BridgeBio Pharma, Inc. — Call Transcript 2025

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 JPMorgan. 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.

Speaker 13: 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. Ladies and gentlemen, thank you for standing by. ladies and gentlemen thank you for standing by My name is Krista, and I will be your conference operator today. 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. 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. 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. 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 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. if you would like to withdraw that question again press star one Thank you. thank you I would now like to turn the conference over to Dr. Neil Kumar, Chief Executive Officer. i would now like to turn the conference over to dr neil kumar chief executive officer Dr. Kumar, please go ahead. dr kumar please go ahead

Speaker 6: 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. Thank you to everyone who joined this call, particularly those of you joining us for the second time this week. 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 . 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. 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. 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. Before I set the corporate context for this readout, I want to begin with the most important slide in this document, slide 4. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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? 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. 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. 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. 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. 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. 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. 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. i'll turn it to ananth and team to tell you more about that now

Speaker 4: 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. Thank you, Neil. 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. 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 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. 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. 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. 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. Encaleret was well- tolerated, with no discontinuations from the active arm of this study. 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. 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. 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 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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 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. 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. 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. 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. i will now hand the call to scott to share the exciting detailed findings of the study

Speaker 11: 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. Thank you, Ananth. 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. 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. 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 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 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. key secondary endpoints also included the responder status for individual biochemical parameters This slide depicts the disposition of the study participants. 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. 70 participants entered period one. 67 of these were randomized with 45 to encaleret and 22 to the standard of care. 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 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. similarly the responder status when comparing the two treatment groups at week 24 confirmed a statistically significant result This is a clinically important point. 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. 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. 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. 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. 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. 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 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 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. 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. 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. We observed a statistically significant difference in the change from baseline at week 24 versus week four for those on encaleret. 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. 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. 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. 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. the frequency of treatment-emergent serious adverse events was low and similar between the two treatment arms There were few related serious adverse events. 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. 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. These data that I have shared with you demonstrate that encaleret restores physiologic mineral homeostasis in patients with ADH1. 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. 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. 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. 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. 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. 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. 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. I will now turn it over to Mary Scott to discuss the next steps for the program. i will now turn it over to mary scott to discuss the next steps for the program

Speaker 5: 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. The team is looking forward to an eventful year ahead. 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. 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. 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. 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. 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. 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. 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

Speaker 18: 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. With today's positive data announcement, BridgeBio 's commercial engine is poised once again to deliver a blockbuster launch, this time in ADH1. 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. 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 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. 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. 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 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. at this time i'll turn it over for the q&a portion of the call

Speaker 13: 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. Thank you. thank you We will now begin the question and answer session. 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 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. 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. 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. your first question comes from the line of tyler van buren with td cowen Please go ahead. please go ahead

Speaker 7: 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. Hey, guys. hey guys Congratulations on another stellar phase III data set within 48 hours. congratulations on another stellar phase iii data set within 48 hours The first question is the 76% response rate and calcium curves. 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. 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? 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. the second question is just related to the larger chronic hypoparathyroidism indication if you believe these results are de-risking for encaleret there

Speaker 6: Thanks, Tyler. I'll let Scott address the question regarding the response rate as well as the translatability to the chronic hypoparathyroidism program. Thanks, Tyler. thanks tyler I'll let Scott address the question regarding the response rate as well as the translatability to the chronic hypoparathyroidism program. i'll let scott address the question regarding the response rate as well as the translatability to the chronic hypoparathyroidism program

Speaker 11: 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. Thank you. 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. 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. 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. 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. 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. 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. 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. 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. 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. we feel very confident moving forward in the program with chronic hypoparathyroidism and we're really looking forward to studying patients with that condition

Speaker 13: Your next question comes from the line of Salim Syed with Mizuho. Please go ahead. Your next question comes from the line of Salim Syed with Mizuho. your next question comes from the line of salim syed with mizuho Please go ahead. please go ahead

Speaker 16: 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. Hey, great, guys. hey great guys Thanks for the question and congrats on the data. 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? 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. thank you

Speaker 6: 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. Wade, these are great questions. wade these are great questions Just remind the audience that these represent top-line results. 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. 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

Speaker 11: Did you ask about hypophosphatemia? Did you ask about hypophosphatemia? did you ask about hypophosphatemia

Speaker 16: Correct. Yeah, I think it was in your phase II slides, but I didn't see anything. Correct. correct Yeah, I think it was in your phase II slides, but I didn't see anything. yeah i think it was in your phase ii slides but i didn't see anything

Speaker 11: Yeah. Yeah. yeah

Speaker 16: Yeah, right. Yeah, but not your phase III. Yeah, right. yeah right Yeah, but not your phase III. yeah but not your phase iii

Speaker 11: 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. Yes, sir. yes sir Certainly, that's right. 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. 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 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. we're very confident moving forward that hypophosphatemia is not going to be a problem in the clinical management of these patients

Speaker 6: 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. Salim, I'll just add perhaps one element that Scott alluded to, which are encouraging. 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. 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. 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. once maintenance doses were achieved these adverse events were resolved with dose adjustment

Speaker 16: Okay. Anything on the bone biomarker data you guys may have measured? Okay. okay Anything on the bone biomarker data you guys may have measured? anything on the bone biomarker data you guys may have measured

Speaker 6: We do not have those data available to us at this time. We do not have those data available to us at this time. we do not have those data available to us at this time

Speaker 16: Okay. All right. Thanks so much, guys. Congrats again. Okay. okay All right. all right Thanks so much, guys. thanks so much guys Congrats again. congrats again

Speaker 11: Thank you. Thank you. thank you

Speaker 13: Your next question comes from the line of Cory Kasimov with Evercore ISI. Please go ahead. Your next question comes from the line of Cory Kasimov with Evercore ISI. your next question comes from the line of cory kasimov with evercore isi Please go ahead. please go ahead

Speaker 8: 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. Great. great Good morning, guys. good morning guys Thanks for taking the question and really quite some streak you're on here. 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. 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? 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? a quick follow-up i have is in your responder analysis were patients allowed to continue using vitamin d Thank you. thank you

Speaker 6: 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. Okay. okay Thank you, Cory. thank you cory There are a few questions there. 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. 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. 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. 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

Speaker 18: 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. Yeah. yeah I mean, I think the way to think about this launch is to expect a gradual but steady launch. 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. when you have a medicine like this that shows these kinds of results people talk about it Patients talk about it. patients talk about it Physicians talk about it. physicians talk about it Other PCPs talk about it. other pcps talk about it That kind of discussion creates awareness, and the more awareness there is, the market naturally grows. 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 . 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

Speaker 6: Okay. Scott, I'll pass it to you on the conventional therapy question as it relates to our response rate. Okay. okay Scott, I'll pass it to you on the conventional therapy question as it relates to our response rate. scott i'll pass it to you on the conventional therapy question as it relates to our response rate

Speaker 11: 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. When patients are started on encaleret, they discontinue their calcium supplements and active vitamin D. 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. 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. 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. with encaleret treatment patients do not require long-term active vitamin d therapy

Speaker 13: Your next question comes from the line of Mani Foroohar with Leerink Partners. Please go ahead. Your next question comes from the line of Mani Foroohar with Leerink Partners. your next question comes from the line of mani foroohar with leerink partners Please go ahead. please go ahead

Speaker 2: 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. A follow-up more on the commercial and strategy part on Tyler's question earlier on parathyroidism. 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? 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. 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

Speaker 6: Right. That's a great question. I'll let Matt address these points. Right. right That's a great question. that's a great question I'll let Matt address these points. i'll let matt address these points

Speaker 18: 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. Yeah. yeah I mean, I think you know the way to think about it, they are two different launches, but they're related. 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 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. 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. 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. 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. 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. If you have your choice, I think this is the way you'd like to do it. 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 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 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 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

Speaker 6: 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. 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. 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. 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

Speaker 2: Thanks, guys. That's helpful. Congrats again. Thanks, guys. thanks guys That's helpful. that's helpful Congrats again. congrats again

Speaker 13: Your next question comes from the line of Biren Amin with Piper Sandler. Please go ahead. Your next question comes from the line of Biren Amin with Piper Sandler. your next question comes from the line of biren amin with piper sandler Please go ahead. please go ahead

Speaker 17: 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. Hi, guys. hi guys Thanks for taking my questions and congrats on the data. 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 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 ? 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. thank you

Speaker 6: Neil, thank you for that question. I'll let Scott address those two questions. Neil, thank you for that question. neil thank you for that question I'll let Scott address those two questions. i'll let scott address those two questions

Speaker 11: 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? 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. 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. 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. 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. 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. 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. 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? can you clarify the second part of the question that you had please

Speaker 17: 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. Yeah. yeah You had observed that patients in the trial achieved the intact PTH above the lower reference range. 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 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. i wanted to understand what the read-through of that is to the chronic hypo pth setting

Speaker 11: 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. Right. right In patients with intact parathyroid glands, they will respond, and that's what we've observed. 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. 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. we now know that is a pth-independent process There is historic data from patients with another genetic disease called familial hypercalcemic hypocalciuria. 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. 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. 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. 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. 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. 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. We are very confident moving forward in the chronic hypopara space because of the PTH-independent effects of encaleret on the kidney. we are very confident moving forward in the chronic hypopara space because of the pth-independent effects of encaleret on the kidney

Speaker 13: Your next question comes from the line of Joshua Schimmer from Cantor. Please go ahead. Your next question comes from the line of Joshua Schimmer from Cantor. your next question comes from the line of joshua schimmer from cantor Please go ahead. please go ahead

Speaker 14: 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. Great. great Congrats on the results, and thanks for taking the question. 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? 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? 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? 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

Speaker 6: 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. Thank you, Josh. 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. 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

Speaker 18: 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. Yeah. yeah Hey, Josh. hey josh Thanks for the question. 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. 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. we're not really seeing those patients on your path I don't think there's a big conversion strategy necessary. 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. 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. 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. 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 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. I just think slowly over time, especially now with the data out, we will identify more and more of those 12,000 patients. 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. 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. 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. 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. 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

Speaker 6: 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. 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. 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. we are observing increased utilization of that icd-10 code as well as increased utilization of genetic testing to identify patients

Speaker 14: Excellent. Thank you. Excellent. excellent Thank you. thank you

Speaker 13: Your next question comes from the line of Andrew Tsai with Jefferies. Please go ahead. Your next question comes from the line of Andrew Tsai with Jefferies. your next question comes from the line of andrew tsai with jefferies Please go ahead. please go ahead

Speaker 1: 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. Hey, good morning, and congrats too on a solid data set. 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? 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? 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. 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? 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? why wouldn't you have direct line of sight to thousands of patients Thank you. thank you

Speaker 6: 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. Thank you, Andy. 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. 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

Speaker 11: 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. Regarding the hard endpoints, this is evidence that would require longer-term follow-up. 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. 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. 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

Speaker 18: 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. For the second part of your question, we already have thousands of patients identified. 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. 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. 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. 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? 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 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. 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. We're going to grow it from where it is today and expand the market beyond the 12,000. we're going to grow it from where it is today and expand the market beyond the 12,000

Speaker 13: Your next question comes from the line of Paul Choi with Goldman Sachs. Please go ahead. Your next question comes from the line of Paul Choi with Goldman Sachs. your next question comes from the line of paul choi with goldman sachs Please go ahead. please go ahead

Speaker 15: 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. Hi. hi Thank you. thank you Good morning, and congrats on going two for two this week. 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? 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? any enrichment or patient population strategies that you can maybe comment on Second, your path got a priority review in its FDA application. second your path got a priority review in its fda application Are you assuming the same here for encaleret? are you assuming the same here for encaleret Thanks for taking our questions. thanks for taking our questions

Speaker 6: 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. Thank you, Paul. 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. 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. the first question regarding subpopulations i'll pass it to scott to address that point

Speaker 11: 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. 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. 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. 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. 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

Speaker 13: Your next question comes from the line of Anupam Rama with JPMorgan. Please go ahead. Your next question comes from the line of Anupam Rama with JP Morgan. your next question comes from the line of anupam rama with jp morgan Please go ahead. please go ahead

Speaker 3: 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. Hey, guys. hey guys Thanks so much for taking the question and congrats on the update. thanks so much for taking the question and congrats on the update Just two quick clarification questions, if I may. just two quick clarification questions if i may The first is on safety. 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? 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? 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? 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. thanks so much

Speaker 6: That's not a problem. On your first question, did you mean hypercalcemia or did you mean to say hyperkalemia? That's not a problem. that's not a problem On your first question, did you mean hypercalcemia or did you mean to say hyperkalemia? on your first question did you mean hypercalcemia or did you mean to say hyperkalemia

Speaker 3: Calcemia, sorry. Calcemia, sorry. calcemia sorry

Speaker 6: Thank you. I'll let Scott address that first point on safety and dose reductions due to hypercalcemia. Thank you. thank you I'll let Scott address that first point on safety and dose reductions due to hypercalcemia. i'll let scott address that first point on safety and dose reductions due to hypercalcemia

Speaker 11: 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. Encaleret is started at a dose of 54 mg twice daily. 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. 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. there is certainly titration early on because of hypercalcemia Importantly, no patient has had to discontinue encaleret for hypercalcemia. importantly no patient has had to discontinue encaleret for hypercalcemia We've been able to manage all patients. 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. they might go down to a dose of 4.5 mg but they're certainly manageable on encaleret

Speaker 6: 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. 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. 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. 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. 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

Speaker 13: Your next question comes from the line of Danielle Brill with Truist. Please go ahead. Your next question comes from the line of Danielle Brill with Truist. your next question comes from the line of danielle brill with truist Please go ahead. please go ahead

Speaker 9: 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. Hi. hi Good morning. good morning Thanks so much for the questions. thanks so much for the questions Let me also extend my congrats on the back-to-back wins here. 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. 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? 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? 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. 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? 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? could you potentially seek an accelerated approval for peds with the upcoming planned trial serving as your confirmatory Thanks. thanks

Speaker 6: 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. Thanks, Danielle. 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. 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. 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. i'll pass it to mary scott for the question on the pediatric program the label Go ahead. go ahead

Speaker 5: 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. Yeah. yeah Thanks, Danielle. 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. 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. 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. 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

Speaker 13: Your next question comes from the line of [Jason Szymanski] with Bank of America. Please go ahead. Your next question comes from the line of [Jason Szymanski] with Bank of America. your next question comes from the line of [jason szymanski] with bank of america Please go ahead. 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. Good morning. good morning Congrats on the data for the second time this week, and thanks for squeezing us in. 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. 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? 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? 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? three any concerns over the potential for adh1 to be added to pth's label Would it challenge use at all? would it challenge use at all We ask because the developer there has commented that, wow, the number of ADH patients has been few. we ask because the developer there has commented that wow the number of adh patients has been few They've responded rather well. they've responded rather well Thanks. thanks

Speaker 6: 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. Okay. 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. 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. 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. 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 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. on the questions on hypophosphatemia or additional ae characterization i'll turn it to scott

Speaker 11: 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. During the titration period, we do see some hypocalcemia and hypercalcemia. 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. i think those are the important events that are observed during the titration period but they're all manageable through again titration of encaleret

Speaker 13: We have time for one more question, and that question comes from the line of Trevor Allred with Oppenheimer. Please go ahead. We have time for one more question, and that question comes from the line of Trevor Allred with Oppenheimer. we have time for one more question and that question comes from the line of trevor allred with oppenheimer Please go ahead. please go ahead

Speaker 12: 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? Good morning. good morning Thanks for taking my question and congrats as well on the great data. 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? 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? 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? would you expect to initially target these groups or would you look to immediately expand into the community to maximally identify the available patients

Speaker 18: 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. Yeah. yeah Thanks, Trevor, for the question. thanks trevor for the question This is Matt. this is matt I'll take that one. i'll take that one I mean, we're definitely going after all the patients wherever they may be. i mean we're definitely going after all the patients wherever they may be Having said that, these patients are all seen by endocrinologists. having said that these patients are all seen by endocrinologists It's not like a needle in a haystack type of patient finding. it's not like a needle in a haystack type of patient finding We know where to go. we know where to go We know where to look. we know where to look With the new ICD-10 codes, these patients are going to start to become easily identified. 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. 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. 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 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. 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. 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. 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. our market access team for instance is fully built and out They already have relationships with payers. they already have relationships with payers In terms of getting access for patients, that's already in place. 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'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. we don't have to do the full build from scratch because we already have a lot of those positions in place

Speaker 13: That concludes our question and answer session. I will now turn the conference back over to Ananth for closing comments. That concludes our question and answer session. that concludes our question and answer session I will now turn the conference back over to Ananth for closing comments. i will now turn the conference back over to ananth for closing comments

Speaker 4: 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. Thank you, operator. 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. 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 are encouraged by the opportunity to serve the patient population with adh1 We hope you all have a great rest of your day. we hope you all have a great rest of your day

Speaker 13: This concludes today's conference call. Thank you for your participation, and you may now disconnect. This concludes today's conference call. this concludes today's conference call Thank you for your participation, and you may now disconnect. thank you for your participation and you may now disconnect