstrates the translation of canvuparatide's precision endocrine peptide design to clinical outcomes, and provides important reinforcement of our Phase III study design. The HP community is very excited that we're on track to start enrolling patients in Q3. The program for today is an overview of canvuparatide from its inventor, Dr. DiMarchi. A clinical perspective on the HP landscape and unmet need from Dr. Michael Collins. A presentation of the one-year data from our CMO, Dr. Sam Azoulay, and will be followed by concluding remarks and a Q&A session. I will now turn it over to Richard. Kent, this is Richard. Thank you for the invitation to participate. I am coming to you from my office in the chemistry building at Indiana University, where I have been for the last 23 years. The next slide in this presentation, the first in my section, captures a century of progress in peptide therapeutics, reaching back to that landmark discovery of animal-sourced human insulin, and focuses most importantly on the last half-century, something that I have personally participated, having arrived at Lilly in 1980 as we were in the midst of the production of human insulin by biosynthetic methods. That method allowed us to get control of the chemistry such that we could begin to optimize the molecule, much as historical medicinal chemists had optimized antibiotics, oncolytics, antihypertensives. It was something that was viewed with some skepticism in the large molecule community; macromolecules, peptides, proteins. Lyspro insulin, as you see, in 1996, was the first registered product that was purposefully optimized. It is a molecule I designed during my tenure at Lilly, and it grew to be the most popular insulin at its peak, demonstrating that chemistry can generate a better medicine. Forteo, the N-terminal 34 amino acid fragment of the endogenous parathyroid hormone, was registered as a bolus administration, sharp up, down within one hour for treating osteoporosis. Then on into the transformative ability to manage type 2 diabetes, and even more so, obesity that we have witnessed over the last two decades, using chemistry to achieve something that could not be achieved with the native hormone. Byetta, twice a day. Victoza, once a day. Trulicity, the first effective once a week treatment for type 2 diabetes. Then on into Ozempic, Zepbound, and more to come. Next slide. This slide just indicates that the chemistry that we have been using is multiple. But notably, at the very last box, acylation for extending the duration of action, and Novo Nordisk deserves the lion's share of the credit for having advanced this through insulin into the incretins that we know so well. It is innovative peptide design. Designing these molecules for exquisite potency, metabolic stability, and this extended duration of action. It is that middle box that really speaks to this prodrug chemistry that we have developed here in Indiana University through support from MBX Biosciences that they are now testing clinically. That provides us the ability not just to control the pharmacokinetics, but to control the pharmacology of the molecule by having extended its duration, but minimizing that burst. Endocrine hormones typically have narrow therapeutic index. Insulin for glucose, parathyroid for calcium, glucagon also for glucose. What we wanted was a means to control the biology of the molecule. Precision, as the company has emphasized, and as our chemistry has brought forth over the last couple of decades. The next slide gives you a cartoon, and it is my final slide in getting on to the biology of this opportunity and of the company. It is a cartoon that shows in the upper left-hand corner near that A, if you can see it, canvuparatide MBX- 2109, as I remember, is a peptide that we produced here in Bloomington. It is a peptide that is fatty acylated at both ends, the N-terminus and the C-terminus, to give it high affinity to circulating plasma proteins, notably albumin. You see that in the middle section called B, where it is residing on albumin as a soluble plasma depot. The magic of this prodrug is that we have designed the N-terminal fatty acid to be hanging onto a dipeptide that will cyclize to a cyclic dipeptide, a diketopiperazine, and leaves the prodrug to give you an active peptide that remains bound to the plasma protein by virtue of the C-terminal fatty acid. In the window C, if you will, you can see the red peptide is turning to a green peptide, connoting that we're going from an inactive substance to an active substance. The conversion is intramolecular, and the importance of that is that it's concentration independence. It's not going to vary dependent upon where you are in your circulating concentration of this prodrug. That cyclization, the time action, and the conversion remains constant. What controls it is temperature and pH, which is virtually invariant in a chemical sense because it's physiological temperature and pH, and you cannot vary that much and still maintain vitality. That cyclization is where the magic is. It controls the burst, keeping it to a minimum amount, and it extends the duration of action so that you end up with a profile that should look like pump infusion, but not requiring the pump. I'm going to conclude here and turn the program over to the physicians, Dr. Michael Collins, to talk about the therapeutic opportunity that led us to apply our chemistry to parathyroid hormone, and also Dr. Sam Azoulay to give you a measure of how close have we met the objective that we set out for, gosh, nearly a decade ago. Thank you so much for the opportunity to participate. Thank you, Richard. Hi, my name is Michael Collins. I'm an endocrinologist, a special volunteer, and senior clinical advisor at the National Institutes of Health. This morning, I'm going to talk to you very briefly about hypoparathyroidism, the disease, and a little bit about the landscape. First, as we all know, hypoparathyroidism results from too little parathyroid hormone. The primary feature that follows from that is hypocalcemia. It's the hypocalcemia and its treatment that leads to many of the problems. Some of them are shown here, and these include brain fog, depression, kidney disease, and even an increased major adverse event risk. Hypoparathyroidism typically onsets at around 40 to 65, and most cases are caused by neck surgery. About 25% of them are caused by other causes shown here. By definition, chronic hypoparathyroidism is defined as 12 months of hypoparathyroidism following surgery, but the onset is typically sooner. This leads to impaired quality of life due to persistent mild symptoms, hypocalcemia, brain fog, et cetera. It's the treatment that can lead to impaired renal function through hypercalciuria, nephrocalcinosis, and nephrolithiasis. Hypoparathyroidism has thousands of patients worldwide. In the U.K. and U.S., over 250,000 patients with an annual incidence of about 7,000 per year. Again, the majority of those are caused by neck surgery. Most patients after neck surgery are really diagnosed within a few months. There's a large population, and this population has increased healthcare utilization needs for effective treatments. This slide really gives you a snapshot of what it's like to be a patient with hypoparathyroidism. You see the symptoms in the top, including tetany. In the middle, there's literally a snapshot of what it looks like to be a patient on hypoparathyroidism taking conventional therapy. You can see the number of pills a patient has to take a day and the burden that this imposes. With this goes along, which is stated in these quotes here, "If I go without my meds, I will be dead within days. If I skip or miss calcium, I will be in the ED in 12 hours. I no longer have the luxury of sleeping throughout the night." It's the treatment that really leads to the hypercalciuria and the renal calcification. A lot of this is driven by the tetany. Tetany is a terrible condition, if a patient has ever had this, they do everything they can to prevent it, this often includes taking extra doses of calcium, which facilitates and promotes hypercalciuria and renal calcification. We know that YORVIPATH, which was introduced recently, has demonstrated clearly the need and the acceptance of injectable PTH for replacement therapy. However, significant gaps remain. Daily injections can lead to injection fatigue. Patients still worry about disruption leading to missed injections, many of the patients continue to experience symptoms while on treatment with the ups and downs of the parathyroid blood levels. From the Phase II trial AVAIL, we know there's compelling efficacy with canvuparatide to confirm the tolerability and to determine the starting dose. Kanvuparatide really has demonstrated promising results in Phase II and the Phase III that will be coming, kicked off in Q3 2026. There's a clear registrational path with endpoints that matter to physicians and payers, we hope to see normalization of blood calcium, independence from active calcium and vitamin D, normalization of urinary calcium, and more patient-reported outcomes. On the left here is shown the potential for canvuparatide. It's a once-weekly injection. It restores normal serum and calcium and phosphate, protects the kidney from long-term damage. It restores bone turnover, it frees patients from daily disease management. Once-weekly canvuparatide really does have the potential to be the new standard of care with patients for hypoparathyroidism. Market research has shown that healthcare professionals would switch PTH-treated patients to canvuparatide. They would start naive patients on canvuparatide, patients also would choose once-weekly canvuparatide. If week-over-week consistency is borne out, it'll eliminate the rollercoaster of crashes and debilitating symptoms. In summary, we've shown that chronic hypoparathyroidism is a damaging disease. There are a lot of patients in the U.S. and EU. We've seen that YORVIPATH validates the need and acceptance of PTH replacement, there are significant gaps. Once-weekly canvuparatide has the potential to set a new standard for treating chronic hypoparathyroidism, the majority of healthcare professionals and patients would choose once-weekly canvuparatide. With that, I'll turn it over to Dr. Azoulay, the Chief Medical Officer. Hi. Good morning. I'm Sam Azoulay, Chief Medical Officer at MBX, and I'm absolutely delighted to present the one-year results of the one-year open- label extension of the AVAIL study, which is in fact the first study to evaluate the safety and efficacy of the weekly canvuparatide in patients with hypoparathyroidism. Let me remind you about the design of the AVAIL study, which enrolled adults with hypoparathyroidism who were receiving calcium supplementation, vitamin D supplementation at a stable dose, and who had albumin-adjusted calcium in the range of 8.2 mg/dL-10.6 mg/dL. Patients were randomized 4:1 to treatment with canvuparatide at starting dose of 400 micrograms, 600 micrograms, 800 micrograms or placebo once- weekly. During the first four weeks of the 12-week treatment period, study medication doses were maintained at the starting level. Beginning at week 5, dose adjustment was permitted at 200 microgram increments as needed on a two-week interval. The maximum canvuparatide dose ranged from 1,200 micrograms-1,600 micrograms depending on the study participant's starting dose. After completion of the eight-week dose adjustment period, patients were eligible for an open- label to enter into the open- label extension study. The primary endpoint of the AVAIL study was a composite response rate at week 12, defined by maintenance of normal serum calcium 8.2 to 10.6, independence from active vitamin D 0, and reduced oral calcium supplement to a maximum of 600 mg per day. To be clear, the open- label extension study is a separate study designed to evaluate the longer-term safety as well as the durability of canvuparatide treatment. Patients originally randomized to canvuparatide could continue active treatment while patients originally randomized to placebo crossover to canvuparatide with dose adjustments allowed to achieve and maintain therapeutic benefit. In addition to responder rate at one year, the open- label extension evaluates several measures that reflect the expected effect of PTH replacement, including changes in urinary calcium excretion, bone turnover biomarker, bone mineral density, immunogenicity, and long-term safety. Importantly, the open- label extension reflected different treatment settings at the parent study with patients transitioning from weekly clinic-based administration and also monitoring during the 12-week parent study to home administration and follow-up assessment every four to six weeks starting around week 14 of the open- label extension. Today, I will review the one-year results from the ongoing open- label extension, highlighting the efficacy, durability, and physiological effect of the once-weekly canvuparatide over time. Now, shown here are the baseline demographics and clinical characteristics for the AVAIL study participants. In this presentation, all data for canvuparatide will reflect the pooled analysis of the three dose groups, and comparison will be for this pooled canvuparatide versus placebo. Overall, the demographic and clinical characteristics were representative of the population of patients with HP, hypoparathyroidism, and similar across the two groups of pooled canvuparatide and placebo. It's a very important point. As expected, the majority of patients enrolled in the study were female with long-standing post-surgical HP, with a mean duration of more than nine years for the disease. Calcium and vitamin D supplement doses and serum parameters, including calcium, were within the expected range. All along the study, the retention of patients was very, very high. Notably, the study retention rate was high in the AVAIL study with 100% and the 64 patients included completed the study. 60 of these patients chose to continue into the open- label extension, corresponding to 94% of the patient pool. At one year into the extension study, 90% of these patients are still ongoing, indicative of the patients' and PI satisfaction with their treatment. As shown, at week 12, 63% of patients in the canvuparatide treatment group achieved the primary composite endpoint against placebo. It is important to note that these results were achieved without the use of any PRN. At one year in the open- label extension study population, 57 of the patients met the composite responder endpoint, demonstrating sustained efficacy over an extended treatment period and supporting the durability of the results observed in the 12-week AVAIL parent study. When we look at each component of the composite endpoint, a high proportion of patients maintain independence from vitamin D, calcium supplement, while maintaining serum calcium within the normal range. It's also worth noting that these results were achieved during an open- label extension in which a majority of patients were reconstituting, preparing, and self-administering canvuparatide at home, providing important experience with long treatment outside of the controlled clinical setting. Taken together, these findings support the potential of once-weekly canvuparatide to provide durable benefit over the one-year treatment period. To help to place this result in context, this slide summarizes selected primary efficacy outcome reported for YORVIPATH in this Phase II program, alongside the canvuparatide data presented today. While cross-trial comparison should be interpreted with caution, the overall efficacy profile observed with once-weekly canvuparatide compares favorably with the currently approved PTH replacement therapy, with comparable data at one year. The key distinction is that canvuparatide achieved these results with a once-weekly dosing regimen compared with the daily administration required for YORVIPATH. This supports our goal of providing a convenient and differentiated PTH replacement option for patients with chronic hypoparathyroidism. Before discussing additional evidence of physiologic PTH replacement, I would like to briefly highlight the pharmacokinetic and pharmacodynamic profile of once-weekly canvuparatide we observed in the Phase II study. On the left side of the slide, canvuparatide continued to demonstrate the controlled and sustained exposure profile it was designed to achieve in patients. The Tmax was approximately two to three days, and we had minimal fluctuation throughout the dosing interval with a peak-to-trough ratio of approximately 1.3 over the course of the week. Importantly, this translated into stable serum calcium control over time. As you can see on the right, mean adjusted serum calcium remained in the normal range through one year. In the Phase II study, we also measured serum calcium at the Cmax and the trough concentration of canvuparatide active drug, showing a mean difference in serum calcium of only 0.59 mg/dL. Taken together, these finding continue to support the potential of once-weekly canvuparatide to provide consistent PTH replacement with stable calcium control over time. I'm looking now to look at urine calcium. As shown on the graph, patients treated by canvuparatide, that's the blue bar, the blue show the reduction in urine calcium at 12 weeks of the Phase II study, which is even more pronounced at one year, while very importantly, maintaining serum calcium within the normal range. On the right side of the graph, you can see that the patient initially treated by placebo also show a reduction in urine calcium, which is driven by the reduction in vitamin D and calcium supplement. In parallel, the serum calcium decreases and fluctuates. When switching to active canvuparatide, the urine calcium decrease further, while the serum calcium this time stays within the normal value. We are going to look specifically at patients who entered the study with elevated urinary calcium excretion, which is one of the key target population of HP patients. This is a key target for treatment. As you recall from the baseline characteristic, 45% of the patients on the study have elevated urine calcium. As shown on the left, patients randomized to canvuparatide experience a substantial reduction in mean 24-hour urine calcium from 426 mg a day at baseline to 229 mg a day at week 12. Further improving to 188 mg a day at one year in the open-label extension. We observed a similar pattern in patients initially randomized to placebo, while urine calcium remained near the upper limit of normal at the end of the parent study. Levels declined substantially following crossover to canvuparatide, reaching 106 mg a day at one year. The particularly striking finding is shown here. Patient previously treated with placebo and moving to canvuparatide had an even further reduction in urine calcium despite having higher serum calcium. Overall, the maintenance of serum calcium level together with a reduction in urine calcium excretion is clinically relevant because it represents an expected physiologic effect of PTH replacement on renal calcium handling. In addition to reduction in urinary calcium excretion, you observe change in several biomarkers that are consistent with the expected renal effect of PTH replacement. Through one year, phosphate level and the calcium phosphate product decreased. 125 remained with the normal range, and we also observed an increase in GFR over time, consistent with a favorable effect on renal function. Again, taken together, this data provide additional evidence that once-weekly canvuparatide is restoring the physiologic PTH activity in the kidneys. I'm going to move to the bone biology. This slide shows the effect of once-weekly canvuparatide on bone turnover biomarker CTX, which is reflective of bone catabolism, and P1NP, reflective of bone anabolism over time, respectively, representative again of destruction of the bone and reconstruction of the bone. As a reminder, bone turnover is typically suppressed in patients with chronic hypoparathyroidism, therefore increase in both bone resorption and bone formation markers expected following initiation of PTH replacement therapy. As you can see here, both CTX and P1NP increase following treatment with canvuparatide, consistent with reactivation of the bone remodeling. There was no change in placebo. Once again, when placebo patients switched to active canvuparatide, both biomarkers increased similarly to what was observed in patients treated initially by canvuparatide. After this initial increase, the marker generally stabilized or slightly decreased through one year of treatment. That's a profile that you want to see. The overall pattern is reassuring because it suggests restoration of bone turnover rather than continued increase over time, and is consistent with the expected skeletal effect of physiologic PTH replacement. Correlated to bone biomarkers, we are now going to discuss the bone effect through the bone mineral density or BMD. We are going to present the Z-score, and we elected to present the BMD through the Z-score because it provide a good comparison with patient bone densities that will be expected for someone of the same age, sex, and values above -2 are generally considered within the normal range. As I mentioned on the previous slide, restoration of bone remodeling following PTH replacement is expected to influence bone density over time, and therefore this finding should be interpreted together with the bone turnover biomarker data. You can see on the four different bone location, which was the spine, the total hip, the femoral neck, and the radius, mean BMD score declined modestly following restoration of bone remodeling and remained within the normal range through one year of treatment. Taken together, this finding is consistent with the restoration of bone metabolism and do not suggest any new bone-related safety concern. Looking now at immunogenicity. Immunogenicity was really minimal in both parent study and the open-label extension, with a single observation of anti-drug antibodies among 59 patients through one year. Notably, the titer of this anti-canvuparatide antibody signal was low, and no detectable titer were found for the active PTH peptide. Looking now at the overall safety profile. Most treatment emergent adverse events were mild or moderate in intensity, with five serious adverse events not deemed to be treatment related. Only 5% of the patients discontinued the study due to treatment emergent adverse event. When we evaluated adverse event of special interest, hypocalcemia, hypercalcemia, and injection site reaction were the most common event, and is absolutely consistent with the patient population with HP, hypoparathyroidism, receiving injectable PTH replacement therapy, and notably began self-administration at home during the open-label extension. In summary, we believe these data demonstrate sustained benefit of once-weekly canvuparatide as a potential PTH replacement therapy for patients with chronic hypoparathyroidism. The results are consistent with restoration of the systemic PTH activity through serum calcium normalization, reduction of urine calcium excretion, restoration of bone metabolism, and increase of eGFR. Response rate of 57% at one year in the OLE is comparable to the Phase II AVAIL rate at 63% at 12 weeks. We had a high retention rate with 90% of patients entering the open-label extension remaining in the study at one year. Kanvuparatide was generally well-tolerated, with no new safety signal during the open-label extension, and importantly, the pharmacokinetics support the once-weekly dosing with, as I've shown you, low peak to trough ratio and stable exposure. Phase III pivotal trials remain on track to initiate the third quarter of this year, and I'm going to give you more information about the Phase III. The Phase III trial is designed as a randomized, double-blind, placebo-controlled study, enrolling approximately 160 patients randomized 3: 1 to once-weekly canvuparatide or placebo. Sorry. Patients randomized to canvuparatide will start at 600 micrograms once- weekly and follow a titration algorithm to maintain albumin-adjusted serum calcium in the normal range while reducing conventional therapy. The primary endpoint at week 26 is a composite responder endpoint requiring patient to meet all the four criteria of normal albumin-adjusted serum calcium, independence from active vitamin D, zero oral calcium supplementation at a maximum of 600 mg per day, and no increase in canvuparatide dose during the final four weeks of treatment. The key secondary endpoint include normalization of urine calcium excretion in patients with elevated baseline value while maintaining normal albumin-adjusted serum calcium, and we added another key secondary endpoint, an important one, which is PROs. The one-year open- label extension data also strengthen our confidence in urine calcium normalization as a key secondary endpoint in this Phase III, particularly among patients with elevated baseline urine calcium. That's where we observed in the Phase II, a meaningful and sustained improvement in calcium excretion. After the 26-week double-blind period, patients will enter 78-week open- label extension. Overall, the Phase III design reflects the totality of evidence observed in the AVAIL study and the one-year open- label extension. We strongly believe that these data support the continued development of once-weekly canvuparatide as a potential replacement therapy, which is designed to provide durable disease control while reducing treatment burden for patients with chronic hypoparathyroidism. With this, I will turn back to Kent. Thank you, Sam. Our one-year OLE data reinforces our conviction that once-weekly canvuparatide is a best-in-class PTH replacement therapy. It demonstrates sustained benefit in hallmark PTH biology in blood, kidney, and bone. The data also supports our Phase III trial design, which we view as a confirmatory study. We have an exciting year ahead for MBX, with several important milestones that we're on track to achieve, including beginning enrollment in our canvuparatide Phase III study in Q3. We have cash to fund our operations into 2029, including fully funding our Phase III pivotal trial and pre-commercial activities that are underway. Our team has a strong sense of urgency because we know that patients are waiting. Operator, please open the line for questions. Thank you. At this time, if you'd like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing star two. Our first question comes from the line of Seamus Fernandez with Guggenheim Partners. Please proceed with your question Great. Just have a couple of questions. If we can first start with Dr. Michael Collins. Dr. Michael Collins, interested to just get your thoughts on the clinical comparison that one would make between YORVIPATH and canvuparatide effectiveness here. Perhaps, improvements that you could see occurring between the Phase II to Phase III results, because we did see an improvement in YORVIPATH's effectiveness as measured at the OLE endpoint. Again, I know it's dangerous to do these cross-trial comparisons, but just interested in your thoughts on the clinical experience with canvuparatide and how you see the opportunity here as impacting patient lives. Then for Sam and Kent and the team, just wanted to get a better sense again of that dynamic as we look at the ability to dose perhaps quite flexibly all the way up to 1,600 micrograms. Just interested to know where the sort of dose range came out in the OLE and what's possible in the Phase III to perhaps even improve upon this response rate at 52 weeks. Thanks, guys, and congrats on the data. Well, thank you, Seamus. I'll just lead off briefly and pass it to Dr. Michael Collins and then to Sam. Again, we're just really delighted with our one-year data, which support the sustained clinical benefit. Recall, this is really the first truly long-acting PTH therapy candidate. Our one-year responder rate really was comparable to the 12-week AVAIL, which achieved its primary endpoint, and to the once-daily YORVIPATH Phase II at one year based on the confidence interval. Importantly, really the expected PTH effects in bone, blood, kidney for a PTH replacement therapy. Really delighted and I'm really excited to hear Dr. Michael Collins' perspective and comparison. Thank you, Kent, and thank you, Seamus, for the questions if I can recall them all. The first that you asked about is the comparison between the two. As you pointed out, this is a dangerous endeavor and one that I won't engage in because they haven't been compared. What we can say is that for both drugs, the results look very good, like what you'd want for a patient with hypoparathyroidism. Of course, the obvious advantage that I see is that this is once-weekly dosing over daily dosing. Patients generally don't like injections, and if you can cut that down from seven a week to one, they'll really like that, I think. One of the questions you asked me, which I'll probably turn over to Sam, was a question something about the design of the Phase III based on what I think essentially are the learnings from Phase II. I actually think there are quite a few and some important ones. I think I'll leave that to Sam to talk about. Thank you, Michael, and thank you, Seamus, for the question. I think we also expect to see even better results in the Phase III because we are learning from Phase II. As a reminder, Phase II is a learning phase, right? We learn as an example, what would be the starting dose in the Phase III, 600 micrograms as we reported will be the starting dose. It's a learning from the Phase II. The big, big difference with the Phase III is that we are going to go ahead with a commercial device. The commercial device as we are intending to implement will be a reliable device. It will be one injector, it will be one dose, and you discard it. Very easy to use, very reliable. It's very different from the Phase II. If you remember my description of the study design, patient was transitioning in the open- label extension to reconstituting themselves and self-injecting the drug. We know that it's not perfect, and we know that it can be source of misdosing, et cetera. We will not have this problem in Phase III. All this should constitute an improvement as compared to Phase II. You also asked a question about the dose in the Phase II. What we experienced in, it's a broad range. We think that we are offering to the patient the right range of doses from 400 micrograms to 1,600 micrograms. These doses will be kept, if you want, and have been confirmed to be evaluated into the Phase III program at the same as I said, starting with 600 micrograms. It touches on the fact that this is personalized medicine really. There is heterogeneity in the HP patient population. We want to serve every patient with HP. We think that the patients and their doctors relate to the fact that they need a PTH replacement therapy. PTH is the missing hormone. We're advancing a dose range that we think fully satisfies their needs. In the six-month Phase III, we expect to get patients to their optimal dose. Very excited to get on with the Phase III shortly. Thanks. Our next question comes from the line of Tyler Van Buren with TD Cowen. Please proceed with your question. Hey, guys. Congrats on the data, and thanks for the very thoughtful presentation. The 57% responder rate at one year demonstrates a nice maintenance of response compared to the 63% at 12 weeks, of course. With that said, can you help us put into context the increased responder rate at six months? Overall, the early, middle, and one-year responder rates seem to line up fairly nicely with the YORVIPATH Phase II data based upon one of your slides. Can you help us understand why that might be a more fair comparison, relative to, say, the YORVIPATH Phase III data? Thank you, Tyler. We do look at our Phase II open-label extension one-year responder rate as comparable to the responder rate at 12 weeks based on the confidence interval it overlays well, and as well to the one-year time point for the Phase II study responder rate for once-daily YORVIPATH. Importantly, with our candidate in once-weekly administration. We do think that Phase II to Phase II makes sense, and the Phase III trial is, of course, different. It's a placebo-controlled study with very active engagement with the investigators, and that's where we're at, getting ready to start next quarter. Anything to add, Sam? No, I think you summarized very nicely. Dr. Collins? No. Thank you. Our next question comes from the line of Michael Yee with UBS. Please proceed with your question. Great. Thanks. Congrats on the data. We had a two-part question, either for the management or for the doctor. On efficacy, I know your 57% finds very much in line with YORVIPATH and at the higher end of their one-year data as well. It came down from the initial six-month data and earlier time points. Can you just qualify how you think the numbers came down, whether from actual compliance factor issues or what you know about the patients who were responders at six months and then were non-responders by definition at 12 months, and what was going on there? Do you have any insight on the patients or compliance factor, given that this was not the pen or the commercial Phase III formulation? Similarly, with the hypocalcemia, I know that the number moved up in the Phase II 12-month portion. It was 8% in the middle of the year. Then went up to 20%. I suspect that those increases were due to some factor that related to the compliance part of the injection. Maybe you have some insight into what happened with the people who were hypocalcemic during that open-label extension portion. Thank you. Well, thank you, Mike. We're very excited about the data, too. When you look at these different time points, you're going to have some variability. Again, they're all very comparable overall. In terms of the open-label extension, you're correct that during the open-label extension, you have this change from going to the PI weekly for blood draws, for getting the drug administered, to going in the wild in your home and you're self-administering, and you're going much less frequently for visits and assessments. That is playing out during the open-label extension portion of the study. Into Phase III, we will have the pen, and we will have the regular weekly assessments. The pen is one that we know from market evaluation is going to be well-received. In terms of the specific safety question, I think it's very related to what I shared, I'll ask Sam to elaborate. Thanks, Mike. I think that the point that Kent made about the monitoring, the frequency of monitoring, but also the patient preparing at home and in self-injective has certainly impacted the hypocalcemia level. I can give you just one rationale, is the percentage of patients with hypocalcemia during this period where they were self-injecting was 53%. 53% of the patients with hypocalcemia were self-dosing at home. We can certainly assume that there was some mistake around the dose. If you look at the other end, which is the initial three-month period of the open-label extension, where patients were still titrating up, well, we have 25% of patients with hypocalcemia in this period. This period at the beginning and at the end accounts for almost 75% of it. If I make one additional comparison with YORVIPATH had in Phase II their commercial device, we will have a commercial device in Phase III, again, I'm very highly confident that this number will drop. Thank you. Our next question comes from the line of Roger Song with Jefferies. Please proceed with your question. Great. Congrats for the data for the one year durability. Thanks for taking our question. Maybe I'll move on to the PD marker for the serum calcium. Very helpful, you give us the peak trough ratio and the differences. Just want to clarify, this is 0.59. How are you going to put it into the context of the placebo getting during the randomized trial or the normal range, you would say? Then also this 0.12, is that a standard error or it's a standard deviation? Thank you. Roger, can you clarify the 0.59 that you're referring to? Yeah, the 0.59 on the slide 24, I believe. It is a peak trough difference. Really what we have established here, by design, we're seeing that flat PK, almost peakless, you might say, about 1.3 over a week or infusion-like without the pump. This translated to the steady PD effects throughout the week. That's the 0.59 mg/dL calcium difference, serum calcium difference, which is not only stable but very normal physiologic fluctuation. The second part of your question again? 1.2 is standard error. Very good. Thank you. Our next question comes from the line of Annabel Samimy with Stifel. Please proceed with your question. Hi, this is Jack on for Annabel. Thanks for taking our questions. Two from us. What percent of patients reach the top dose by year one? Could they have potentially remained underdosed? As in, did you see patients uptitrating consistently throughout the year and then getting capped at 1,600? Or did you see patients hitting their target dose relatively early and staying there? Then on bone health, the trended BMD looks like it's getting a bit closer to the normal limits, particularly in the radius. What are your expectations for where that might end up at year two? Would BMD stabilize at this point, or would you expect that to continue trending lower without intervention? Thank you. I'll ask Sam to address your two-part question. Yeah. The patient can be titrated at any point if the physician thinks that it's needed. I'm explaining. At the end of the AVAIL study, if you remember, just by design, two groups couldn't reach 1,600 micrograms. That when they switched to the open-label extension, it was possible for this patient, if they were not responder, to be titrated up. Again, same thing with the placebo. When they switch to the active treatment in the open-label extension, again, they can be titrated. If for any other reason during the course of the study, a patient needed to have a change in the comparator, that it was possible and the only thing was respecting the interval of two- to three- week between the dose increase. You ask a question about the BMD and the question was related to- Standardization. Standardization. Oh, yes. Let me explain the radius first. The decline you see in the radius, we looked at really in detail the starting, the baseline start, if you want. What we noticed is in fact, the patients who decrease the most are the one who start the highest. That's exactly what you want, right? To reduce the BMD and trending towards zero. That's what you want to see. When you look at this population again, the other patients, especially the one which are the lowest level, didn't change. It was perfectly stable. It's really nice to see, in fact, even in more detail, I didn't show the slide, but we have really the effect you want to see. Patients starting high decreasing towards zero, patients starting low staying where they were. That's exactly what you want to see. Having said that, obviously, we'll continue to follow up these patients. We'll have additional data over next year, et cetera, we will be a long-term monitoring. Thank you. Our next question comes from the line of Jessica Fye, JPMorgan. Please proceed with your question. Hey, guys. Good morning. Thanks so much for taking our questions. I have one for the management team and one for Dr. Collins. For the MBX team, have you analyzed the 52-week data using the FDA's responder definition, the one that seems stricter than what the companies use in clinical trials, that I think requires the last four weeks to have zero PRN, zero active vitamin D and calcium 600 or higher, or north of 600? For Dr. Collins, I was curious what you make of the 15% use of active vitamin D in the one-year data. Maybe if I could add one more in, just following up on the last question on BMD. Did you just overall, Dr. Collins, see these baseline BMD measures as consistent with a typical hypoparathyroidism population? Thank you. Thank you, Jess. I'll lead off. This is a Phase II study open- label extension. What we did look at is a three-part primary endpoint that's quite comparable to the Phase III endpoint, why we look at this Phase III study as a confirmatory study. We went the extra mile beyond this three-part Phase II endpoint and looked at PRN use during the week of evaluating the primary endpoint. We found there was none, zero use. Again, this is really typical for a Phase II. The Phase III will be different. It will be a placebo-controlled blinded, weekly visits, monitoring, and we are very confident that we have designed this study and will implement this study to have a high responder rate in the primary endpoint that's been established and aligned with the key regulatory bodies. In terms of Dr. Collins, can you please respond? Yes. Hi, thank you for the question. The two questions. The first is my impression, I take it, of the use of active vitamin D in the latter part of the OLE. I think this was, to some extent, probably already explained by Sam when it was noted probably because of the lack of a device and the fact that the patients were not using the drug correctly, that they had more episodes of hypocalcemia, and then the doc did the appropriate response of giving some active vitamin D. I would also say parenthetically that my personal feeling as a clinician about this is I'm not that concerned, in fact, if a patient needs to take a little bit of calcitriol, and I'm more concerned about the fact that patients or the providers and the FDA are so rigorous about this because the concern with not using active vitamin D or calcium supplements has the tendency to lead to over-treatment, which could have deleterious effects on the bone. Which leads to your next question was about what my thoughts were about the baseline values of bone density in these patients. I think that they were perfectly consistent with what's seen in other studies. I think what was seen here and is seen in other studies and to me is a bit of a surprise, is there are some patients who enter this with hypoparathyroidism, who we generally think of as having high bone mass, that at some sites, and particularly at the radius, actually have fairly low bone mineral density. This has been a bit of a surprise. We actually did dig into this, and what Sam said is absolutely true, that those with the lowest bone density really stayed quite stable. That I think was very reassuring. Thank you, Mike. I can add in terms of quantity of vitamin D, active vitamin D. It was very low. In fact, the median use was 0.3 micrograms per day. Very low. In those subjects who used it. Yeah. They were not responders. Of course. Just to be clear. Yeah. Due to the three-part- Exactly three-component endpoint. Yeah. Thank you. Thank you. Thank you. Our next question comes from the line of Ellie Merle with Barclays. Please proceed with your question. Hey, guys. Thanks so much for taking the question. Just to clarify on the hypo- and hypercalcemia events, what proportion of these events were symptomatic, and I guess what were the average duration of these cases? If you could just clarify what the severe treatment-related adverse events were in the AE slide on 31. Sorry, last question. I know you touched on it a bit, but just can you help us understand what you attribute to the increase in the response rate at month six and then the decline at week 52? I guess more importantly, how you think about the stability of the response beyond week 52 and sort of the confidence that it remains stable from there. Thanks. I'm going to take the first part and let Sam follow up on your multi-part question. You have different time points in these studies and overall, we see comparable results. The primary endpoint for the Phase III is six months. I think it's a really great period to optimize the dose and show the effect, and we of course will have an OLE as well for the Phase III. We just think the hallmark PTH physiology is there, including the flat PK that I mentioned, the infusion-like, that translated to steady PD. We see this as a very effective PTH replacement therapy, and we believe we've designed a Phase III that's going to demonstrate that very clearly. Turning it over to Sam on the other parts. Yeah, I think I'm going to start with the hypercalcemia. The hypercalcemia is exactly within what was expected. In fact, we had a few patients with hypercalcemia, and we had exactly seven subjects. No surprise there, I would say. For the hypocalcemia, I think I provided you with the rationale why we got this hypocalcemia, explaining around 75% of the occurrence of hypocalcemia. We have a good explanation for the hypocalcemia. In terms, I think you asked a question about the serious adverse events, right? That was the question, one was related to appendicitis. Obviously not drug-related. The other one were related to the hypocalcemia for four episodes. The rest of the hypocalcemia, back to your question, were mild to moderate. There was no impact. Didn't last long. Very few discontinued for hypocalcemia or hypercalcemia. In fact, zero patients discontinued for hyper. Overall, we think that this hypocalcemia will be absolutely manageable and will be manageable in the rest of the study. Thank you. Our next question comes from the line of Jon Wolleben with Citizens JMP. Please proceed with your question. Hey, congrats on the data. Thanks for taking the question. In the release, you guys mentioned some patient-reported outcome data, and I was hoping if you could just give some context qualitatively about what you saw there. I might have missed this in an earlier answer, but just wanted to check if you could confirm what percentage of patients, if any, were at the top allowed dose at year one. Thanks. Thank you, Jon. Sam will address both of those. I think for the top doses, I can tell you that we had patients up to 1,600 micrograms, and as I told you, the median dose was 1,000 micrograms. That's what we can say at this point, at this juncture. In terms of PRO, yes, you're absolutely right. We had a nice positive trend in the PROs that was observed, especially for the SF-36 and some of the components of the HP questionnaire. However, we did not have enough patients at baseline to be able to draw a conclusion, especially against placebo. What we are going to do, it's a learning for Phase III. We are so confident in these parameters and PROs that we decided to make it as a key secondary endpoint. We worked with the FDA in order to be aligned with what we'll be exploring. It will be an endpoint that will be part of the Phase III study. Just building on that, we really were excited with the high retention rate of 90% of the patients who entered the OLE remaining on the study at one year. I think that really indicates satisfaction with once-weekly canvuparatide. This is just consistent when we speak to the patients. They want to reclaim their freedom from the daily burden of their disease, taking pills day and night, with a therapy they can take easily once- weekly and then forget about their disease for the rest of the week. We're really excited about the Phase III and on track for beginning enrolling next quarter. It's very helpful to run the Phase II to confirm the study design. Thank you. Ladies and gentlemen, our final question this morning comes from the line of Srikripa Devarakonda with Truist Securities. Please proceed with your question. Hi, guys. Thank you so much for taking my question and congratulations on the data. You noted that there was zero contribution from rescue therapy in the last week of the treatment period. I was wondering if you can talk about PRN calcium outside of just the last week throughout the OLE. That's one question. Then, you talked about your market research, which suggests that HCPs would switch a large majority of patients over time. Do you have any sense of if a patient is already stabilized on YORVIPATH, you still have the weekly benefit. What would be a specific clinical trigger doctor would use to justify a switch to once-weekly canvuparatide parathyroid? Thank you, Krupa. I'm going to ask Sam to address the first part, then we are joined by Mark Soued, our Chief Commercial Officer, he will address your market research question. Thanks, Krupa. We had a really thorough review of the data, We can confirm that there was no use of PRN in the last week of the evaluation. The definition of PRN was not going above the prescribed dose of 600 mg of calcium at any point during the week. It was not an average. It was at any time. Obviously, no use of vitamin D at all. That was a very strong criteria. That's why we were pleased to report that the same sample, the AVAIL study and the open-label extension, we didn't have any use of PRN the last week. Yeah. Krupa, this is Mark. Just to build on the point about physician preference. Indeed if YORVIPATH is approved, really it would represent, frankly, a new standard of care with- Once-weekly canvuparatide parathyroid. I was going to say, exactly, with once- weekly. When we presented this to physicians, to patients as a TPP, what we saw very clearly is for newly diagnosed patients that are PTH naive, the vast majority of physicians said that would become the preferred choice. Same with patients. For those patients that are already on PTH treatment, what we heard very clearly is the vast majority would also be switched over time. I think your question is, what would be those triggers? Well, I think Dr. Collins pointed to some of those. There is a injection fatigue. We've seen this very clearly in the research, and that's something that's very real. Imagine injecting yourself every day, the anxiety that still remains from potentially missing your dose during that day, some sort of a daily disruption. Again, we see a large portion of those patients switching over time, as we said, I think as physicians and patients get experience with the therapy, if it's approved, we're going to see that dynamic play out very strongly. Thank you. Ladies and gentlemen, that concludes our question and answer session. I'll turn the floor back to Mr. Hawryluk for any final comments. I want to thank everyone for participating in this call and stay tuned for more about our Phase III trial. Thank you. That concludes today's conference call. You may disconnect your lines at this time. Thank you for your participation.