Capital Markets Day Transcript - MBX 2026-06-12

Operator

Greetings, and welcome to the MBX Biosciences Business Update Call. At this time, all participants are in a listen-only mode. A question-and-answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press stop 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 Harla, President, CEO, and co-founder of MBX Biosciences. Please go ahead, sir.

P. Kent Hawryluk, CEO

Good morning, and thank you for joining us to review the once-weekly Canbu Paratide one-year data from the Phase II Open Label Extension Study. I am Kent Harlick, 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 DeMarkey, 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 in 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 Kanbu paratide 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 Kanbu's precision endocrine peptide design to clinical outcomes and provides important reinforcement of our phase three study design. And 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 CANVU from its inventor, Dr. DeMarkey, a clinical perspective on the HP landscape and unmet need from Dr. Michael T. Collins, a presentation of the one-year data from our CMO, Dr. Sam Azule, and will be followed by concluding remarks and a Q&A session. I will now turn it over to Richard.

Richard DiMarchi, Other

This is Richard. Thank you for the invitation to participate. I'm coming to you from my office in the chemistry building at Indiana University, where I've 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, And Lyspro Insulin, as you see in 1996, was the first registered product that was purposefully optimized. It's 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. Borteo, 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, and then on into the transformative ability to manage type 2 diabetes and even more so obesity that we've witnessed over the last two decades using chemistry to achieve something that could not be achieved with the native hormone. Bayetta, twice a day. Victosa, once a day. Trulicity, the first effective once-a-week treatment for type 2 diabetes, and 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, fatty acylation for extending the duration of action, and the Noble Corporation deserves the lion's share of the credit for having advanced this through insulin into the incretins that we know so well. It's innovative peptide design, designing these molecules for exquisite potency, metabolic stability, and this extended duration of action. And it's that middle box that really speaks to this pro-drug chemistry that we have developed here in Indiana University through support from the MBX Corporation 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. And so 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 getting on to the biology of this opportunity and of the company. It's a cartoon that shows in the upper left-hand corner near that A, if you can see it, can who paratybe, MBX2109, 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. And 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 diketopiprazine, 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. And in the window C, if you will, you can see the red peptide is turning to a green peptide, connotating 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 independent. 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. And 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. And so 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. And so 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 Aguilet 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.

Michael Collins, Analyst — Endocrinologist, NIH

Thank you, Richard. My name is Michael Collins. I'm an endocrinologist, a special volunteer, and senior clinical advisor at the National Institutes of Health. And 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 nesters. 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. And it's the treatment that can lead to impaired renal functions, hypercalceria, nephrocalcinosis, and nephroesiasis. Hypoperithiardism has thousands of patients worldwide. In the UK and US, over 250,000 patients with an annual incidence of about 7,000 per year. And again, the majority of those are caused by neck surgery. And most patients after neck surgery are really diagnosed within a few months. So 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. And in 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 patients, the number of pills a patient has to take a day and the burden that this imposes. And with this goes along what's 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. And it's the treatment that really leads to the hypercalciuria and the renal calcification. And a lot of this is driven by the tetany. Tetany is a terrible condition, and if a patient has ever had this, they do everything they can to prevent it. And this often includes taking extra doses of calcium, which facilitates and promotes hypercalciuria and renal calcification. Now, we know that YorvaPath, 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. And 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 available, we know there's compelling efficacy with canvoparatide. It confirmed the tolerability, and it determined the starting dose. So, canvoparatide really has demonstrated positive results in Phase II and 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, and And we hope to see normalization of blood calcium, independence of active calcium and vitamin D, normalization of urinary calcium, and more patient-reported outcomes. On the left here is shown the potential for Candivateratide. 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, and it frees patients from daily disease management. One-sweekly canvateratide 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 canvateratide. They would start naive patients in canvateratide. And patients also would choose once-weekly canvateratide. And if week-over-week consistency is borne out, it will eliminate the roller coaster of crashes and debilitating symptoms. So in summary, we've shown that chronic hypoparathyroid is a damaging disease. There are a lot of patients in the US and EU. We've seen that YorvaPath validates the need and accept them a PTH replacement, but there are significant gaps. When one-sweasly camviparathyroid has the potential to set a new standard for treating chronic hypoparathyroidism, the majority of health care providers and patients would choose one-sweasly camviparathyroid. With that, I'll turn it over to Dr. Azoulay, the Chief Medical Officer.

Sam Azoulay, Other

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 AVEN study, which is, in fact, the first study to evaluate the safety and efficacy of the weekly convuparotide in patients with hypoparotaritis. Let me remind you about the design of the EVEL study which enrolled adults with hypoparaturidism. We were receiving calcium supplementation, vitamin D supplementation at a stable dose and who had albumin-adjusted calcium in the range of 8.2 to 10.6 mg per deciliter. Patients were randomized 4-1 to treatment with conviparatate 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, 30 medication doses were maintained at the starting level. Beginning at week 5, dose adjustment was permitted at 200 microgram increment, as needed, on a two-week interval. The maximum conviparotide dose ranged from 1,200 to 1,600 micrograms, depending on the study participants' starting dose. After completion of the eight-week dose adjustment period, patients were eligible to enter into the open-label extension study. The primary endpoint of the AVEL 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, zero, and reduced oral calcium supplement to a maximum of 600 mg a 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 contviparatide treatment. Patients originally randomized to contviparatide could continue active treatment, while patients originally randomized to placebo cross over to contviparatide with those adjustments allowed to achieve and maintain therapeutic benefits. 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 convuparotide overtime. Now, shown here are the baseline demographics and clinical characteristics for the Aval study participants. In this presentation, all data for chondroparotide will reflect a pooled analysis of the three dose groups, and comparisons will be for this pooled chondroparotide versus placebo. Overall, the demographic and clinical characteristics were representative of the population of patients with HP, hypoparatyridism, and similar across the two groups of pulled conviparatide 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 EVEL study with 100% and 64 patients, 64, the 64 patients included, completed the study. 60 of these patients choose 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 patient's and PI satisfaction with their treatment. At week 12, 63% of patients in the counter-pubriotide 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 Avel 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 is 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 canviparatide at home, providing important experience with long treatment outside of the controlled clinical setting. Taken together, these findings support the potential of once-weekly canviparatide to provide durable benefit over the one-year treatment period. To help to place this research in context, this slide summarizes the selected primary efficacy outcome reported for YerviPath in this Phase II program alongside the Conviparatide data presented today. While cross-trial comparison should be interpreted with caution, the overall efficacy profile observed with once-weekly Conviparatide compares favorably with the currently approved PTH replacement therapy with comparable data at WANIA. The key distinction is that country paratide achieves these results with a once-weekly dosing regimen compared with the daily administration required for Yorvitas. 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 convuparathyde we observed in the Phase II study. On the left side of the slide, convuparathyde continues to demonstrate the controlled and sustained exposure profile it was designed to achieve in patients. The Tmax was approximately 2 to 3 days and we had minimal fluctuations 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 2 study, we also measured serum calcium at the C-max and the trough concentration of chondroparotide active drug, showing a mean difference in serum calcium of only 0.59 mg per deciliter. Taken together, these findings continue to support the potential of once-weekly chondroparotide to provide consistent PTH replacement with stable calcium control over time. I'm going now to look at urine calcium. As shown on the graph, patients treated by controparotide, that's the blue bar, the blue in blue, showed a reduction in urine calcium at 12 weeks of the phase 2 study, which is even more pronounced at while here, while very importantly, maintaining serum calcium within the normal range. On the right side of the graph, you can see that a patient initially treated by placebo also show a reduction in urine calcium, which is driven by the reduction in vitamin D and calcium supplement. But in parallel, the serum calcium decreases and fluctuates. When switching to active conviparatide, the urine calcium decreases further, while the serum calcium this time stays within the normal value. Now 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 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 conviparatrize experience a substantial reduction in mean 24-hour urine calcium from 426 milligrams a day at baseline to 229 milligrams a day at week 12, further improving to 188 milligrams 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 conviparatite reaching 106 mg a day at one year. A particularly striking finding is shown here. Patient previously treated with placebo and moving to conviparatite had an even further reduction in urine calcium, despite having higher serum calcium. Overall, the maintenance of serum calcium level, together with the 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 a 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, conviparatide is restoring the physiological pth activity in the kidneys. Now I'm going to move to the bone biology. This slide shows the effect of once-weekly countryparatide on bone turnover biomarker, CTX which is reflective of a catabolism, bone catabolism, 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 hypoparotiritis. Therefore, increase in both bone resorption and bone formation mark as expected following initiation of PTH replacement therapy. As you can see here, both CTX and P1NP increased following treatment with conviparatide, consistent with reactivation of the bone remodeling. There was no change in placebo. However, once again, when placebo patients switched to active conviparatide, both biomarkers increased similarly to what was observed in patients treated initially by conviparatide. After this initial increase, the marker generally stabilized or slightly decreased through one year of treatment. That's the profile that you want to see. The overall pattern is reassuring because it suggests restoration of bone turnover rather than continuity increase over time and is consistent with the expected skeletal effect of physiologic PTH replacement. Correlated to bone biomarkers, we are not going to discuss the bone effect through the bone mineral density of BMD. And we are going to develop to present the Z-score, and we elected to present BMD through the Z-score because it provides a good comparison with patient bone densities that will be expected for someone of the same age, sex and values about negative 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 these findings should be interpreted together with the bone turnover biomarker data what you can see on the four different locations bone location, which was the spine, the total hip, the femoral neck, and the radius, mean BMD scores 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 year one, and notably, the titer of this anti-country paratide 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 events. When we evaluated adverse events of special interest, hypocalcemia, hypercalcemia, and injection cell reaction were the most common event, and this 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 this data demonstrates sustained benefit of once-weekly controparathy as a potential PTH replacement therapy for patients with chronic hypothyroidism. 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 rates of 57% at one year in the OLE is comparable to the Phase II aval 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. Canva-paratide was generally well-tolerated with no new safety signal during the open-label extension. And importantly, the pharmacokinetics supported once-weekly dosing with, as I've shown you, low PQ-TREF 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, on rolling approximately 160 patients, randomized 3-1 to once-weekly convuparaltyde, or placebo, sorry. Patients randomized to convuparaltyde 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 patients to meet all the four criteria of normal albumin-adjusted serum calcium, independent from active vitamin D zero, oral calcium supplementation at a maximum of 600 mg per day, and no increase in conviparatite dose during the final four weeks of treatment. The key secondary endpoints 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 PIROS. The one-year open-label extension data also strengthened our confidence in urine calcium normalization as a key secondary endpoint in this Phase III, particularly among patients with elevated baseline during 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 a 78-week open-label extension. Overall, the Phase III design reflects the totality of evidence observed in the AVEN study and the one-year open-label extension. We strongly believe that these data support a continued development of once-weekly confuparitide as a potential replacement therapy, which is designed to provide durable disease control while reducing treatment burden for patients with chronic hypoparituridism. With this, I will turn back to Kent. Thank you, Sam.

P. Kent Hawryluk, CEO

Our one-year OLE data reinforces our conviction that once-weekly Canbuparatite 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 three 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 CANVU 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.

Operator

Thank you. At this time, if you'd like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 to remove your questions from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing. Our first question comes from the line of Seamus Fernandez with Guggenheim Partners. Please proceed with your question.

Seamus Fernandez, Analyst — Guggenheim Partners

Great. Just have a couple of questions. If we can first start with Dr. Collins. You know, Dr. Collins, interested to just get your thoughts on the comparison between, you know, the clinical comparison that one would make between Yorvipath and Canva Paratide's effectiveness here, you know, And perhaps, you know, improvements that you could see occurring between the phase two to phase three results, because we did see an improvement in Yorvopath's effectiveness as measured by the, at the OLE endpoint. But, again, I know it's dangerous to do these cross-trial comparisons, but just interested in your thoughts on the clinical experience with tamiparatide and how you see the opportunity here as impacting patient lives. And then for, you know, 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 patients. um perhaps quite flexibly uh all the way up to 600 uh 1600 micrograms um just interested to know where the sort of dose range came out uh in the ole and um you know what's possible in the phase three uh to perhaps even improve upon uh this response rate at 52 weeks thanks guys and congrats

P. Kent Hawryluk, CEO

on the data. Well, thank you, Seamus. I'll just lead off briefly and pass it to Dr. Collins and then to Sam. You know, again, we're just really delighted with our one-year data, which support the sustained clinical benefit. And recall, this is really the first truly long-acting PTH therapy candidate. And, you know, our one-year responder rate really was comparable to the 12-week avail, which achieved its primary endpoint, and to the once-daily Yorvi Phase II at one year, based on the confidence interval. And importantly, you know, really the expected PTH effects in bone, blood, kidney, for a PTH replacement therapy. So, you know, really delighted, and I'm really excited to hear Dr. Collins'

Michael Collins, Analyst — Endocrinologist, NIH

perspective and comparison. Thank you, Kenan. Thank you, Seamus, for the questions, if I can recall them all. So, the first that you asked about is the comparison between the two. And 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. And I actually think there are quite a few and some important ones, and I think I'll leave that to Sam to talk about.

Sam Azoulay, Other

Thank you, Michael, and thank you, Seamus, for the question. Yeah, I think we also expect to see even better results in the Phase 3, and because we are learning from Phase 2. As I remind you, Phase 2 is a learning phase, right? So we learn, as an example, what would be the starting dose in the Phase 3. 600 micrograms, as we reported, will be the starting dose, and it's a learning from the Phase 2. The big, big difference with the Phase 3 is that we are going to go ahead with a commercial device, and the commercial device that we're 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 two, if you remember my description of the study design, patients while transitioning in the open-label extension to reconstituing themselves and self-injecting the drug. And you know that it's not, we know that it's not perfect, and you know that it can be a source of misdosing, etc. So we will not have this problem in Phase III. So all this should constitute an improvement as compared to Phase II. You also asked a question about the dose in the phase two. So what we experience, it's a broad range, and we think that we are offering to the patient the right range of doses from 400 micrograms to 1,600 micrograms. And 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.

P. Kent Hawryluk, CEO

Yes, and it touches on the fact that this is personalized medicine, really. There is heterogeneity in the HP patient population, and we want to serve every patient with HP, and we think that the patients and their doctors relate to the fact that they need a PTH replacement therapy. PTH is the missing hormone. And so we're advancing a dose range that we think fully satisfies their needs. And in the six-month Phase 3, we expect to get patients to their optimal dose and very excited to get on with the Phase 3 shortly.

Operator

Thank you. Our next question comes from the line of Tyler Van Buren with C.D. Cowan. Please proceed with your question.

Tyler Van Buren, Analyst — TD Cowen

Congrats on the data, and thanks for the very thoughtful presentation. Yeah, so the 57% responder rate at one year demonstrates a nice maintenance of response compared to the 63% at 12 weeks, of course. And with that said, can you help us put into context the increased responder rate at six months? And overall, the early, middle, and one-year responder rates seem to line up fairly nicely with the YorvaPath Phase 2 data based upon one-year slides. So, can you help us understand why that might be a more fair comparison relative to, say, the YorvaPath Phase 3 data?

P. Kent Hawryluk, CEO

Thank you, Tyler. we do look at our phase two 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 the one-year time point for the phase two study responder rate for once daily your v-pat but importantly with our candidate in once-weekly administration. So we do think that phase two to phase two makes sense, and the phase three trial is, of course, different. It's a placebo-controlled study with very active engagement with the investigators. And that's where we're getting ready to start next quarter. Anything to add, Sam? No, I think you summarized very nicely. Or Dr. Collins?

Operator

Thank you. Our next question comes from the line of Michael Yee with UBS. Please proceed with your question.

Michael Yee, Analyst — UBS

Great, thanks. Congrats on the data. We had a two-part question, either for the management or for the doctor. On efficacy, I know you are 57% lines, very much in line with URBPATH 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, if you have any insight on the patients, or compliance factor, given that this was not the PEN or the commercial phase three formulation. And similarly with the hypocalcemia, I know that the number kind of moved up in the phase to 12-month portion. It was 8% in the middle of the year and then went up to 20%. I suspect that those increases were due to some factor that related to the compliance part of the injection, but maybe you have some insight into what happened with the people who were hypocalcemic during the open-label extension portion. Thank you.

P. Kent Hawryluk, CEO

Yeah, well, thank you, Mike. We're very excited about the data, too. And, you know, when you look at these different time points, you're going to have some variability. Again, they're all very comparable overall. And 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 kind of going in the wild in your home, in your self-administering, and you're going much less frequently for visits and assessments. So that is playing out during the open label extension portion of the study. And in the phase three, we will have the PIN, and we will have the regular weekly assessments. The pen is one that we know from market evaluation is going to be well received. So in terms of the specific safety question, I think it's very related to what I shared, and I'll ask Sam to elaborate.

Sam Azoulay, Other

Yeah, 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 is certainly a source of, has certainly impacted the hypocalcemia level. And 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. So we can certainly assume that there was some mistake around the dose. Then 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. So this period at the beginning and at the end accounts for almost 75% of it. So if I make one additional comparison with Yorvipath, Yorvipath had in Phase 2 their commercial device, and we will have a commercial device in Phase 3. And again, I'm very highly confident that this number will drop.

Operator

Thank you. Our next question comes from the line of Roger Song with Jeffrey. Please listen to your question.

Roger Song, Analyst — Jefferies

Great. Congrats for the data, for the one-year durability, and thanks for taking our question. Maybe I'll move on to the PD marker for the serine 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? And then also this 0.12, is that a standard error or it's a standard deviation? Thank you.

P. Kent Hawryluk, CEO

Roger, can you clarify the 0.59 that you're referring to?

Roger Song, Analyst — Jefferies

Yeah, the 0.59 on the slide, 24, I believe. It is a peak trough difference.

P. Kent Hawryluk, CEO

Excellent. So 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. And this translated to the steady PD effects throughout the week. That's the 0.59 calcium difference, serum calcium difference, which is not only stable but very normal physiologic fluctuation. And the second part of your question again? 1.2.

Sam Azoulay, Other

the standard error. 1.2 is a standard error. Very good. Thank you. Our next question comes

Operator

from the line of Annabelle Samimi with Stiefel. Please proceed with your question.

Jack (for Annabelle Samimi), Analyst — Stifel

Hi, this is Jack on for Annabelle. Thanks for taking our questions. So two from us. So what percent of patients reach the top dose by year one? And could they have potentially remained underdose? As in, did you see patients up titrating consistently throughout the year and then getting capped at 1600? Or did you see patients hitting their target dose relatively early and staying there? And then on bone health, the trend in DMD looks like it's getting a bit closer to the normal limit, particularly in the radius. What are your kind of expectations for where that might end up at year two? Would DMD kind of stabilize at this point, or would you expect that to kind of continue trending lower without intervention.

P. Kent Hawryluk, CEO

Thank you. I'll ask Sam to address your two-part question.

Sam Azoulay, Other

The patient can be titrated at any point if the physician thinks that it's needed. I'm explaining. At the end of the Evel study, if you remember, just by design, two groups couldn't reach 1,600 micrograms. 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 up. But if for any other reason during the course of the study, a patient needed to have a change in a confuparitate, it was possible, and the only thing was respecting the interval of two to three weeks between those increase in terms of you ask a question about the BMD and the question was related to oh yes yes so let me explain the radius first what the decline you see in the radius we looked at really in detail just starting the baseline start if you want and what we noticed is, in fact, the patients who decrease the most are the ones who start the highest. So that's exactly what you want, right? To reduce the BMD and trending toward zero. That's what you want to see. And when you look at this population again, the other patients, especially the ones which are the lowest level, didn't change. It was perfectly stable. So 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. So that's exactly what you want to see. Now, having said that, obviously, we'll continue to follow up these patients. We'll have additional data over next year, et cetera, so that will be

Operator

long-term monitoring. Thank you. Our next question comes from the line of Jessica Five,

Jessica Fye, Analyst — JP Morgan

JP Morgan. 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, that, like, 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, you know, active vitamin D and calcium 600 or higher, or north of 600. And then for Dr. Collins, I was curious what you make of the 15% use of active vitamin D in the one-year data, and 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 hypopara population? Thank you.

P. Kent Hawryluk, CEO

Thank you, Jeff. I'll lead off. So, this is a phase two study open label extension, And what we did look at is a three-part primary endpoint that's quite comparable to the phase three endpoint, why we look at this phase three study as a confirmatory study. We went the extra mile beyond this three-part phase two endpoint and looked at PRN use during the week of evaluating the primary endpoint. We found there was none. Zero use. And again, this is really typical for a phase two. The phase three 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 endpoints that's been established and aligned with the regulatory bodies. And in terms of Dr. Collins, can you please respond?

Michael Collins, Analyst — Endocrinologist, NIH

Yes. Hi. Thank you for the questions. So 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 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 supplement has the tendency to lead to overtreatment 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. And 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 hypoparathyrasin 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. And we actually did dig into this, and what Sam said is absolutely true, that those with the lowest bone density really stayed quite stable. So that, I think, was very reassuring.

Sam Azoulay, Other

I can add in terms of the quantity of vitamin D, active vitamin D. It was very low. In fact, the median use was 0.3 microgram per day, so very, very low.

P. Kent Hawryluk, CEO

In those subjects who used it. And they were not responders, just to be clear, due to the three-part, three-component endpoint. Thank you. Thank you.

Operator

Our next question comes from the line of Ellie Merle with Barclays. Please proceed with your question.

Ellie Merle, Analyst — Barclays

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? And then if you could just clarify what the severe treatment-related adverse events were in the AE slide on 31. And then, 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 MUM 6 and then the decline at Week 52? And 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.

P. Kent Hawryluk, CEO

I'm going to take the first part and let Sam follow up on your multi-part question. You know, again, 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. And we just think the hallmark PTH physiology is there, including the flat PK that I mentioned, and the infusion-like, that translated to steady PD. So we see this as a very effective PTH replacement therapy, and we believe we've designed a phase three that's going to demonstrate that very, very clearly. So turning it over to Sam on the other parts.

Sam Azoulay, Other

Yeah, I think I'm going to start with the hypercalcemia. I mean, the hypercalcemia is exactly what was expected. In fact, we had a few patients with hypocalcemia, and we had exactly seven subjects, and no surprise there, I would say. For the hypocalcemia, I think I provided you with a rationale why we got this hypocalcemia, explaining around 75% of the occurrence of hypocalcemia, so 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 that was the question and so one was related to appendicitis so obviously not regulated and the other one were related to the hypocalcemia for four episodes the rest of the hypocalcemia back to your question were mild to moderate and there was no no impact that didn't last long in fact didn't last long and in fact very few discontinued for hypocalcemia so or hypercalcemia so in fact zero patients continued for hyper so overall that I think that we think that this hypocalcemia will be absolutely manageable and will be manageable in the rest of the study.

Operator

Thank you. Our next question comes from the line of John Walden with Citizens Bank. Please proceed with the question.

John Walden, Analyst — Citizens Bank)

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. And I might have missed this in an earlier answer, but I just wanted to check if you could confirm what percentage of patients, if any, were at the top allowed dose at year one.

P. Kent Hawryluk, CEO

Thank you, John. Sam will address both of those.

Sam Azoulay, Other

Yeah, 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. microgram. 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 trend, a positive trend in the PRO that was observed, especially for the SF36 and some of the components of the HP questionnaire. However, we didn't have enough patients at baseline to be able to draw a conclusion, especially against placebo. So what What we are going to do is learning for Phase III. And we are so confident in these parameters and PROs that we decided to make it as a key secondary endpoint. And we worked with the FDA in order to be aligned with what we will be exploring, and it will be an endpoint that will be part of the Phase III study.

P. Kent Hawryluk, CEO

Yeah, and 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. And I think that really indicates, you know, satisfaction with once-weekly CANVU. And this is just consistent when we speak to the patients. They want to reclaim their freedom from the daily burden of their disease, you know, 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. So we're really excited about the Phase 3 and on track for beginning enrolling next quarter. And it's very helpful to run the Phase 2 to confirm the study design.

Operator

Thank you. Ladies and gentlemen, our final question this morning comes from the line of Kripa Debra Fonda with Truist Security. Please proceed with your question.

Kripa Devarakonda, Analyst — Truist Securities

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 CRM calcium outside of just the last week throughout the OLE. That's one question. And then, you know, you talked about your market research, which suggests that ACPs would switch a large majority of patients over time. Do you have any sense of, if a patient is already stabilized on your repath, you still have the weekly benefit. So what would be a specific clinical trigger a doctor would use to justify a switch to once-weekly cannoparathype?

P. Kent Hawryluk, CEO

Thank you, Karepa. I'm going to ask Sam to address the first part, and then we are joined by Mark Swate, our chief commercial officer, and he will address your market research question.

Sam Azoulay, Other

So we had a really thorough review of the data, and we can confirm that there was no use of PRN in the last week of the evaluation. And 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. And obviously no use of vitamin D at all. So that was a very strong criteria. So that's why we were pleased to report that the same thing for the Avel study and the open-label extension, we didn't have any use of PRN until last week.

Mark Swate, Other

Yeah, and Krupa, this is Mark. Just to build on the point about physician preference, you know, indeed, you know, if the OrbitPath is approved, really it would represent, frankly, a new standard of care.

P. Kent Hawryluk, CEO

Once weekly can be fair.

Mark Swate, Other

That's what I was going to say, exactly, once weekly. And 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. And same with patients. And for those patients that are already on PTH treatment, what we heard very clearly is the vast majority would also be switched over time. And I think your question is, what would be those triggers? Well, I think Dr. Collins pointed to some of those. There is daily 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. So, again, we see, you know, a large portion of those patients switching over time, as we said. And I think, you know, as physicians and patients get experience with the therapy, if it's approved, we're going to see that dynamic play out very strongly.

Operator

Thank you. Ladies and gentlemen, that concludes our question and answer session. I'll turn the floor back to Mr. Harlick for any final comments.

P. Kent Hawryluk, CEO

I want to thank everyone for participating in this call and stay tuned for more about our Phase III trial.

Operator

Thank you. That concludes today's conference call. You may disconnect your minds at this time. Thank you for your participation.