MBX Biosciences, Inc. ($MBX)

Greetings, and welcome to the MBX Biosciences Business Update Call. [Operator Instructions]. 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, and thank you for joining us to review the once-weekly cembuparatide 1-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 MVX 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 1-year data demonstrates sustained benefit of once-weekly Canvuparatide 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 Tambo's precision endocrine peptide design to clinical outcomes and provides important reinforcement of our Phase III 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 Cambo from its inventor, Dr. DiMarchi a clinical perspective on the HP landscape and unmet need from Dr. Michael T. Collins. A presentation of the 1-year data from our CMO, Dr. Sam Azoulay, and will be followed by concluding remarks and the Q&A session. I will now turn it over to Richard.

This is Richard. Thank you for the invitation to participate on coming to you from my office in the chemistry building at Indiana University, where I had been for the last 23 years. The next slide in this presentation, first in my section, captures a century of progress in peptide therapeutics, reaching back to that landmark discovery of animal-sourced human insulin and focus is 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 chemist had optimized antibiotics, oncolytics, anti-hypertensives. It was something that was viewed with some skepticism in the large molecule community, macro molecules, peptides, proteins and Life Pro 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 data medicine. Forteo, the N-terminal 34 Mino acid fragment of the endogenous parathyroid hormone was registered as a bolus administration, sharp up, down within 1 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 2 decades using chemistry to achieve something that could not be achieved with the native home. Byetta twice a day, the too once a day trulicity the first effective once-a-week treatment for type 2 diabetes and then on into Ozempic, Zeon 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 say isolation for extending the duration of action and the Novo Corporation deserves the lion's share of the credit for having advanced this through insulin into the incretins that we know so well. Its 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 prodrug 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, glucose, 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 and getting on to the biology of the 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 Canvuparatide MBX-2109. As I remember, is a peptide that we produced here in Bloomington, it is a peptide that is fatty isolated at both ends, the end 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 end terminal fatty acid to be hanging on to a dipeptide that will cyclase to a cyclic a dipeptide a diketopiprasine and leave 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 committing that we're going from an inactive substance to an active substance. The conversion is intermolecular. And the importance of that is that it's concentration independent. Not going to vary, dependent upon where you are in your circulating concentration of this prodrug. That cyclization, the time action in the conversion remains constant and what controls it is temperature in PH, which is virtually in variant in a chemical sense because it's physiological temperature in PH. And you cannot vary that much and still maintain vitality. And so that cyclization is where the magic is. It controls the verse 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 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. My name is Michael Collins. I'm an endocrinologist, a special volunteer and senior clinical adviser 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 2 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 fall, depression kidney disease and even an increased major adverse event risk. Hypoparathyoidism typically onsets at around 40 to 65, in most cases are caused by Nester. About 25% of them caused by other causes shown here. By definition, chronic hypoparathyroidism is defined type of 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 function with 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. 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 health care 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 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 that patients have to take a day and the burden that this imposes. And with this goes along with stated in these quotes here, if I go without my meds, it 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 a 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 the 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 AVAIL, we know there is compelling efficacy with Canvuparatide to confirm the tolerability and then determine the starting dose. So Canvuparatide really has demonstrated positive 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 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 has 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 that restores phone turnover and it frees patients from daily disease management. Once leuki Canvuparatide really does have the potential to be the new standard of care with patients for hypoparathyroid Market research has shown that health care professionals would switch PTH treated patients to Canvuparatide. They would start naive patients in Canvuparatide, and patients also would choose once weekly Canvuparatide 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 hyperthroid is a damaging disease. There are a lot of patients in the U.S. and EU. We've been showing -- we've seen that Yorvapath validates the need and acceptance of PTH replacement, but there are significant gaps. When 1 with Canvuparatide has the potential to set a new standard for treating chronic hypoparathyroidism, the majority of health care providers and patients would choose once we see amdoparatide. And with that, I'll turn it over to Dr. Azoulay the Chief Medical Officer.

Good morning. I'm Sam Azoulay, Chief Medical Officer -- and I'm absolutely delighted to present the 1-year result of the 1-year open-label extension of the AVENT study. which is, in fact, the first study to evaluate the safety and efficacy of the weekly Canvuparatide in patients with hyperthyroidism. Let me remind you about the design of the EVENT study, which enrolled adults with high proprietary is. We were receiving calcium supplementation, determine the supplementation at a stable dose and who had albumin-adjusted calcium in the range of 8.2 to 10.6 milligrams per deciliter. Patients were randomized 41 to treatment with Canvuparatide, a starting dose of 40 micrograms, 600 microgram, 800 micrograms or placebo once weekly. During the first 4 weeks of the 12-week treatment period, study medication doses were maintained at the starting level. Beginning at week 5, those adjustment was permitted at 200-microgram increments, as needed on a 2-week interval. The maximum Canvuparatide dose range from 1,200 to 1,600 micrograms, depending on the study participants starting dose. After completion of the 8-week dose adjustment period, patients were eligible for an open letter 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 activity and reduced oral calcium supplement to a maximum of 600 milligrams 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 Canvuparatide treatment. Patients originally randomized to Canvuparatide could continue active treatment while patients originally randomized to placebo crossover to Canvuparatide with those adjustments allowed to achieve and maintain therapeutic benefit. In addition to responder rate at 1 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 expansion reflect a different treatment settings at the parent study. With patient transitioning from weekly clinic-based administration and also monitoring during the 12-week parent study, 2 home administration and follow-up assessment every 4 to 6 weeks starting around week 14 of the open-label extension. Today, I will review the 1-year results from the ongoing open-label extension highlighting the efficacy, durability and physiological effects of the once-weekly Canvuparatide over time. Now shown here are the baseline demographics and clinical characteristic for the Avail study parties. In this presentation, all data for Canvuparatide will reflect the pooled analysis of the 3 dose groups and comparison will be for this pool Canvuparatide versus placebo. Overall, the demographics and clinical characteristics were representative of the population of patients with HP proprietary is and similar across the 2 groups of full contuparatide and placebo. It's a very important point. As expected, the majority of patients enrolled in this study were female with long-standing post-surgical HP with a mean duration of more than 9 years for the disease. Calcium and vitamin D supplement doses and serum parameters, including calcium, where within the expected range. All along the study, the retention of patients was very, very high. Notably, the steady retention rate was high in the Avail study with 100 and 64 per patient, 64, the 64 patients included completed the study. 60 of these patients choose to continue into the open-label extension corresponding to a 94% of the patient pool. At 1 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 a primary composite endpoint against placebo. It is important to note that these results were achieved without the use of any PRN. At 1 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 stage. 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 control clinical setting. Taken together, this finding supports the potential of once-weekly Canvuparatide to provide durable benefit of the 1-year treatment period. To help to place this result in context, this slide summarizes selected primary efficacy outcome reported for VPAs in this Phase II program alongside the concept data presented today. While cross-trial comparisons should be interpreted with Cogent, the overall efficacy profile observed with once weekly unduparotide compared savorably with a currently approved PTH replacement therapy with comparable data at 1 year. The TV station is at Canvuparatide achieved these results with a once-weekly dosing regimen compared with the daily administration required for Yorvpath. This supports our goal of providing a convenient and differentiated PTH replacement option for patients with chronic hypopara -- 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 2 to 3 days, and we had minimal fluctuation throughout the dosing interval with a big 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, MIN adjusted serum calcium remained in the normal range through 1 year -- in the Phase II study, we also merged SeroCalcium as the Cmax and the trust concentration of Canvuparatide active drug showing a main difference in serum calcium of only 0.59 milligram per DCB. Taken together, this finding continued to support the potential of once weekly Canvuparatide to provide consistent PTH replacement with stable calcium control over time. I'm not going now to look at the year-end calcium. As shown on the graph, patients treated by current priorities, that's the blue bar, the blue in blue, shows a reduction in urine calcium at 12 weeks of the Phase II study which is even more pronounced at while, 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. But in parallel, the serum calcium decrease and fluctuate. While switching to active Canvuparatide, the urine calcium decreased further, while the seriatim this time stays within the normal value. Now we are looking going to look specifically at patients who enter the study with elevated urinary calcium exploration, which is one of the key target population for patients of HP patients. its 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 counterpartied experienced a substantial reduction in mean 24-hour urine calcium from 426-milligram a day at baseline to 229 milligrams a day at week 12, further improving to 188-milligram a day at 1 year in the open label extension. We observed a similar pattern in patients initially randomized to placebo, while urine calcium remain near the upper limit of normal at the end of the parent study, levels declined substantially following crossover to Canvuparatide reaching 106 milligrams a day at 1 year. The particularly striking finding is shown here, patients previously treated with placebo and moving to concept at 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 exploration, you observe change in several biomarkers that are consistent with the expected renal effect of PTH replacement. Through 1 year, phosphate level and the calcium phosphate product decreased. 125 remains with a normal range. And we also observed an increase in GFR over time, consistent with the favorable effect on reloxfunction. Again, taken together, these data provide additional evidence that once weekly Canvuparatide is restoring the physio physiologic PTH activity in the kidneys. Now I'm going to move to the bone biology. This slide shows the effect of once-weekly conduparatide on bone turnover biomarker, CTX, which is reflective of catabolite, bone catabolism, categories P1NP reflective of board anabolism over time, respectively, representative, again, of destruction of the bone and the 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 mark as 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, However, once again, when placebo patients switched to active canduparatide, both biomarkers increased similarly to what was observed in patients treated initially by part. After this initial increase, the market generate stabilized or slightly decreased through 1 year of treatment. That's the profile that you want to see. The overall pattern is reassuring because it suggests restoration of bone turnover RAS and continued 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 BT. And we're 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 density that will be expected for someone of the same age, same sex and values about negative 2 are generally considered within the normal range. As I mentioned on the previous slide, restoration of both remodeling following PTH replacement is expected to influence bone density over time. And therefore, these findings should be interpreted together with a bold turnover biomarker data. What you can see on the 4 different locations, bold location, which was a spine as a total hip, the femoral neck and the radius MINBMD score declined modestly following restoration of bone remodeling and remain within the normal range through 1 year of treatment. Taken together, this finding is consistent with the restoration of bone metabolism and do not suggest any new bond-related safety concern. Looking now at immunogenicity. Immunome was really minimal in both parent study and the open-label extension with a single observation of OT drug antibodies among 59 patients through year 1 -- and notably, the titer of this anti-contratide antibody signal was low and no detect tighter were for the active active PTH peptide. Looking now at the overall safety profile. Most treatment emergent adverse events were mild or moderate in intensity with 5 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 this is absolutely consistent with the patient population with HP, proprietary is 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 conduparatide as a potential PTH replacement rep for patients with chronic hypopara. The results are consistent with restoration of the systemic PTH activity to serum calcium normalization, reduction of urine calcium exploration, restoration of bone metabolism and increase of EGFR, response rate of 57% at 1 year in Dorel is comparable to the Phase II Al 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 enduratide was generally well traded with no new safety signals during the open-label extension. And importantly, the pharmacokinetics support the once-weekly dosing with, as you have shown you, low vehicle trap 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 II -- the Phase III trial is designed as a randomized, double-blind, placebo-controlled study on drawing approximately 160 patients randomized 3:1 to once weekly or placebo. So patients randomized to contupalatide 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 full criteria of normal albumin-adjusted serum calcium, independence from active or calcium or acute supplementation at a maximum of 600 milligrams per day and no increase in contuperatide dose during the final 4 weeks of treatment. The key secondary endpoints include normalization of urine calcium exploration in patients with elevated baseline value while maintaining normal albumin-adjusted serum cat -- and we added the Northsea endpoint, an important one, which is Pro. The 1-year open-label expansion 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 double-blind 6-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 Avail study and the 1-year open-label extension. We strongly believe that this data support the continued development of once-weekly countryparatad 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 1-year OLE data reinforces our conviction that once weekly Canvuparatide is a best-in-class PTH replacement therapy. It demonstrates sustained benefit and hallmark PTH biology and 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 CanboOPhase III study in Q3. We we have cash to fund our operations into 2029, including fully funding our Phase III pivotal trial and precommercial 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 Instructions]. Our first question comes from the line of Seamus Fernandez with Guggenheim Partners.

Great. Just have a couple of questions. If we can first start with Dr. Collins. Dr. Collins, interested to just get your thoughts on the comparison between the clinical comparison that 1 would make between Yorvipath and Canvuparatide effectiveness here. and perhaps improvements that you could see occurring between the Phase II to Phase III results because we did see an improvement in orbit effectiveness as measured 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 Canvuparatide and how you see the opportunity here as impacting patient lives? And 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 600 -- 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.

Well, thank you, Seamus. I'll just lead off briefly and pass it to Dr. Collins and then to Sam. Again, we're just really delighted with our 1-year data. We support the sustained clinical benefit and recall, this is really the first truly long-acting PTH therapy candidate. And our 1-year responder rate really was comparable to the 12-week Avail, which achieved as primary endpoint and to the once-daily ORV Phase II at 1 year based on the confidence interval. And importantly, really the expected PTH effects in bone blood, kidney for a PTH replacement therapy. So really delighted, and I'm really excited to hear Dr. Collins perspective in comparison.

Thank you, Ken, and thank you, Seamus, for the questions. If I can recall them, I'll the first that you asked about is the comparison between the 2. And as you pointed out, this is a dangerous endeavor and 1 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 7 a week to 1, Bill really like that, I think. One of the questions you asked me, which I'll probably turn over to Sam was question, something about the design of the Phase III based on what I think essentially are the learnings from Phase 2. 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.

Thank you, Michael, and thank you, Seamus the question. Yes, I think we also expect to see even better results in the Phase III and because we are learning from Phase II. As I remind, Phase 2 is the learning phase, right? So we -- as an example, what would be the starting dose in the Phase III 600-microgram as we reported, will be the starting dose, and it's a learning from the Phase I -- the big, big difference with the Phase III is that we are going to go ahead with the commercial device. And the commercial device as we 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 with transitioning in the open-label extension to reconstituting 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 sourced of misdosing et cetera. 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 I. So what we experienced in -- 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 been confirmed to be evaluated into the Phase III program at the same, as I said, starting with 600 micrograms.

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 6-month Phase III, we expect to get patients to their optimal dose and very excited to get on with the Phase III shortly.

Our next question comes from the line of Tyler Van Buren with TD Cowen.

Congrats on the data, and thanks for the very thoughtful presentation. Yes, so the 57% response rate at 1 year demonstrates a nice maintenance of response compared to the 63% of 12 weeks, of course. And with that said, can you help us put into context the increased responder rate at 6 months. And overall, the early middle and 1-year responder rates seem to line up fairly nicely with the orvipathPhase II data based upon 1 of your slides. So can you help us understand why that might be a more fair comparison relative to, say, the Urbat Phase III data?

Thank you, Tyler. We do look at our phase to open-label extension, 1-year responder rate as comparable to the responder rate at 12 weeks based on the confidence in our goal of overlays well and as well to the 1-year time point for the Phase II study responder rate for once-daily Yorvipath, but importantly, with our candidate in once-weekly administration. So we do think that Phase I to Phase II makes sense. And the Phase III trial is, of course, different. Your placebo-controlled study. with a 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 it very nicely.

Dr. Colin.

No.

Our next question comes from the line of Michael Yee with UBS.

Great. Congrats on the data. We had a 2-part question. either for the management or for the doctor on efficacy, I know you're 57% decline very much in line with Yorvipath and at the higher end of their 1-year data as well. It came down from the initial 6-month or 6-month data and earlier time points. Can you just qualify how you think that numbers came down whether from actual compliance factor issues or what you know about the patients who are responders at 6 months and then were nonresponders 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 III 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, maybe you have some insight into what happened with the people who were hypocalcemic during the open-label extension portion.

Yes. Well, thank you, Mike. We're very excited about the data, too. And 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 and 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 III, we will have the pen and we'll 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.

Yes. Thanks, Mike. I think that the point that Ken made about the monitoring, the frequency of monitoring, but also the patient preparing at home and instead injective is certainly a source of -- certainly impacted hypocalcemia level. And then I can give you just 1 rationale is a percentage of patients with hypocalcemia during this period where they were self-injecting was 53% patients with hypocalcemia were cell 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 3-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 1 additional comparison with a via had in Phase II their commercial device, and we will have a commercial device in Phase III. And again, I'm very highly confident that this number will drop.

Our next question comes from the line of Roger Song with Jefferies.

Great. Congrats for the data for the 1-year durability -- maybe I will move on to the PD marker for the siren calcium, very helpful, you gave us the peak trough ratio and the differences. Just want to clarify this 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 12, is that a standard error or it's a standard deviation?

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

Yes, the 0.9 on the Slide 24, I believe, it is a peak trough difference.

Excellent. So really, what we have established 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. Calcium difference, serum calcium difference, which is not only stable, but very normal physiologic fluctuation. And the second part of your question ports not.

1.2 is the standard there are.

Very good.

Our next question comes from the line of Annabel Samimy with Stifel.

This is Jack on for Annabel. So 2 from us. So what percent of patients reached the top dose by year 1? And could they have potentially remained under dosed as in -- did you see patients uptide trading consistently throughout the year and then getting capped at 1,600 -- or did you see patients getting their target dose relatively early and staying there? And then on bone health, the trended DMD looks like it's getting a bit closer to normal limits, particularly in the radius what are your kind of expectations for where that might end up at year 2? Would BMD kind of stabilize at this point? Or would you expect that to kind of continue trending lower without extensions?

Thank you. I'll ask Sam to address your 2-part question.

Yes. The patient can be titrated at any point if the physician thinks that it's needed, and I'm explaining. At the end of the olathe end of the EVAL study, if you remember, just by design, 2 groups couldn't reach 1,600 micrograms. So that when they switch to the open-label extension, it was possible for this patient if they were not responded 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. But for any other reason during the course of the study, patients needed to have a change in the concept that it was possible. And we -- the only thing was respecting the interval of 2 to 3 weeks between the dose increase. In terms of -- you asked a question about the BMD and the question was related to -- yes. Yes. So let me explain the radio first. What the decline you see in the radius, we looked at really in detail starting the baseline start, if you want. And what we noticed is, in fact, the patients who decreased the most are the one to start the highest, so that's exactly what you want, right, to reduce the BMD to ward and trending towards 0. That's what you want to see. And 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. So it's exactly what you -- 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 hike to decreasing towards 0, patients starting low staying where they were. -- 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 we will be a long-term monitoring.

Our next question comes from the line of Jessica Fye JPMorgan.

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 1 that seems stricter than what the company is using clinical trials that I think requires the last 4 weeks to have 0 PRN, 0 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 1-year data and maybe if I could add 1 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, Jess. I'll lead off. So this is a Phase II study, open-label extension. And what we did look at is a 3-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 3-part Phase II endpoint and look at PRN use. During the week of evaluating the primary endpoint, we found there was none, 0 use -- and 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 the study and we'll implement the study to have a high responder rate in the primary endpoints that's been established and aligned with the key regulatory bodies. And in terms of Dr. Collins, can you please respond?

Thank you for the question. So the 2 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 on the lack of a device and the fact that the patients were not using the drug correctly that they had more episodes of hypo calcium and then the dock, 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 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 Mike's thoughts were about the baseline values of bone density in these patients. And I think that they were perfect consistent with what's seen in other studies. I think what we've seen here and has 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. 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.

Yes, I can -- thank you, Mike. I can -- Jess, I can add in terms of the quantity of of vitamin the activity. I mean, it was very low. In fact, the million use was 0.3 microgram per day. So very low.

In those subjects who used the

Yes. And they were responders just equal

Due to the 3 parts component endpoints.

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

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 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 Nox 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.

I'm going to take the first part and let Sam follow up on your multipart question. Again, you have different time points in these studies. And overall, we see comparable results. The primary endpoint for the Phase III is 6 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, 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 III that's going to demonstrate that very, very clearly. So turning it over to Sam on the other parts.

Yes. I think I'm going to start with the hypocalcemia. CFCs exactly with what was expected -- in fact, we had a few patients with hypercalcemia and we had exactly 7 subjects. And no surprise there, I would say. Both the Fok and semi, I think I provided you with the rationale why we got this hypocalcemic 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 event, right? That was the question. And so 1 was related to appendicitis. So obviously not regulated. -- and the other 1 were related to the hypocalcemia 4 episodes. The rest of the epoCat, back to your question, were mild to moderate, and there was no impact, didn't last long, in fact, didn't last long. And in fact, very few discontinued hypocalcemia or hypercalcemia, so in fact, 0 patients continued for hyper. So overall, I think that we think that this hypocalcemia, will be absolutely manageable and will be manageable in the rest of the study.

our next question comes from the line of Jon Wolleben with Citizens Bank.

Congrats on deal. 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 1.

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

Yes. I think for the top doses, I can tell you that we had patients up to 1,600 microgram. And as I told you, the median dose was 1,000 microgram. -- 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 SF-36 and some of the component of the question. However, we did not have enough patients at baseline to be able to draw a conclusion especially against placebo. So what we are going to do is learning learning for Phase III. And we are so confident in these parameters and PROs that we decided to make it as a key secondary end point. And we worked with the FDA in order to be aligned with what we'll be exploring and it will be tenant that will be part of the Phase III study.

Yes. And I'm 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 1 year. And I think that really indicates satisfaction with once-weekly Cando. And 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 the 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 III and on track for beginning and rolling next quarter. And it's very hopeful to run the Phase II to confirm the study design.

Ladies and gentlemen, our final question this morning comes from the line of Kripa Devarakonda with Truist Securities.

Congratulations on the data. You noted that there was 0 contribution from rescue therapy in the last week of the treatment period. I was wondering what -- if you can talk about trend calcium outside of just the last week throughout the OLE. That's 1 question. And then you talked about your market research would suggest that HCPs would switch a large majority of patients over time. Do you have any sense of -- if a patient has already stabilized on your path, you still have the weekly benefit. So what would be a specific clinical trigger doctors would use to justify a switch to once weekly Canvuparatide.

Thank you, Kripa. I'm going to ask Sam to address the first part, and then we are joined by Mark Swad, our Chief Commercial Officer, and he will address your market research questions.

So we had -- thanks, Kripa. 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 milligrams of calcium at any point during the week. It was not an average, it was at any time. And obviously, no use of vitamin at all. So that was a very strong criteria. So that's why we were pleased to report that the same sense for the AVL study and the open-label extension, we didn't have any use of parent last week.

Yes. Kripa, this is Mark. Just to build on the point about physician preference, indeed, the path is approved, really would represent, frankly, a new standard of care with weekly I was going to say exactly a once weekly, and when we presented this to physicians, to patients as a TPP, what we saw very clearly is for new -- newly diagnosed patients that are PTH naive, the vast majority of physicians said that would become the preferred choice. And staying 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 a injection [indiscernible]. 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 a large portion of those patients switching over time, as we said. And 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.