Ladies and gentlemen, thank you for standing by. My name is Krista, and I will be your conference operator today. At this time, I would like to welcome everyone to the BridgeBio Pharma Autosomal Dominant Hypocalcemia Type 1 ADH1 CALIBRATE phase III top-line results webinar. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during that time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw that question, again, press star one. Thank you. I would now like to turn the conference over to Dr. Neil Kumar, Chief Executive Officer. Dr. Kumar, please go ahead.
Thank you to everyone who joined this call, particularly those of you joining us for the second time this week. Together with our amazing team, I'm grateful to be able to share with you on behalf of the extraordinary physicians, patients, families, and caregivers involved, the positive phase III data of our CALIBRATE clinical trial for patients with Autosomal Dominant Hypocalcemia Type 1 . As you've likely read already in our PR, today marks a new day for ADH1 patients, present and future. Those who have previously endured lifelong symptoms that include fatigue, brain fog, seizures, and downstream kidney disease, today embrace a new and more hopeful reality that there is a therapy that targets this well-described condition at its source, and in doing so, normalizes pathology in a majority of patients.
Before I set the corporate context for this readout, I want to begin with the most important slide in this document, slide 4. It is once again my privilege to offer a heartfelt thank you to the amazing and inspiring patients and families, advocates, physicians, clinical research staff, and collaborating research partners that made this study possible. A special thank you, and I'll have more to say about this in a moment, to Dr. Michael Collins, whose ideas and passion for serving patients with ADH1 gave rise to this program. As we have hopefully demonstrated in the past, we recognize our responsibility to the community that made our work possible, and therefore plan to move expeditiously to provide this medicine to patients as broadly as possible. Turning to slide five, I'll take a brief moment to provide some corporate context for today's data.
After nearly 10 years, Bridge has generated three approvals, two positive phase III readouts, LGMD2I earlier this week, and today ADH1, along with a wealth of other clinical and regulatory milestones. Our achondroplasia phase III is the next significant top-line readout expected in the coming months. That sits alongside significant ongoing research and clinical work in areas like hypochondroplasia and chronic hypoparathyroidism, which should provide, on a risk-adjusted basis, a reasonable tapestry of impact for the patients we serve and for investors alike. Bridge has been and continues to be an experiment in maximizing the speed of creating as many new and meaningful drugs that have profound impact on patients as possible. It's incredibly rewarding to see our work translating to potential impact at scale.
Turning back to the program of the moment on slide six, I thought I'd make a few final observations that are distinct from those that I shared earlier this week on the LGMD2I program. What is remarkable about both data sets, by the way, is that treated patients aren't simply staving off decline, but are improving, or in this case, fully normalizing their calcium and PTH status. When we speak of cures and therapeutic medicine, this is the type of impact we seek. On this slide, we show how we aim to provide such impact. We often start hand in hand with an academic that deeply understands the mechanism of biology and the needs of the patient population we seek to serve. In this case, we were privileged to work with the aforementioned Dr. Collins, who we had first met in the context of an early collaboration on infigratinib.
Building on his knowledge and therapeutic hypotheses, we rapidly translated scientific insights into a medicine and then proved its worth in a series of clinical trials. As we interrogated and calibrated ADH1, and as the medicine demonstrated a safe and efficacious profile, we also asked, what else can be done for patients with this drug? Many a time, the answer to that question arises from genetics, moving from, say, a homozygous recessive population to a heterozygous loss of function population, or moving from one mutation to the next in the same gene, as we've done in achondroplasia going to hypochondroplasia. In this case, however, the answer came from the physiologic impact of the drug.
Noting that calcium sensing receptor antagonism could be an orthogonal, but potentially safer and more efficacious way to address chronic hypoparathyroidism with an oral ROA, we have been pursuing this opportunity and look forward to initiating a phase III next year. We intend to leave no stone unturned in helping patients with the medicines we make. That is what's to come, and it's all predicated on today, a new day for patients with ADH1. I'll turn it to Ananth and team to tell you more about that now.
Thank you, Neil. I'd like to start by sharing a summary of the top-line results of the CALIBRATE phase III study of encaleret in Autosomal Dominant Hypocalcemia Type 1 , or ADH1. We are thrilled to share that the study met and exceeded all criteria set forth as an upside target based on our learnings from the phase II study. We observed a statistically significant response on the primary endpoint with encaleret, demonstrating superiority over conventional therapy. 76% of study participants were able to achieve target serum and urine calcium within 24 weeks of starting dosing with encaleret. Importantly, among these responders, none required conventional treatment when administered encaleret. Additionally, over 90% of the study participants demonstrated a parathyroid response to encaleret, demonstrating an activity of the molecule in a broad swath of the patients administered the treatment.
Encaleret was well- tolerated, with no discontinuations from the active arm of this study. To put these results in context, ADH1 is a serious genetic condition for which there are no therapies currently indicated. We estimate that the prevalence of individuals carrying variants associated with ADH1 to be approximately one in 25,000. This estimates to about 12,000 individuals in the U.S. alone who may exhibit symptoms and signs of ADH1. This prevalence estimate comes from a triangulation of several general population genetics databases, including Geisinger, All of Us, the UK Biobank, and the Mass General Biobank , which support an estimate of one in 25,000. Of those carrying variants associated with ADH1, we currently believe about 3,000- 5,000 are diagnosed today in the United States, with an anticipated increase with improved recognition of this condition. ADH1 is uniformly driven by activating or gain-of-function variants of the calcium-sensing receptor, abbreviated CaSR.
These variants of the receptor increase its sensitivity to extracellular calcium, leading to dysregulation of calcium homeostasis, causing the parathyroid glands and the kidneys to behave as if the blood calcium concentration is higher than it actually is. As a result, individuals living with ADH1 experience chronic hypoparathyroidism characterized by low parathyroid hormone, low serum calcium, and elevated urinary calcium excretion. The clinical manifestations of ADH1 are primarily associated with hypocalcemia in the acute setting and hypercalciuria, or elevated urinary calcium in the chronic setting. ADH1 patients may experience hypocalcemic seizure, tetany, and neuromuscular irritability, and exhibit calcifications of the kidney due to activating variants of the CaSR. Encaleret is an investigational oral medication from the class of drugs called calcilytics, which act as negative allosteric modulators of the calcium sensing receptor. Through its mechanism of action, encaleret decreases the sensitivity of the CaSR to extracellular calcium.
By correcting the sensitivity of the CaSR , encaleret is theorized to restore PTH secretion, decrease urinary calcium loss, and maintain serum calcium and urine calcium within their respective reference ranges. We designed encaleret on the following three principles, the first of which being that it is the only investigational treatment directly targeting ADH1 at its source. We hypothesize that by targeting the CaSR , mineral homeostasis can be restored in patients with ADH1. Secondly, encaleret addresses the common clinical hallmarks of this disease, namely low parathyroid hormone, low serum calcium, and the associated symptoms of hypocalcemia, and high urinary calcium excretion associated with long-term renal complications. Finally, encaleret is presented in a convenient oral tablet that can be taken by mouth. I will now hand the call to Scott to share the exciting, detailed findings of the study.
Thank you, Ananth. Before I present the study design and share the top-line results from CALIBRATE, I want to take a moment to acknowledge the incredible dedication of the study participants, their families, and the investigators and study staff who made this research possible. Your contributions to clinical research are invaluable. The CALIBRATE study is a randomized global open-label active comparator study of encaleret for the treatment of Autosomal Dominant Hypocalcemia Type 1. The study was run in 25 clinical centers in 10 countries in North America, Europe, Australia, and Japan. The study enrolled patients with genetically confirmed ADH1, biochemical findings of hypoparathyroidism, including hypocalcemia and inappropriately low parathyroid hormone. Patients aged 16 and above were enrolled. After signing informed consent, they entered a 16-week standard of care optimization period, during which time they had calcium and active vitamin D doses adjusted to pre-specified target serum and urine calcium values.
Once optimized, they entered a four-week standard of care maintenance period, period one, during which time doses of standard of care were kept stable. Following this period, they underwent randomization in a 2 to 1 ratio to either encaleret or to remain on standard of care. At the time encaleret was initiated, both calcium and active vitamin D were discontinued. Patients randomized to encaleret were initiated on 54 mg twice daily, and the encaleret dose was titrated based on serum calcium assessments through the dose titration period, period two. Those that remained on standard of care, the doses of standard of care were managed to avoid hypocalcemic symptoms and to minimize urine calcium excretion. Following this 20-week period, they entered a four-week encaleret or standard of care dose maintenance period, period three, during which time doses were kept stable.
Efficacy was evaluated at the end of period three at week 24 by assessing clinically meaningful biochemical parameters, including the albumin-corrected serum calcium, the 24-hour calcium excretion, and intact PTH. Additional measures of 1,25-hydroxyvitamin D, magnesium, and phosphate, bone turnover markers, bone mineral density, kidney function, and quality of life measures were also assessed as secondary endpoints. The primary endpoint was the responder status of individual participants. To be deemed a responder, the albumin-corrected serum calcium and the 24-hour urine calcium excretion had to be in the respective target ranges for each of these objective parameters. This composite endpoint is the first time that a drug is being evaluated to demonstrate both normalization of serum and urine calcium in a clinical trial in this patient population. Key secondary endpoints also included the responder status for individual biochemical parameters. This slide depicts the disposition of the study participants.
70 participants entered period one. 67 of these were randomized with 45 to encaleret and 22 to the standard of care. One participant on standard of care withdrew due to the inability to comply with the study protocol. 66 participants completed period three. One participant in the standard of care arm opted not to enter the long-term extension. Ultimately, 65 patients continued to be followed in the long-term extension. This next slide describes the baseline demographics, and there was a similar distribution in age, sex, and race across the two treatment groups. Among the 67 participants randomized, 46 unique calcium-sensing receptor variants were represented. The baseline biochemical characteristics were similar between the two treatment groups and consistent with the known clinical presentation of ADH1, with hypocalcemia, hypercalciuria, low serum PTH, high normal phosphate, and low normal magnesium concentrations. Approximately 80% had evidence of calcification of the kidneys by renal ultrasound.
The primary efficacy analysis was performed on the group randomized to encaleret, comparing the responder status of both serum and urine calcium at week four when they were on stable doses of standard of care to the responder status at week 24 when they were on stable doses of encaleret. 76% of participants randomized to encaleret met the primary endpoint, achieving both albumin-corrected serum calcium and 24-hour urine calcium excretion in the target ranges, and the difference of 71% was statistically significant from the responder status at week four. A key secondary analysis was performed, comparing the responder status of two treatment groups at week 24, those randomized to encaleret and those randomized to standard of care, and confirmed a statistically significant difference between the two groups. Among encaleret responders at week 24, none required conventional therapy during period three.
In another key secondary analysis evaluating the ability of encaleret to increase endogenous PTH, 91% of those randomized to encaleret had intact PTH concentrations above the lower limit of the reference range at week 24, compared to 7% while they were receiving standard of care at week four. Similarly, the responder status when comparing the two treatment groups at week 24 confirmed a statistically significant result. This is a clinically important point. Encaleret drives the secretion of endogenous PTH by the parathyroid glands and the reabsorption of calcium by the kidneys, both of which are responsible for the physiologic regulation of the serum calcium concentration. We next looked at the impact of encaleret on the individual components of the primary endpoint, namely the albumin-corrected serum calcium and the 24-hour urine calcium over time. First, the serum calcium.
Those participants randomized to encaleret had a rapid and sustained increase in the albumin-corrected serum calcium into the target range, as shown in the blue curve. The serum calcium remained below the reference range for those randomized to remain on standard of care, as depicted in the gray line. The difference in the change from baseline at week 24 versus week four was statistically significant. The difference in the change from baseline was also statistically significant when the between-group analysis was performed for week 24. When we turned to the 24-hour urine excretion, for those participants randomized to encaleret, there was a reduction in the mean 24-hour urine calcium excretion, as observed by the blue curve, while the mean urine calcium excretion was unchanged for those who remained on standard of care, in the gray line.
We observed a statistically significant difference in the change from baseline at week 24 versus week four for those on encaleret. The difference in the change from baseline was also statistically significant when the between-group analysis was performed for week 24. These serum and urine calcium data confirm the restoration of calcium homeostasis achieved when standard of care is discontinued and encaleret is administered over a six-month treatment period. Encaleret was well- tolerated, with no discontinuations in the encaleret arm. The frequency of treatment-emergent serious adverse events was low and similar between the two treatment arms. There were few related serious adverse events. The majority of adverse events were mild or moderate in severity, and the encaleret-related adverse events were generally due to signs and symptoms related to ADH1 or to the mechanism of action of encaleret.
These data that I have shared with you demonstrate that encaleret restores physiologic mineral homeostasis in patients with ADH1. We randomized and evaluated 67 participants with genetically confirmed ADH1 and demonstrated statistically significant differences in responder status in patients randomized to encaleret compared to when they were on conventional therapy. Among the responders on encaleret, none required conventional therapy during the encaleret dose maintenance period. Encaleret was able to meaningfully restore endogenous physiologic PTH secretion when compared to treatment with conventional therapy. Clinically meaningful changes in serum and urine calcium in those administered encaleret were observed at week 24. In general, encaleret was well- tolerated, and the adverse events were expected and consistent with the known mechanism of action. Encaleret has the potential to be a novel and important treatment for patients with ADH1.
I will now turn it over to Mary Scott to discuss the next steps for the program.
The team is looking forward to an eventful year ahead. We plan to continue to engage with the FDA in the coming months as we prepare for an NDA submission in the first half of 2026, and we're targeting submission of a marketing application in Europe in the second half of next year. Because of these exciting and promising data, the team is looking to extend the potential patient populations that may benefit from encaleret. We aim to initiate a phase II/III study in pediatric patients with ADH1 early next year, as well as a phase III study in chronic hypoparathyroidism. Finally, we look forward to sharing results from the CALIBRATE study with the medical and scientific community at relevant conferences in the upcoming year.
Alongside these efforts, our commercial leadership team will be preparing for a planned launch of encaleret, and I will pass it to Matt to provide more details.
With today's positive data announcement, BridgeBio 's commercial engine is poised once again to deliver a blockbuster launch, this time in ADH1. Built on the foundation of the successful launch of Attruby, we will leverage our proven commercial infrastructure to successfully bring encaleret to patients. Our commercial functions, including market access, strategy, analytics, operations, and marketing, are already activated and have been preparing in parallel with Attruby's launch to ensure we are fully prepared for this next opportunity. Our proven launch playbook enables fast and efficient mobilization, allowing us to capitalize on the best-in-class data you heard today and offer patients a therapy that addresses the underlying cause of ADH1, defining the standard of care. We will continue to shape the market by educating on disease state awareness as we prepare for launch.
This will all be done in the backdrop of broad global access as we plan to launch encaleret across the world to as many patients as possible. Our approach is data-driven and highly targeted, leveraging AI and analytics to identify the right patients. Similar to the ATTR-CM market in 2019, ADH1 remains significantly underrecognized, representing a meaningful opportunity to expand diagnosis and treatment. The ADH1 market is also fairly concentrated, with most patients being managed by endocrinologists. This allows us to launch in a focused, cost-effective, and sustainable way. Together, these capabilities allow us to reach patients faster and deliver encaleret with precision and impact. We are also well-positioned from a market access standpoint, with systems and payer relationships already in place to support coverage, titration, and long-term adherence.
This proven infrastructure, refined through our Attruby launch, ensures we can move quickly to secure access for patients while maintaining a high-touch support model for providers and caregivers. As we move closer to approval, we look forward to discussing more of our commercial strategy, but the message for today is clear: BridgeBio is ready, our engine is built, our playbook is proven, and we are well- prepared to deliver another successful blockbuster launch. At this time, I'll turn it over for the Q&A portion of the call.
Thank you. We will now begin the question and answer session. If you would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw that question, again, press star one. We kindly ask that you limit yourself to one question and one follow-up. Your first question comes from the line of Tyler Van Buren with TD Cowen. Please go ahead.
Hey, guys. Congratulations on another stellar phase III data set within 48 hours. The first question is the 76% response rate and calcium curves. They're particularly impressive considering the point estimate is higher in this multi-center phase III compared to the single-center phase II and in a more diverse set of variants. Can you elaborate on the responses and the calcium curves and if they were consistent across the variants and biologically why that might be the case? The second question is just related to the larger chronic hypoparathyroidism indication, if you believe these results are de-risking for encaleret there.
Thanks, Tyler. I'll let Scott address the question regarding the response rate as well as the translatability to the chronic hypoparathyroidism program.
Thank you. Regarding the first comment about the variants, what we've seen is that the variants that are responsive all seem to behave similarly. We get good quality PTH responses. The dose might be different in individual variants, but we do see robust PTH responses and then subsequently see increases in the blood calcium and decreases in the urine calcium. What we've seen to date has been very consistent across all the variants that we've observed. Regarding the chronic hypoparathyroidism question, the phase III study and the phase II study have established that encaleret is a safe medication for patients with hypoparathyroidism. The calcium- sensing receptor is responsible for activity in the parathyroid glands as well as in the kidney.
What we do know from the proof of concept study from a month ago that was presented at the ASBMR is that there are PTH-independent effects of the calcium-sensing receptor that result in low urine calcium and a maintenance of blood calcium. We feel very confident moving forward in the program with chronic hypoparathyroidism, and we're really looking forward to studying patients with that condition.
Your next question comes from the line of Salim Syed with Mizuho. Please go ahead.
Hey, great, guys. Thanks for the question and congrats on the data. I guess one for me on the safety side here, could you just maybe comment on the hypophosphatemia data and perhaps any bone biomarker data that you may have measured? Thank you.
Wade, these are great questions. Just remind the audience that these represent top-line results. We do not have individual line listing data at this time, but I will pass it to Scott to address our overall safety observations with the expectation that more evidence will follow with more wholesome analysis.
Did you ask about hypophosphatemia?
Correct. Yeah, I think it was in your phase II slides, but I didn't see anything.
Yeah.
Yeah, right. Yeah, but not your phase III.
Yes, sir. Certainly, that's right. In phase II, we did see some hypophosphatemia that was transient and related to the dose of encaleret that was administered, and it was reversible upon lowering the dose of encaleret. We did not see very, we may have seen very few hypophosphatemia events during the phase III study, but again, these would be easily managed by lowering the dose of encaleret. We're very confident moving forward that hypophosphatemia is not going to be a problem in the clinical management of these patients.
Salim, I'll just add perhaps one element that Scott alluded to, which are encouraging. The data we observed in this phase III study seem highly consistent with the observations from our phase II evaluation of the molecule. In the reminder from that study, most of the adverse events that were reported were reported early in the titration of the molecule. Once maintenance doses were achieved, these adverse events were resolved with dose adjustment.
Okay. Anything on the bone biomarker data you guys may have measured?
We do not have those data available to us at this time.
Okay. All right. Thanks so much, guys. Congrats again.
Thank you.
Your next question comes from the line of Cory Kasimov with Evercore ISI. Please go ahead.
Great. Good morning, guys. Thanks for taking the question and really quite some streak you're on here. I want to ask, first of all, on your confidence level in the ADH1 commercial opportunity, there's some noise out there about the number of patients as well as the ability to find and diagnose them. Can you speak to the effort that's going to be required here to build this into the billion-dollar-plus market you foresee? A quick follow-up I have is, in your responder analysis, were patients allowed to continue using vitamin D? Thank you.
Okay. Thank you, Cory. There are a few questions there. I'll start with the first, and on the patient opportunity, I would start by saying there are a couple of tailwinds that we described in our webcast last month that provide encouraging data points of where these patients are and the current diagnosis rates. Those being a new ICD-10 code that has been established specifically for Autosomal Dominant Hypocalcemia, wherein the claims data in 2024 alone show over 900 claims attributed to that ICD-10 code, as well as new guidelines that were published earlier this year that recommend genetic testing in all non-surgical hypoparathyroidism patients. I'll pass it to Matt to elaborate briefly on our commercial plans, and then we'll address your latter question on the response criteria on conventional therapies.
Yeah. I mean, I think the way to think about this launch is to expect a gradual but steady launch. When you have a medicine like this that shows these kinds of results, people talk about it. Patients talk about it. Physicians talk about it. Other PCPs talk about it. That kind of discussion creates awareness, and the more awareness there is, the market naturally grows. Of course, we're going to continue to mine the data, but we feel very confident in the commercial viability of this product and that it will be another outstanding launch for BridgeBio .
Okay. Scott, I'll pass it to you on the conventional therapy question as it relates to our response rate.
When patients are started on encaleret, they discontinue their calcium supplements and active vitamin D. With the administration of encaleret, it will stimulate parathyroid hormone. As you may know, parathyroid hormone then has activity in the kidney to activate the enzymes to create active vitamin D in the patients endogenously. With encaleret treatment, patients do not require long-term active vitamin D therapy.
Your next question comes from the line of Mani Foroohar with Leerink Partners. Please go ahead.
A follow-up more on the commercial and strategy part on Tyler's question earlier on parathyroidism. As you think about developing this in that second indication where the availability of options is a little bit different than ADH1 patient populations, everything's a little bit different, how should we think about sort of the cost-effectiveness analysis side, pricing, just the justified pricing and value, and how do you think about commercial strategy given that you're going to be launching plausibly in that indication quite a few years out? Just give a little bit of compare and contrast of the strategy of launching into each of these two indications, given the competitive dynamics are quite different.
Right. That's a great question. I'll let Matt address these points.
Yeah. I mean, I think you know the way to think about it, they are two different launches, but they're related. I mean, you're still, you know, it's all about getting awareness out, both of the different disease states, but also what the medication can actually do. I think the fact that, you know, as of today, we're reporting hitting all primary and secondary endpoints, it doesn't get really any better than that. Yes, we have to go out and educate, but that data alone is going to pull people in. As we move into more indications within that, it's just kind of this natural progression. In some ways, it's nicer to start with the smaller indication because you can get your sales force established, you can get their routing established, kind of work out any kinks that you need to, and then move into the larger opportunity.
If you have your choice, I think this is the way you'd like to do it. I think that just benefits us to make sure that then both launches will go extremely well. I think, you know, in terms of competitiveness, again, the data speaks for itself. I think we have a lot of confidence based on what we've presented today that this medication is going to do extremely well in as many indications as we can get it approved for.
I think there are elements of the evidence side that help bridge that commercial opportunity if we are privileged to expand our indications in the patient population eligible for encaleret. Two points being, one, this would be the only orally administered medicine if we are successful with the broader development in the chronic hypoparathyroidism indication, as well as a consistent safety profile that we've demonstrated, as Scott alluded to, in these patients with ADH1 and the historic development program of encaleret.
Thanks, guys. That's helpful. Congrats again.
Your next question comes from the line of Biren Amin with Piper Sandler. Please go ahead.
Hi, guys. Thanks for taking my questions and congrats on the data. Maybe the first question is, how long did it take for patients in the encaleret arm to reach an optimal dose? Maybe a second question is, what's the read-through on achieving intact PTH above the lower reference range in ADH1 and the read-through to chronic hypo PTH ? Thank you.
Neil, thank you for that question. I'll let Scott address those two questions.
With the administration of encaleret, we've known since early phase I that patients will have a PTH response within 30 minutes of administration of the drug. That's been true for phase II as well as in phase III. Subsequent to the increase in PTH, we see increases in serum calcium within the first couple of days. Within the phase III study, by day three, we saw 71% of the patients had achieved a blood calcium within the reference range. That's very, very excellent data for us. The patients will then continue their titration, and most patients will wind up on their maintenance dose within two to four weeks after starting the drug. Can you clarify the second part of the question that you had, please?
Yeah. You had observed that patients in the trial achieved the intact PTH above the lower reference range. I think it was 91% of patients in the encaleret arm achieved that. I wanted to understand what the read-through of that is to the chronic hypo PTH setting.
Right. In patients with intact parathyroid glands, they will respond, and that's what we've observed. What's really important is that the calcium-sensing receptor expressed in the kidney also has very strong control over calcium reabsorption. We now know that is a PTH-independent process. There is historic data from patients with another genetic disease called familial hypercalcemic hypocalciuria. Those patients had hypercalcemia and hypocalciuria, and they actually were treated with parathyroidectomy in the past. It's interesting because now they had no PTH, but they were able to maintain a normal blood calcium and a very low urine calcium. The expectation, based on the proof of concept data that we shared last month at the ASBMR, is a similar phenomenon. Patients who don't have PTH, we will give them encaleret, which will suppress their urine calcium excretion and be able to maintain a blood calcium. That's the expectation.
We are very confident moving forward in the chronic hypopara space because of the PTH-independent effects of encaleret on the kidney.
Your next question comes from the line of Joshua Schimmer from Cantor. Please go ahead.
Great. Congrats on the results, and thanks for taking the question. Can you talk to the pace at which you continue to identify new ADH1 patients with your efforts? As you identify patients, are you finding that any are already on your path? If so, what percent, and how do you think about the dynamics of perhaps converting them from your path to encaleret and what challenges there might be in doing so? Thank you.
Thank you, Josh. I'll let Matt address your questions around the pace at which we are identifying new patients and the proportion of those patients that may be treated with PTH analog.
Yeah. Hey, Josh. Thanks for the question. You heard probably earlier on, we think that the prevalence is around 12,000 and that we've identified already about 3,000- 5,000 patients. We're not really seeing those patients on your path. I don't think there's a big conversion strategy necessary. I mean, I don't want to say it's not effective, but it doesn't seem like doctors are reaching for that. You know now with specific data in ADH1 patients, I don't think that the convincing will be in terms if this is going to be more of a finding the patients, and then once you find the patients, the data is so good that those patients will then take it. It's like you just it's an identification game more than a switching game. I don't think that's going to be our what we need to do from a commercial front.
I just think slowly over time, especially now with the data out, we will identify more and more of those 12,000 patients. The 12,000 patients arguably should also grow over time because, again, there's now a very good option for patients. When there's not a good option out there, people don't look for patients and they're not really thinking about treating. Now with a great option, people start looking, they get more curious, and that leads to more diagnosis. I think you're going to see just that steady increase over time, both leading to the 12,000 and then expanding the 12,000 to a bigger number.
Qualitatively, Josh, I would characterize that our observation is the rate of diagnosis continues to increase with time and with building awareness around the community. We are observing increased utilization of that ICD-10 code as well as increased utilization of genetic testing to identify patients.
Excellent. Thank you.
Your next question comes from the line of Andrew Tsai with Jefferies. Please go ahead.
Hey, good morning, and congrats too on a solid data set. First, can you give us a teaser on how the harder endpoints looked in the study? Did you look at urgent care visits, hospitalizations, renal endpoints, and anything else? It looks like you do have at least 3,000 patients diagnosed adjustable today. By the time you launch in the first half of 2027, how many patients do you think will be ready to go? Why wouldn't you have direct line of sight to thousands of patients? Thank you.
Thank you, Andy. I'll defer to Scott on the first question regarding our clinical outcome measures in the study, and I'll let Matt address the second question regarding the current patient population.
Regarding the hard endpoints, this is evidence that would require longer-term follow-up. We are continuing to follow patients in the long-term extensions for the renal outcomes as well as for, you know, bone health, like bone mineral density, because those are endpoints you wouldn't see any changes over the first six months. With the effects that we're seeing with encaleret, again, being able to manage the blood calcium and the urine calcium over long periods of time, we are expecting that we'll see benefits in these harder endpoints over time.
For the second part of your question, we already have thousands of patients identified. I think we're well on our way to being able to serve as many patients as possible. You really need an option, not only for patients to be out seeking treatment, but for physicians to be considering looking for that particular diagnosis. Remember now, with the new ICD-10 code, we've also made that diagnosis not only easier in terms of finding those patients and making sure everybody understands what it is they're dealing with, but that helps payers from a specific reimbursement perspective. It also helps with the awareness so that physicians start thinking, "You know what? I should be looking for this because if I find it, I can treat it and I can treat it effectively." I think you're right. I do think the number is going to grow.
We're going to grow it from where it is today and expand the market beyond the 12,000.
Your next question comes from the line of Paul Choi with Goldman Sachs. Please go ahead.
Hi. Thank you. Good morning, and congrats on going two for two this week. My first question is, based on the data you've seen so far, can you maybe comment on whether any subpopulations you're seeing that might inform your enrollment criteria for your planned hypoparathyroidism study? Any enrichment or patient population strategies that you can maybe comment on? Second, your path got a priority review in its FDA application. Are you assuming the same here for encaleret? Thanks for taking our questions.
Thank you, Paul. On the latter question, while encaleret is eligible for priority review based on its fast-track designation and the lack of indicated options for ADH1 today that may be considered, we have not received confirmation nor had the appropriate dialogue with the FDA to confirm that. The first question regarding subpopulations, I'll pass it to Scott to address that point.
With the chronic hypoparathyroidism, first of all, with the ADH1 program, it's not a large enough patient population that we studied that we have subpopulations that identify anything. What I will say with the chronic hypopara study moving forward is that we will be focusing on patients that have hypercalciuria. Again, because of the effects that we're seeing with encaleret, the physiologic effect on the kidney, the focus will be on patients with hypercalciuria.
Your next question comes from the line of Anupam Rama with JP Morgan. Please go ahead.
Hey, guys. Thanks so much for taking the question and congrats on the update. Just two quick clarification questions, if I may. The first is on safety. Can you talk about if there were any dose reductions due to hyperkalemia for encaleret or anything we should be considering there? The second question is, can you just remind us why you compared on the primary endpoint of serum calcium relative to standard of care at week four versus encaleret at week 24 for the primary endpoint? I know in that slide you also say that week 24 responder hits stats for that comparison, but should we be thinking about proportions there that are similar to the primary analysis? Thanks so much.
That's not a problem. On your first question, did you mean hypercalcemia or did you mean to say hyperkalemia?
Calcemia, sorry.
Thank you. I'll let Scott address that first point on safety and dose reductions due to hypercalcemia.
Encaleret is started at a dose of 54 mg twice daily. What we've observed to date is that approximately 75% of the patients wind up on 54 mg or lower. There is certainly titration early on because of hypercalcemia. Importantly, no patient has had to discontinue encaleret for hypercalcemia. We've been able to manage all patients. They might go down to a dose of 4.5 mg, but they're certainly manageable on encaleret.
To your second point on the question of the primary endpoint comparing week 24 to week four, this was a pre-specified primary endpoint as it enables a within-patient control. Given potential heterogeneity in the calcium-sensing receptor variant and the individual response curves to either conventional therapy or encaleret, the within-patient control allows individuals to serve as the control arm for the primary analysis, which enables a more robust and complete comparison to conventional therapy. As you mentioned, the secondary analysis, a pre-specified key secondary analysis, was also met with a highly statistically significant response comparing the response at week 24 of encaleret to conventional therapy.
Your next question comes from the line of Danielle Brill with Truist. Please go ahead.
Hi. Good morning. Thanks so much for the questions. Let me also extend my congrats on the back-to-back wins here. I have two questions, one regulatory, and maybe I'll start with the AEs as a follow-up to Anupam's question. Can you characterize the hypercalcemia AEs that you observed with encaleret a bit more, particularly in period three? Like when did these events typically occur, and is a 22% rate acceptable? On the regulatory front, you guys enrolled patients down to 16 years of age. Is it possible you could get a label that's inclusive of the pediatric population? Could you potentially seek an accelerated approval for peds with the upcoming planned trial serving as your confirmatory? Thanks.
Thanks, Danielle. On your first question, we do not have the complete data on the time points of these reported AEs, but if we look at our phase II data, which maps quite well, these were experienced early in dose initiation and resolved with dose adjustment. As Scott mentioned, we observed that for the majority of patients, maintenance doses were achieved within the first month of initiation. I'll pass it to Mary Scott for the question on the pediatric program. The label. Go ahead.
Yeah. Thanks, Danielle. Given these promising data, I completely understand why you asked the question and why we would love to be able to expand to a broader patient population. What we anticipate is that the indication would reflect the population that we studied in the CALIBRATE study, so down to 16 years of age. This extending to younger pediatric patients, so down to birth, is what we're intending to do by starting the phase II /III study in pediatrics that will enroll our first patient early next year.
Your next question comes from the line of [Jason Szymanski] with Bank of America. Please go ahead.
Good morning. Congrats on the data for the second time this week, and thanks for squeezing us in. Three quick clarifying questions for me, if I may. Regarding safety and tolerability, I know you touched upon hypophosphatemia, but did any other AEs of note arise? Two, just to confirm, in the responder analysis, did patients discontinue using vitamin D? Three, any concerns over the potential for ADH1 to be added to PTH's label? Would it challenge use at all? We ask because the developer there has commented that, wow, the number of ADH patients has been few. They've responded rather well. Thanks.
Okay. On the third point, I'm not quite sure if we've seen any evidence of ADH1 response to PTH in a population level. I don't think that's been prospectively studied or reported. We've seen some case reports, but certainly not a robust comparison in a cohort. On your second question regarding vitamin D in the responder analysis, I'll just remind folks that none of the responders of encaleret, the 76% that we reported at week 24, required conventional therapy with either calcium supplements greater than 600 mg a day or active vitamin D. On the questions on hypophosphatemia or additional AE characterization, I'll turn it to Scott.
During the titration period, we do see some hypocalcemia and hypercalcemia. I think those are the important events that are observed during the titration period, but they're all manageable through, again, titration of encaleret.
We have time for one more question, and that question comes from the line of Trevor Allred with Oppenheimer. Please go ahead.
Good morning. Thanks for taking my question and congrats as well on the great data. I just want to ask commercially, is there anything you can disclose regarding sales rep deployment? Are these patients seen in endocrinologist centers of excellence? Would you expect to initially target these groups, or would you look to immediately expand into the community to maximally identify the available patients?
Yeah. Thanks, Trevor, for the question. This is Matt. I'll take that one. I mean, we're definitely going after all the patients wherever they may be. Having said that, these patients are all seen by endocrinologists. It's not like a needle in a haystack type of patient finding. We know where to go. We know where to look. With the new ICD-10 codes, these patients are going to start to become easily identified. I wouldn't expect that we're going to need a large sales force in order to tackle this, but we're looking into all of that right now. The nice thing is we have a little bit of time to put that together. I think this is going to be fairly straightforward. I'm not anticipating an overly complicated launch or any need to overly complicate our sales team.
Just keep in mind, too, with the Attruby launch already almost a year underway, we have a lot of the teams already in place and in the field. Our market access team, for instance, is fully built and out. They already have relationships with payers. In terms of getting access for patients, that's already in place. We're really just talking about adding the sales reps, which is kind of a nice position to be in. We don't have to do the full build from scratch because we already have a lot of those positions in place.
That concludes our question and answer session. I will now turn the conference back over to Ananth for closing comments.
Thank you, operator. I would like to close just by reiterating our gratitude to the collaborators that have made these incredibly robust and encouraging results possible. We are encouraged by the opportunity to serve the patient population with ADH1. We hope you all have a great rest of your day.
This concludes today's conference call. Thank you for your participation, and you may now disconnect.