Ladies and gentlemen, greetings and welcome to MBX Biosciences conference call. Today's call is being recorded, and all lines have been placed on mute, and all participants are in listen-only mode. The question and answer session will follow the formal presentation. As a reminder, this conference is being recorded. It is now my pleasure to turn the call over to MBX Biosciences Senior Director of Investor Relations and Communications, Jim Deneen.
Thanks, Rod. Good morning, and thank you for joining us this morning to review the exciting top-line results from our AVAIL Phase II clinical trial. I'm very pleased to report that earlier this morning we issued a press release announcing positive results from our Phase II trial of once-weekly candiparatide in patients with hypoparathyroidism, as well as six months' results from the ongoing open-label extension study. The press release and presentation slides are available on our website. Before I turn the call over to our speakers, I want to remind everyone that this presentation includes forward-looking statements. These statements are based on current expectations and projections and are subject to risks, uncertainties, and assumptions. I encourage you to review the risk factors and other disclosures outlined in our most recent SEC filings, all of which are available on our website.
Joining me on the call today from MBX Biosciences are Kent Hawryluk, CEO and co-founder, Dr. Sam Azoulay, CMO, and Rick Bartren, CFO, who will be joining for Q&A. I'll now turn the call over to Kent.
Thank you, Jim. Good morning and welcome. Today we are thrilled to share positive top-line results from our AVAIL Phase II trial. The results exceeded our expectations and reinforced the potential of once-weekly candiparatide as a best-in-class treatment for hypoparathyroidism. We took a peptide, PTH, with a natural half-life of an hour and engineered it into a therapy that can be given once weekly. This is a powerful demonstration of our precision endocrine peptide, or PEP platform technology. Today marks a seminal moment for the company and the patients we serve. We committed to provide 12-week results this quarter. Due to the rapid enrollment of the trial and the high rate of patients choosing to continue into the extension study, in today's update we are able to include six months' results alongside the 12-week double-blind portion.
These data offer a comprehensive picture of once-weekly candiparatide's clinical profile and provide a strong foundation as we plan for Phase III and ultimately registration. I know you're eager for the data, so let's begin with the top-line results shown on slide 4. These results are exceptional, and they redefine what's possible for patients in our PEP platform. At week 12, 63% of patients receiving once-weekly candiparatide achieved the primary composite endpoint, compared with 31% who responded on placebo, representing a statistically significant difference. Importantly, every patient completed the 12-week study, and 94% chose to continue into the open-label extension. We view this exceptionally high rollover as a clear testament to patients' enthusiasm for continuing their once-weekly treatment. In the ongoing open-label extension, overall responder rates increased to 79% at six months, highlighting the consistency and potential durability of response with once-weekly candiparatide as doses are optimized over time.
At week 12, urine calcium excretion was reduced in candiparatide-treated patients with elevated baseline values, highlighting the therapy's ability to help restore calcium balance. We also saw increases in bone biomarkers in candiparatide-treated patients at week 12, with continued improvement at six months, which is consistent with reestablishing normal bone physiology. Once-weekly candiparatide was well tolerated in the 12-week trial, with no treatment-related serious adverse events or discontinuations. Together, we believe these results underscore the potential of once-weekly candiparatide to establish a new standard of care for adults with hypoparathyroidism and strongly support advancement into Phase III development. Before diving deeper into the results, let's review the disease background. As shown on slide 5, HP is a chronic condition with significant unmet needs that affects over 250,000 people in the U.S. and EU combined.
The disease is caused by a deficiency of parathyroid hormone, or PTH, most often due to inadvertent removal of the parathyroid glands during neck surgery. Because PTH is responsible for maintaining calcium homeostasis in the blood and in tissues such as nerves and muscles, its absence disrupts multiple systems. It is important to note that acute symptoms and long-term complications, which include kidney stones and chronic kidney disease, arise both from PTH deficiency itself and from the standard of care. Turning to slide 6, due to the limitations of existing treatment options, patients on standard of care do not have restoration of the body's natural physiology and may experience large swings in serum calcium. Conventional therapy is burdensome, requiring patients to take pill supplements frequently throughout the day and night. A PTH replacement therapy was approved in 2024 but requires an injection every day.
In contrast, candiparatide is designed as a potential once-weekly, best-in-class, long-acting PTH replacement therapy with continuous infusion-like PTH exposure. Increasingly, we're seeing in multiple therapeutic areas, such as type 2 diabetes and obesity, that patients and prescribers rapidly adopt the weekly treatment option for both its convenience and its improved real-world outcomes. We believe once-weekly candiparatide can offer these same advantages. I will now turn it over to Sam to go over the results from our Phase II AVAIL trial and ongoing open-label extension study.
Thank you, Kent. Let me start first by telling you how excited I am to share these results with you. I will begin with an overview of the AVAIL Phase II trial design and open-label extension study. The AVAIL trial was a randomized, 12-week, double-blind, placebo-controlled Phase II study designed to establish the optimal dosing range and titration strategy for Phase III while also assessing the efficacy and safety of once-weekly candiparatide. Eligible patients were adults with a confirmed diagnosis of HP for at least six months, who required conventional therapy consisting of activated vitamin D plus calcium above pre-specified minimum threshold levels. After an optimization period, a total of 64 patients were randomized and equally distributed into one of four treatment arms, once-weekly candiparatide starting at 400, 600, or 800 micrograms or placebo.
The 12-week blinded treatment period consisted of a four-week fixed dose period followed by an eight-week dose adjustment period where patients could adjust their dose every two weeks in a 200-microgram increment up to a maximum of 1,600 micrograms depending on their starting dose. Throughout the 12 weeks, patients could also receive conventional therapy as needed to maintain normal serum calcium by following a pre-specified titration algorithm. The primary composite endpoint was a proportion of responders at week 12, which is defined on the slide. Select secondary and exploratory endpoints are also listed and will be discussed in more detail today. All 64 patients completed week 12 and 60 elected to continue into a two-year open-label extension study. We view this as a strong indication of both patient interest in remaining on the once-weekly candiparatide and the favorable profile observed in the study.
The objective of the open-label extension is to evaluate the long-term safety, potential durability of effect, and optimize dosing of once-weekly candiparatide as patients continue treatment beyond the initial 12-week study. Turning now to slide 9, we review the patient demographics and baseline characteristics. Overall, the groups were well-balanced across the four treatment arms. The median age was 49 years, and females made up 80% of the study population, which is typical for this indication. Race and ethnicity were well-balanced across groups. Similarly, on slide 10, we have the baseline disease characteristics. The mean duration of HP for the total patient population was approximately 10 years. About 90% of patients had chronic HP in the post-surgical setting, which was one of the two stratification factors, while the remainder had HP from other causes, including idiopathic, genetic, or autoimmune.
At study entry, the median daily calcium dose was 2,000 milligrams, with a wide range from 800 to 13,500 milligrams per day, while the median active vitamin dose was 0.75 micrograms per day, ranging from 0.5 to 2.5 micrograms. These numbers illustrate the high treatment burden patients were carrying at baseline. The mean baseline serum albumin-adjusted calcium was 9.2 milligrams per deciliter in all patients, and mean serum PTH level ranged from 9.2 to 12.1 nanograms per liter across treatment arms, with slightly higher levels noted in the placebo group. These low PTH levels were consistent with the disease. The other stratification factor was patients with 24-hour urine calcium above or below 250 milligrams per day, and fewer than half of patients in the trial had baseline urine calcium excretion above 250 milligrams per day.
Overall, we believe our trial enrolled a very representative HP population, also similar to patients studied in other recent clinical programs. Let's now review the clinical results, which we believe highlight the exciting potential of the once-weekly candiparatide. Here, on slide 12, are the results of the pre-specified primary composite endpoint. At week 12, 63% of patients across all starting doses of once-weekly candiparatide achieved the primary composite endpoint compared with 31% of patients on placebo. This was a statistically significant difference. Patients met this endpoint in the pooled candiparatide treatment group with zero contribution from PRN, demonstrating that response rates were achieved with the once-weekly administration without the need for rescue therapy. When looking at the proportion of patients meeting each individual component of the composite criteria at week 12, all three showed a statistically significant difference between candiparatide-treated patients and placebo.
These results provide strong evidence of once-weekly candiparatide's potential efficacy across these key measures of disease control. On slide 13, we look at responder status at week 12 by starting dose group, which was a pre-specified secondary endpoint designed to explore the dose response. As shown in the table, 50% of patients in the 400-microgram arm achieved responder status at week 12, compared with 69% of patients in the 600 and 800-microgram arms, with the 800-microgram arm achieving statistical significance. In addition, the 800-microgram dose was the median dose for responder at week 12. Overall, these data demonstrate that responder rates were generally higher at the 600 and 800-microgram starting dose compared with the lowest 400-microgram starting dose.
This data not only demonstrates once-weekly candiparatide dose response and a wide therapeutic band range across multiple dose levels, but also helps inform dose selection for Phase III and increases our confidence in identifying the optimal dosing strategy moving forward. On slide 14, we are showing the albumin-adjusted serum calcium level over 12 weeks. It's a key measure in HP patients since maintaining calcium within the normal range is a central goal of therapy. Over time, patients treated with candiparatide consistently maintained serum calcium within the normal range at every visit. Placebo patients trended downward initially, but then leveled out through continued use of conventional therapy. We'll take a closer look at supplement use later in the presentation. We believe these results support the profile of the once-weekly therapy providing stable control.
Now, let's turn to slide 15, which shows the effect of once-weekly candiparatide on the 24-hour urine calcium excretion, which is an important endpoint, as elevated urine calcium is a well-recognized complication of conventional therapy and a major contributor to long-term renal risk. As expected with PTH replacement therapy, 24-hour urine calcium decreased in patients treated with candiparatide, with a more pronounced reduction in patients who entered the trial with elevated baseline levels. In this subgroup, at week 12, urine calcium decreased by 203 milligrams in the candiparatide group versus 117 milligrams in placebo. This reduction in the candiparatide group occurred while maintaining serum calcium in the normal range, with less reliance on conventional therapy compared to placebo. In summary, the 12-week result shows that once-weekly candiparatide achieves a primary endpoint and helps restore the key features of PTH physiology.
Now, we are going to turn to the result from the ongoing open-label extension study. At six months in the open-label extension, 79% achieved responder status, an increase from 63% observed at week 12 in the blinded portion of the study, which is a terrific result. Patients who had already been receiving candiparatide continued at their last assigned dose, with the option for further titration if needed, while those previously on placebo started at 400 micrograms once weekly and followed the same titration algorithm to reach their optimized dose. Now, I'm going to break it down by component. 90% of patients gained independence from active vitamin D, 81% gained independence from therapeutic doses of oral calcium, and 95% maintained adjusted serum calcium within the normal range.
The results of the individual components were comparable or higher than what we observed at week 12, providing highly encouraging evidence of the potential durability of once-weekly candiparatide over time. On slide 18, you can see changes in serum calcium levels from the start of the AVAIL Phase II clinical trial through month six in the open-label extension. Calcium levels were in the normal range in both the candiparatide and placebo groups before treatment. As we have already shown, candiparatide-treated patients maintained normal serum calcium through 12 weeks. In the extension, those patients continued to maintain stable calcium at six months, supporting the durability of once-weekly candiparatide beyond the initial treatment period. In the placebo group, calcium levels declined early and remained low through week 12, despite ongoing use of active vitamin D and calcium supplements.
However, after switching to candiparatide in the open-label extension, shown in light blue, serum calcium levels in these patients increased to well within the normal range, demonstrating a direct effect of once-weekly candiparatide in restoring physiological calcium control. This occurred while active vitamin D and calcium supplements were gradually decreased or discontinued, which we'll review on the next slide. On this slide, slide 19, you can see the changes in the active vitamin D dose and total daily calcium dose from the start of the Phase II study through six months in the open-label extension. On the left, in the candiparatide-treated group, active vitamin D dose decreased rapidly within the first two weeks, and nearly all patients discontinued use altogether. In contrast, a substantial proportion of placebo patients were still taking active vitamin D during the 12-week period.
Upon crossing over in the open-label extension at the starting dose of 400 micrograms of candiparatide, those patients were able to decrease active vitamin D and ultimately discontinue. On the right, you see a similar pattern for calcium supplements, with patients on candiparatide reducing their daily intake, while placebo patients required a higher dose until they transitioned into the extension. Overall, this result demonstrates the durability of effect of candiparatide in both patients who started on therapy and those who switched from placebo, maintaining normal serum calcium while greatly reducing the heavy pill burden of conventional therapy. One final result I would like to highlight here on slide 20 is the effect of once-weekly candiparatide on bone health in patients with HP. As a reminder, in the absence of PTH, the skeleton cannot properly release calcium and phosphate. This leads to abnormally low bone turnover.
Here, we are showing three markers of bone turnover and formation over the 12-week double-blind period and through six months into the open-label extension. TTX is a marker of bone resorption and overall turnover, while BSP, BFP, and P1NP are bone formation markers. The blue line represents patients treated with once-weekly candiparatide and includes patients who crossed over from placebo after 12 weeks. What we observed is a substantial increase in all three bone markers during the first 12 weeks in candiparatide-treated patients in comparison to placebo. This upward trend continued through the six months. We are very encouraged by this finding. They show that once-weekly candiparatide is restoring normal bone remodeling activity, both formation and resorption, which is a hallmark of reestablished PTH physiology and a contributing factor to long-term bone health. Now, let's turn to the safety.
On slide 22, we demonstrate that once-weekly candiparatide was generally well tolerated. As you can see in the top row, 73% of candiparatide-treated patients and 63% of placebo patients experienced treatment-emergent adverse events, with rates that were fairly similar between all treatment cohorts. Importantly, the vast majority of events were reported as mild or moderate in severity and recovered without dose interruption. Approximately half of patients in the pooled candiparatide group and approximately 40% of placebo patients experienced adverse events that investigators considered related to the drug, and I will go into those details on the next slide. There was one serious adverse event in the 600-microgram cohort, a case of Bell's palsy that was not considered treatment-related and resolved without sequelae. Finally, there was no study drug-related discontinuation, no study discontinuation, and no deaths during the 12-week treatment period.
On slide 23, we provide additional detail on the most commonly reported adverse events. This table lists any treatment-emergent adverse event that occurred in more than 5% of patients in any treatment group and at least 2% more frequently than in the placebo group. The most commonly reported events among candiparatide-treated patients were headaches, hypercalcemia, arthralgia, and nausea. On slide 24, we will take a closer look at adverse events of special interest. Starting with hypercalcemia, this was reported in approximately 13% of patients in the 400 and 600-microgram group and 31% of patients in the 800-microgram group, compared with 6% or one patient in the placebo arm. Hypercalcemia is an expected outcome from PTH replacement therapy, and it was also observed more frequently in the highest dose cohorts during the four-week titration phase when patients were still titrating down from conventional therapy. Importantly, none of the cases required hospitalization.
Hypocalcemia was reported in four treated patients, one patient in each of the 400 and 600-microgram group and two patients in the 800-microgram group, compared with three patients on placebo. As expected, nearly all hypocalcemic events occurred within the first weeks of the titration period, again, while patients were still titrating down from conventional therapy. None of the patients with reported hypocalcemia required hospitalization. We are also very pleased to see that injection site reactions were infrequent overall, occurring in 18.8% of treated patients versus 12.5% on placebo. Finally, I would like to close by highlighting safety data from the ongoing open-label extension, and that is so far to date, we are seeing a similar trend as to what we observed in the double-blind study and are highly encouraged by the favorable safety profile.
Taken together with the efficacy results, we believe these data strongly support the potential of once-weekly candiparatide to become a new standard of care for patients with HP. With that, I will hand it back to Kent.
Since our IPO one year ago, we set out to deliver on the promise of once-weekly candiparatide, so it is particularly gratifying to share data that bring that vision to life. These results are very encouraging and reinforce our conviction that candiparatide is poised to be best-in-class. The strong AVAIL Phase II data unequivocally demonstrate that once-weekly candiparatide can generate high responder rates in treated patients. Data from our open-label extension study show the potential of even higher responses on candiparatide as patients are titrated to their appropriate doses. Our results are already competitive to historical studies of an FDA-approved once-daily injection. Hypoparathyroidism is a chronic disease and is a significant unmet medical need. We estimate the U.S. and the EU represent a multibillion-dollar market opportunity, and once-weekly candiparatide is well poised with a best-in-class profile.
The reason we believe that once-weekly candiparatide may grow to be preferred by both healthcare providers and patients is simple. Highly competitive results to date, infusion-like PTH exposure with far fewer injections. Patients don't want to have to think about the disease every day, let alone inject themselves daily. Once-weekly candiparatide can provide freedom by relieving patients from the significant burden of current standard of care and daily injections. Going all in on this program, I wanted to share some of the upcoming milestones. First, we plan to debut our data at the International Hypoparathyroidism Conference being held October 3 to 5 in Texas. We'll be scheduling our end-of-Phase II meeting with the FDA. Additionally, we will be presenting full Phase II data at a major medical conference and in publication.
In 2026, we plan to report 52-week results from our open-label extension trial, as well as begin dosing patients at our global Phase III registration trial. Finally, I'd like to thank the patients and their caregivers, the investigators, partners, and the passionate team at MBX Biosciences who made all this possible. Now, we'll turn the call back to the operator to open up the line for questions.
Thank you. We'll now be conducting a question and answer session. If you'd like to ask a question at this time, you may press star one from your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to withdraw your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we pull for questions. Thank you. Thank you, and our first question today comes from the line of Seamus Fernandez with Guggenheim Partners. Please proceed with your question.
Hey, thanks, guys, and congratulations on the data. A couple of things to just clarify. We get a lot of questions on the placebo response here, and there's also a lot of questions on relative comparisons around that. Just hoping you could help us understand the 31% placebo response. Admittedly, I think the dose response that you see with the 600 and 800 microgram clearly suggests a very wide margin between placebo on your endpoint. Maybe you can just help us understand how you're looking at these data from a comparison perspective versus the YORVApath Phase II data that we have. Really appreciate those data. Again, congratulations. Appreciate the OLE data as well. I think it's important to look at the characterization of the response when you kind of convert from the OLE.
Last question is just, what other opportunities might you have to improve upon the response rate in the Phase III? I think 79% in the OLE would suggest that that's going to be a little bit challenging to improve upon. How do you think about Phase III design? Is it identical to this Phase II, or are there other nuances that you could bring to the table to perhaps improve the response or even improve upon what's already a great safety profile? Thanks.
Thank you, Seamus. We are very happy with our statistically significant results at week 12, despite the placebo response. As you point out, the fact that the response rate in the treatment group increased further at six months, we believe, confirms the potency of candiparatide in this patient population. The placebo group was higher than originally planned, but it's not unusual, noting the small sample size. There is also a precedent in hypoparathyroidism. The daily injectable showed a placebo response of 27% in Phase II, which reduced to 5% in Phase III, and we would expect that trend in our Phase III study. That said, it's an important question, and our team has looked very closely into it. I'll ask Dr. Sam Azoulay to provide some more color.
Yeah, thank you, Kent. We also checked our results with four experts and authors of the hypoparathyroidism guidelines. After looking at the baseline characteristics and the responder rates across the different arms, we decided to perform a sensitivity analysis, including patients with PTH less than 20 pg/mL before treatment. Patients with low PTH are usually considered as more severe than patients with inappropriately normal PTH. A PTH above 20 pg/mL indicates some residual PTH secretion, also not sufficient to maintain serum calcium levels in the normal range for a long time. When you apply this criterion, we identified a total of eight patients, three in the placebo group, five in the treatment group, that were excluded from this sensitivity analysis.
Excluding these patients from both groups, the placebo response declined to 15%, and the candiparatide-pooled responder maintained a robust response at 60% at the 12-week time point, which is highly statistically significant, with a p-value of less than 0.01. The active-to-placebo difference was 45%. We also carried over this rule into the open-label extension study and excluded those eight patients, and our responder rate was still very strong, with 76%. We believe that, I mean, really, this sensitivity analysis strengthens our primary analysis and confirms our conviction in our results. It's also a learning for Phase III, in which these patients will be stratified between treatment and placebo to ensure equal distribution. That was one of the learnings already from the Phase II.
Just on that Phase III. Oh.
The Phase III, the possibilities, you know, is it, you know, do you see any need changes in Phase III that would be necessary other than just sort of the stratification you talked about? Is there a possibility of perhaps even titrating weekly, or does that put too much of a burden on the clinical trial or the population? Certainly, I could see a faster response rate being achieved if you were to titrate or allow for a titration after four weeks that was a little bit faster.
We really don't see the need to change to a more rapid titration at this time. We're evaluating the data, and we'll be finalizing our Phase III study design following the anticipated end-of-Phase II meeting with the agency. I'd also like to point out the very high responder rate we got from the placebos after they, if you will, crossed over following the 12-week AVAIL Phase II clinical trial, with 14 and 15 becoming responders by the end of the analysis we did at six months. We are really encouraged by these results.
Seamus, it's a dose finding study. This Phase II, so we'll be looking at every detail and apply the learning to the Phase III program just to make sure that here we are delivering the top-line result, but we'll be looking at all in order to optimize the Phase III program.
Great. Thanks so much, and congratulations. The sensitivity on the placebo was also super helpful. Appreciate that.
And great.
The next question comes from the line of Jessica Fye with JPMorgan. Please proceed with your question.
Hey, guys. Good morning. Thanks for taking our questions. I had a few here. First, can you please clarify the definition of PRN calcium used in the trial? My specific question is, if a patient had reached a daily calcium dose of zero and then they took 300 milligrams of calcium, would that be a PRN event even though the daily dose was still under 600? Does the same definition apply to the six-month open-label extension data? What, if any, was the contribution of oral calcium to the six-month open-label responder rate? I have a follow-up. Thanks.
The PRN was initially defined as more than one day of use of any vitamin D or calcium supplement for a total dose of more than 600 milligrams a day. However, we went one step further and looked at any use of anything during the week of the evaluation, and patients didn't take any additional calcium or any vitamin D during that period. We went, it's really being very, very conservative and going very strict in terms of use. We are very pleased to report that none of the patients took any PRN or any calcium supplement or vitamin D during the last week.
Is it the same definition for the six-month data, and was it also zero contribution to the six-month responder rate?
It's a similar thing in the open-label extension, and we are looking in more detail in the results because the patients are seen a little bit less frequently, right? We can guarantee that what we observed in the Phase II, 12-week, will be reproducible and reproduced into the open-label extension.
Right. PRN is not driving our response in this trial.
That's the key message.
Thank you.
Okay. Just a couple of follow-ups were, what does the PD data look like over the dosing interval? I think you took measurements at Cmax as well as troughs. How does the hypercalcemia rate look over the six-month OLE? Are you seeing less of that as the trial goes on, like less in the second three months than in the first three months?
It is an ongoing trial, Jess. As Dr. Sam Azoulay said, we're seeing similar safety in the open-label extension, and as you would expect, as more patients are normalized and we provided the calcium, the serum calcium measures are in the slides. Sam, you're welcome, man.
Yeah, the retention rate is pretty good. Also, something to confirm that the patients feel good about candiparatide. That's a good sign.
Great. The PD at max and trough?
We didn't see anything that will be of concern. In fact, we saw that serum calcium stayed within the normal fluctuation and didn't create any episode of hypercalcemia, etc. When we looked at hypercalcemia, there was no pattern in terms of when the hypercalcemia happened during the week. It was not particularly a certain day during the week. It was at any point, could happen.
Overall, I had a low occurrence of hypercalcemia in the trial.
Great. Thank you.
The next question is from the line of Roger Song with Jefferies. Please proceed with your question.
Great. Congrats for the impressive data. Thank you for taking the question. Maybe my question relates to the dose response. I think you showed us the 12-week period. Just curious about the open-label extension portion, how the dose response looked like. Another question leading to that is, what's your current thinking about the dose selection for the Phase III, considering this, you know, since the higher efficacy at the 800, but also a little bit higher hypercalcemia? Thank you.
I'm going to start with the dose selection for the Phase III. We are analyzing the results, and it's a dose finding study. The main objective is to find the right dose to start this patient into the Phase III program. We'll be looking not only at efficacy, but also the best tolerability profile, especially when we are decreasing the vitamin D and the calcium supplement. There's more to come in terms of dose selection and finalizing the dose for Phase III.
Got it. How about the dose response for the LE portion?
I'm not sure I understand the question because the 79% referred to the open-label extension dose response.
That's the pooled patients. How about each individual different doses? Starting dose.
As a patient, though, in the open-label, it's a wide range of response. Confirming one thing, that it's some sort of personalized medicine, and every patient will need a different dose level to satisfy their needs. That's what we will be releasing the data later when we will have the full set of information. For now, it's top-line results.
Got it. Thank you.
Our next question is from the line of Jonathan Wallenburn with Citizens. Please proceed with your question.
Hey, congrats on the data, and thanks for taking the questions. Just another one on the Phase III trial design and dose optimization. Wondering if you expect to see kind of an improvement in the hyper-hypocalcemia as you perhaps dose slower or start at a lower dose, given the mention that most of these events happen during dose titration. I have a follow-up as well.
I think that fundamentally with our PEP platform design, we have an excellent TK curve with a peak to trough over a week that's comparable to the competition over a day, and a bit of a self-titration built into our molecule. I think that's reflected in the stable control we've demonstrated and the really strong safety.
I think the initial PK data that we got from the patient also confirmed that the PK we observed in healthy volunteers is similar to the one we observed in patients, for now, a peak to trough ratio, which is also in the same order. This is really good news in terms of comparing healthy volunteers' PK and patients. Very happy with that.
With the six-month data today that we, you know, weren't quite expecting, how do you think about additional disclosures from the open-label study? Is it going to be on a set time period of follow-up, or when you think there's a fulsome update or an opportunity to present? How should we think about additional disclosures, and how do you think candiparatide's profile will evolve over time?
Expect to present 52-week follow-up data on the open-label extension, and we think that our profile is excellent.
Thanks, Ken.
Our next question is from the line of Tyler Van Buren with TD Cowen. Please proceed with your question.
Hey, guys. Good morning, and congratulations on the tremendous data update. Can you just, the zero PRN utilization at week 12, that's clearly very impressive. Can you discuss if that was maintained through the end of the six months in the open-label extension? Was the dose for candiparatide set in the last four weeks of the open-label extension, or were patients continued to be titrated? Second question, just on quality-of-life data, what quality-of-life data are you collecting in the trial, if any, or maybe any anecdotes you've heard from investigators or patients in the trial following treatment with candiparatide?
The PRN available data are not available yet. We'll review those when they arrive and plan to present those at an upcoming meeting. In terms of anecdotes, we've heard very strong interest in our once-weekly drug. I think that's a drug candidate that's reflected in the strong 94% entry into the OLE and the retention as well through the OLE.
Yeah, can I answer? In terms of quality of life, I'm seeing a good testimony of patients being confident in the product is a raise, the % of patients moving from the double-blind to the open-label. 94% of patients moved from the double-blind to the open-label extension. I think it's good, and the retention rate that we observed for PIF is pretty good. In terms of, I can tell you that the PRN in the open-label extension is not driving the result, just to be clear. I think you had another question about changing the dose when moving to the open-label extension. I'm going to get back a little bit to the study design. In the study design, by design, we had four different groups: 400, 600, and 800 micrograms. Only the 800 micrograms could get to the 1,600.
During the eight-week period, you can increase by 200 micrograms every other week. It's four opportunities to increase the dose. When the patients switch to the open-label extension, and if by any chance they are not responding at the time of the switch, they can definitely see their dose increased if needed once again. That's why in the open-label extension, we will see patients taking up to 1,600 micrograms. Does it answer your question?
Yep, thanks so much.
Thank you. Thank you.
Our next question is from the line of Annabelle Simimi with Stephel. Please proceed with your question.
Hi. Excuse me. Thanks for taking my question and congratulations on the data. Just on the prior question regarding the titration during the open-label extension, you mentioned that patients who were at the 800 microgram were the only ones to reach the 1,600 microgram. To what extent did the other patients have to titrate up? Do you have the various % of patients who had to continue titrating up? In other words, do you feel that patients had, for the most part, reached a steady state at 12 weeks, and it was just a little bit of tinkering in the doses going forward? I guess, secondly, during the open-label extension period, the secondary biomarker data were great. I was just wondering if you had any additional biomarker data, the urinary calcium biomarker data and the bone biomarker data, all the way through the six-month period.
If you don't, do you have any sense of whether it remained going in the right direction? Thank you.
To go back to the design and the result, in terms of responders, 63% at the end of the double-blind period were responders, right? This number increased up to 79% at the end of the open-label extension. I think it's down also to continuing to titrate up the patients who needed to be titrated up. I hope that this answers your question. About bone biomarkers, bone biomarkers on the slide, in fact, you see the result at 12 weeks, but also at six months, including the patients who were initially on placebo and switched to treatment. You see that that still continued to improve in terms of all the bone biomarkers, CTX, PA1NP, and on the right, very good right direction and maintenance of the positive effect that we saw at 12 weeks.
Okay. Did you have the same for urine calcium as well at six months?
At this stage, we don't have this result. As I said, we had to make some choices in terms of top-line results. We got them quite a week ago, and we had to really analyze the data as much as possible.
Okay. Got it. Just one other question. You mentioned that you had the sensitivity analysis regarding the stratification of patients based on PTH level. Are you planning on doing that stratification in Phase III, and did YORVApath do that stratification to get the placebo responses lower? Just trying to understand if it's going to be similar design as to what YORVApath did in Phase III.
We are going to analyze in depth our Phase II data and look at what could influence furthermore, even from the sensitivity analysis that could influence the placebo response and adapt it and include this potential modification into the Phase III. As I said, the PTH is a good marker, and it would make sense to stratify. It's likely that we'll be doing it.
In general, we'll be looking to the precedent of Phase III studies in this disease, not really thoughtfully inventing the wheel.
Okay, got it. Great, thanks a lot.
Our next question is from the line of Trevor Allred with Oppenheimer. Please proceed with your question.
Hey, everybody. My congrats on the data as well. I've got a few questions. First, is there anything you can share about the active dose levels where we saw AEs? Since we're titrating here, were these presentations seen above 800 micrograms? Also, can you give us any detail on what the placebo response rate might be if there was no PRN use there? Can you also clarify PRN criteria was only for the last week?
PRN criteria was for the last week of the evaluation because patients could be titrated up to week 10. We thought that it was appropriate to look at PRN the last week of the period at the time of the evaluation, if you want. The placebo were not, I mean, they were not responded for most of them, 70% of them. The PRN use was not interesting as an information. We looked also at the five patients with placebo, but I don't remember if I had the PRN use or not. We looked mainly into our active treatment.
Got it. Is there anything you can share about the active dose levels where we saw some of those AEs? Were they seen above 800 micrograms?
Yeah, the AEs happen mostly during the titration period, mostly because that's why you see it at 800 micrograms. When you start decreasing the calcium supplement and vitamin D, it may not be fast enough when you start a higher dose. That's the reason why we observed this hypercalcemia at the time of the titration and with the 800 micrograms. That's the rationale behind.
Got it. Okay, thanks for taking my questions, and congrats again on the data.
Thank you.
Thanks, Tyler.
Our next question is from the line of Uri Ear with Mizuho Securities. Please proceed with your question.
Hey, guys. Yeah, thanks. Congrats on the data, and thanks for taking our question. I guess one question that we've gotten is, could you sort of help us clarify the proportions of patients that may be titrated up and those that titrated down in the study? The second question that we have is, you know, I guess you expect to meet with the FDA. Maybe just sort of help us understand the timeline to that meeting. Thanks.
Okay. I don't know if the proportion of responders exactly is the exact proportion of responders, but I can tell you already that most of them were titrated up. You can see in the table, you can see that the extent of the dose, some in the 600 and 800 micrograms, if I remember correctly, the dose could go down to 400 micrograms. That's an option the investigator has to not only go one direction, if needed, go the other direction. Clearly, the goal and what we observed is, in most cases, we're titrating up.
We were really thrilled with our positive top-line results and our clear clinical proof of concept for investing class. We are eager to request an end-of-Phase II meeting, and the team is just very energized to go pursue our global Phase III registration studies with a sense of urgency.
Good. All right. Thank you.
Thank you. At this time, we've reached the end of our question and answer session. I'll hand the call back to Kent for closing remarks.
I'd like to thank everyone again for joining us today to discuss the compelling top-line results from our AVAIL Phase II trial. We cannot be more thrilled with the results and look forward to sharing further progress as we continue to advance candiparatide therapy development with the goal of bringing a best-in-class once-weekly treatment option to patients in need.
Thank you. This concludes today's conference. We will disconnect your lines at this time. We thank you for your participation. Have a wonderful day.