BridgeBio Pharma, Inc. (BBIO) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to the BridgeBio Pharma to discuss Phase IIb data and Phase III trial design for Encaleret in ADH1. [Operator Instructions] As a reminder, this conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today, Dr. Neil Kumar, Chief Executive Officer of BridgeBio. The floor is yours.

Thanks so much, operator, and thanks to everyone joining us for your time. Before I dive in, I just wanted to remind everyone that I will be making forward-looking statements today. And if you need additional details, please refer to our SEC filings. It's my privilege to kick this call off and introduce our most recent data from our Phase II ADH1 or autosomal dominant hypocalcemia type 1 program. Drs. Rachel Gafni and Mary Scott Roberts will provide the bulk of what's going to be useful today on this call. But I wanted to take a moment to set up the discussion and provide a bit of perspective. Before I do that, though, I wanted to thank the investigators and patients that participated in this trial, along with the patient advocates at the HP Association. It's always true, but even more so during COVID, and we've seen this across many of our clinical trials that a biotech relies on its partnership with those who are on the front lines of care and caring. And so we thank them for their inspired effort here. I want to start on Slide 4, if we could go there by highlighting, first, this program's efficiency. In a little under 3 years, this capable team took this program from IND to the doorstep of a well-designed Phase III. This was also accomplished in a little under $100 million. This is the same cardiorenal team that here at Bridge accomplished something very similar with our ATTR cardiomyopathy program, and we anticipate more data points like this. Analogous to what we did in LGMD2i, where as many of you recall, we had positive Phase II data that was announced earlier this year, and we expect more of this type of thing to come in the next 12 months. Given current market constraints, as you all know, efficient prosecution of late-stage programs is the only way to build value for patients and investors in rare disease markets, and we think we can reproducibly execute on that and are building a track record to prove it. So maybe if we advance to the next slide, we can drill into the program of interest today, and I'll begin by reiterating that we're taking our normal BridgeBio approach to trying to help patients here, which is to target a well-described disease at its source. In this case, as will be discussed in greater detail later, this involves negative allosteric modulation of the calcium-sensing receptor to counteract disease causing heterozygous gain of function mutations occurring in that receptor's gene. That's the good news that this disease, thanks to pioneers like Dr. Michael Collins and others, is well described. The bad news is that there is a large unmet need that warrants our immediate attention. Against any of the 2 axes against which we understand disease burden, that as patient numbers or disease severity, we can see that ADH1 exacts a significant toll. On Slide 5, we see the estimated prevalence of ADH1 in the U.S. at a little over 10,000, a large unmet need analogous to the XLH unmet need that was addressed by Ultragenyx and others in their program over the past couple of years. Many ADH1 patients are luckily currently on or misdiagnosed in the hypopara community and estimated 3,500 patients are diagnosed today. If you flip to Slide 6, you can see also that a majority of these patients identified experienced moderate to severe symptoms, which include both acute symptoms like seizures or tetany and others that you'll hear about in longer-term complications like nephrocalcinosis and CKD. Importantly, even mild patients that don't appear to have appreciable acute burden often go on to experience longer-term kidney complications. Against this diaspero symptomatology, current standard of care is able to do very little, as shown on the right-hand side of this chart here, you can see that it normalizes fewer than 5% of patients on both serum and urine calcium. Okay. So we have a program here addressing a large and severe unmet need by targeting this well-described disease at its source and being prosecuted by a group of very experienced drug developers and academic partners who have efficiently led the development of the program to its doorstep into a high POTS or probability of technical success Phase III clinical trial. In doing so, hopefully, we can provide some hope for ADH1 patients and provide a stellar example of how the BridgeBio model can work. I'm going to turn it over to Dr. Gafni now to get into the more interesting stuff. So you can see here, she heads the Mineral Homeostasis Studies group at the NIH and as a senior research position there as well. We're privileged to be working with her and learning from her. Rachel?

Thank you very much. It's really exciting to present our data from this novel therapy, which really takes a precision medicine approach to treating a rare form of hypoparathyroidism. I have a disclosure slide up there, I think -- or no, okay. So we're going to start with -- I don't see a slide number. So we're going to start with a slide that has 9, Slide 9. Thank you. So in normal circumstances, blood calcium levels are kept within a narrow physiologic range, and this tight control is mediated by 4 organs under the regulation of parathyroid hormone. When the calcium level is low, the parathyroid glands respond by synthesizing and secreting PTH, which in turn, acts to increase calcium levels by several mechanisms. In the bone, PTH stimulates bone resorption, and this liberates calcium into the bloodstream. In the kidney, PTH increases renal calcium reabsorption and promotes conversion of 25 hydroxy vitamin D to the active form of vitamin D 125 dihydroxy vitamin D, which in turn promotes intestinal absorption of calcium. PTH also inhibits renal phosphate reabsorption. And now while PTH is an important circulating hormone that's doing a lot of work, it's in fact the calcium sensing receptor that's controlling this complicated dance. In the parathyroid, when the calcium sensing receptor senses high levels of calcium, PTH synthesis and secretion are decreased. Likewise, in the renal tubule, high levels of calcium sensed by the calcium sensing receptor leads to decreased calcium reabsorption to rid the body of the excess calcium. Go to the next slide, please. Heterozygous activating variance in the calcium-sensing receptor cause a rare form of hypoparathyroidism called autosomal dominant hypocalcemia or ADH1. And these variants in the calcium-sensing receptor increased tissue sensitivity to extracellular calcium essentially tricking the parathyroid and the kidneys into thinking that the blood calcium level is higher than it actually is. As a result, patients with ADH1 have decreased PTH secretion, decreased blood calcium and increased urinary calcium. The clinical manifestations of ADH1 are similar to other forms of hypoparathyroidism and long-term complications may include nephrolithiasis, nephrocalcinosis and chronic kidney disease. It's important to note that hypercalciuria may be worse in ADH1 compared with other forms of hypoparathyroidism because these patients experienced both decreased PTH as well as altered calcium sensing leading to reduced calcium reabsorption. Treatment is often difficult and conventional therapy with calcium and activated vitamin D does not correct the underlying pathophysiology and has the potential to worsen long-term complications. Next slide. Encaleret is an investigational oral medication from the class of drugs called Calcilytics, which are negative allosteric modulators of the calcium-sensing receptor. And through this mechanism, encaleret decreases the sensitivity of the calcium-sensing receptor to extracellular calcium, effectively shifting the responsivity curve in the parathyroids and the kidney to the right. And restoration of the calcium-sensing receptor sensitivity towards normal has the potential to correct the hypocalcemia, hypercalciuria, and low PTH in individuals with ADH1. Next slide. Our study is a Phase IIb open-label design that is divided into 4 sections. During period 1, 6 patients with ADH1 received encaleret in escalating doses over 5 days while undergoing frequent blood and urine sampling. Period 2 was a second inpatient period that included those 6 patients, plus an additional 7 patients for a total N of 13. During period 2, patients received individualized dose titration for 5 days. The 13 participants then entered a 24-week outpatient phase with scheduled assessments occurring every 1 to 8 weeks. The key study objectives were safety and tolerability and calcium metabolism, with additional secondary measures listed here. While taking encaleret, patients did not receive calcitriol and were instructed to consume at least 1,000 milligrams of dietary calcium per day. The 1 patient with a low dietary calcium intake was given a calcium supplement to meet that goal. Next slide. These are the baseline characteristics of the study participants. 13 subjects with a mean age of 39 years bearing 9 different calcium-sensing receptor variants were enrolled, all with the typical biochemical features of ADH1, hypocalcemia, low PTH, hyperphosphatemia and inappropriately normal or frankly elevated urine calcium. 3/4 had nephrocalcinosis on renal ultrasound. And the renal function was variable with a mean eGFR of 84. All were being managed with calcium and calcitriol supplements in fairly typical doses divided throughout the day. Next slide. This slide shows the dosing regimen for the study. In period 1, the dose escalation was fixed with all subjects receiving once daily dosing on days 1 to 3, increasing from 30 milligrams to 90 milligrams to 180 milligrams, followed by 180 milligrams twice daily on days 4 and 5. Only 1 subject had the final dose decrease to 120 milligrams because of the calcium level slightly above 10 milligrams per deciliter. In Period 2, the day 1 starting dose was originally 180 milligrams twice daily, but was then decreased to 90 milligrams twice daily as it became clear that individual dose requirements were quite variable. Over the course of the 5 days, the mean encaleret sulfate dose decreased, with patients ultimately receiving between 10 milligrams to 180 milligrams twice daily. The third graph shows the individualized dosing over 24 weeks in period 3. Most patients were maintained at doses similar to their dose at the end of period 2, again, ranging from 5 milligrams to 190 milligrams twice daily by week 24. Next slide. Safety and tolerability were primary endpoints for this study. Encaleret was well tolerated with very few adverse events and no serious adverse events reported. The only treatment-related adverse events were instances of transient blood phosphate levels below 2 milligrams per deciliter and some instances of mild hypercalcemia with no patient exceeding a corrective calcium level of 10.9 milligrams per deciliter. All treatment-related AEs result either spontaneously or with adjustment of the encalaret dose. No other concomitant therapies were required. Next slide. These graphs show the individual and mean responses on day 1 and 5 for the 6 subjects in period 1. The day 1 blood calcium and PTH values shown by the light blue bars were drawn just prior to administration of the first dose of encaleret, while the urine calcium reflects the 24-hour excretion at the screening visit. By day 5, shown by the dark blue bars, all subjects had average blood calcium levels that were in the normal range and normal or undetectable 24-hour urine calcium. 4 patients maintained an average PTH value within the normal range on day 5, while 2 had elevated mean values. Next slide. These figures display the mean pharmacodynamic responses to individualize BID dosing of encaleret over 5 days in period 2 and 24 weeks in period 3. In the upper panel, we see the mean albumin-corrected blood calcium gradually increase into the normal range by day 2 and remain normal during period 3. Concurrently, the mean 24-hour urinary calcium excretion, shown in the bottom panel, decreased into the normal range within the first 24 hours of dosing and remain normal throughout. Next slide. Similar to period 1, the PTH response to encaleret in periods 2 and 3 shown in the top figure was robust, increasing from a very low mean baseline value well into the normal range, 30 minutes after the first dose on day 1 and remaining normal during period 3. Likewise, the mean blood phosphate level decreased from a high normal level into the mid-normal range. Mild hypophosphatemia was noted in several subjects usually within a few hours of the morning dose. However, these episodes were asymptomatic, transient and result either spontaneously or with the reduction of the encalaret dose. Next slide. Both the mean blood magnesium shown in the top panel and the 125 dihydroxy vitamin D in the bottom panel were low normal prior to encaleret and increased. Next slide. These graphs show the bone turnover markers CTX on the left and P1NP on the right during period 3. Because the normal range is age- and sex-specific, we are presenting the values as a ratio of the level over the upper limit of normal for that patient. Thus, a value of 1 indicates a bone turnover marker at the upper limit of normal. As expected, the bone turnover markers increased significantly while on encaleret, consistent with the increase in PTH levels. While 3 or 4 subjects had slightly elevated levels, most subjects remained within the normal range. Next slide. Same slide, excuse me. At the bottom, you see a table showing the DXA scans, which were obtained at screening and at the 24-week visit of period 3. As we typically see in hypoparathyroidism, the mean BMD Z-score was elevated as screening for the total body, lumbar spine and hip and there were no significant changes in BMD Z-score, except for a slight decrease in the total hip. Next slide. To summarize, in 13 patients with ADH1, encaleret administered twice daily for 24 weeks restored mineral homeostasis, as demonstrated by an increase in PTH, correction of hypocalcemia, normalization of the mean 24-hour urine calcium, reduction in blood phosphate, increase in mean magnesium and 125 dihydroxy vitamin D, an increase in bone turnover while remaining in the normal range in most participants. Encaleret was well tolerated over 24 weeks with no serious adverse events reported and outpatient evaluation of encaleret in the Phase IIb long-term extension is ongoing, with a Phase III study planned for later this year. Thanks very much, and I'm happy to answer any questions. But first, Dr. Roberts is going to present.

Thank you, Dr. Gafni. We can go to Slide 23, please. So given the data that Dr. Gafni presented from our Phase II study, we are very excited to initiate the CALIBRATE Phase III pivotal trial, which will be a global, randomized, open-label, 2-arm study that is informed by our learnings from Phase II. We are looking to enroll patients with genetic and biochemical evidence of ADH1 aged 16 years and older and following a screening period that includes standard of care optimization, approximately 45 participants will enter a 4-week standard of care maintenance period. Then participants will be randomized in a 2:1 manner to receive either encaleret or to continue on standard of care treatment for a total of 24 weeks. Following period 3, participants in the encaleret treatment arm can continue on encalaret treatment while patients in the standard of care arm can initiate encaleret in the long-term extension, which will last approximately 48 months. Our primary endpoint for this study consists of the proportion of participants achieve a composite of both blood calcium in the target range and 24-hour urine calcium, either within the reference range or greater than or equal to 50% decrease from their baseline value. The secondary endpoints can be seen on the right-hand bottom portion of the screen and include the effects of encaleret on other markers of mineral homeostasis, as well as following the renal function and renal ultrasounds in these patients with ADH1 as well as the impact of treatment on their quality of life. Next slide. We are encouraged about our probability of success to meet the primary endpoint in the CALIBRATE Phase III study by data from our Phase II trial, which you can see here. No participants had blood calcium in the target range while simultaneously having 24-hour urine calcium in the normal range on standard of care at screening. While 69% of the participants in the Phase II study met both of these parameters after 24 weeks of encaleret. And I would just like to note here that for the urine calcium, we are only able to assess urine calcium in the normal range, which is only one part of the Phase III endpoint criteria that I just shared with you for urine calcium. And that's because we only had a single-screening measure on standard of care, so calculating the change from baseline was not possible with this particular study data. Next slide. So to summarize what Dr. Gafni had shared previously, the Phase II trial demonstrated that encaleret normalized mean corrected blood calcium and 24 hour urine calcium excretion, and this was maintained for 24 weeks. The increase in calcium was mediated by increased PTH secretion, which also led to decreases in blood phosphate. Encaleret was well tolerated when administered twice daily for 24 weeks with no serious adverse events reported. And these consistent improvements in mineral homeostasis suggests that encaleret may be an effective treatment for ADH1. And we're thrilled to study this further in our Phase III CALIBRATE study that is set to initiate in the second half of this year. We anticipate completing enrollment early in 2023 and having top line data available at the end of next year. And as we look into 2023 and beyond, we'll have additional long-term safety and efficacy data, as Dr. Gafni continues to follow Phase II participants and the long-term extension. And then as you can see in the time line below on the bottom right, we have some other exciting work ahead of us, including clinical studies in pediatric patients with ADH1, as well as assessing the potential for encalaret treatment of other nongenetic forms of hypoparathyroidism. Thank you.

And with that, operator, we can open the line for Q&A.

[Operator Instructions] Our first question comes from Eli Merle with UBS.

Congrats on the updates. Maybe first for Dr. Gafni, can you just elaborate a little bit on the titration period and thoughts on moving into the outpatient setting? I'm thinking about this for the Phase III as well as potentially long term in the commercial sort of real-world treatment setting. And then just a question for Dr. Roberts. When you guys are thinking about the Phase III enrollment, any kind of color in terms of the site identification that you've done so far that sort of informed some of the time lines that you guys are talking about? And you alluded to this at the end by sort of future plans for studying encaleret and other potential forms of hypoparathyroid as well, if you could just elaborate there.

Thanks for those questions, Eli. So we'll pass it to Dr. Gafni for your first question and then to Dr. Roberts for your second.

I'm not 100% sure you were asking about the titration period from period 2 into period 3. Is that correct? Or how we do it...

Yes.

Or how we foresee doing it in the real world. I mean, it was actually pretty straightforward. The -- we did monitor patients on a weekly basis initially after they left the inpatient unit to adjust their doses. And in cases where we needed to make adjustments more frequently, we monitored their labs more frequently, but it was actually pretty straightforward for most of the patients. And they stayed on this -- once we got -- it took again, a few days to figure out their dose. And for the most part, they stayed quite stable. So it was very easy to adjust. I'm not sure if that's answering your question.

Yes, that's helpful. And I guess, maybe just implication, I guess, in the real world outside of the clinical trial setting, I mean, do you expect this to need to be sort of any type of inpatient monitoring or how this can be sort of monitored on an outpatient visit as you get to sort of this maintenance dose?

Yes. I definitely think this can be done on an outpatient dose for the most part. It would be really very speculative because I've never actually started anybody as an outpatient. So it's a little hard for me to know for sure, but I've managed a lot of other hypoparathyroid patients and with PTH and conventional therapy. And in general, unless there's really an acute situation, I generally don't need to check labs more than twice a week when I make an adjustment. That's sort of a maximum twice a week. So it's doable in outpatient, but I can't say specifically for this because I've never actually done it with this drug.

Okay. Got it.

And Eli, this is Dr. Roberts. Just to add to that, in case it wasn't clear when I went through the Phase III study design. Our intention for the Phase III pivotal trial is that it will be all based on an outpatient basis. And so we've taken our learnings from the dosing range in the Phase II study and chosen dose that we think will be safe for most patients and then the ability to titrate up or down as needed, just as Dr. Gafni was suggesting. So we'll learn more when we have the data from Phase III.

Great. Makes sense. And I guess last question for me. Just any color you can give in sort of the real-world identification or any patient registries in terms of the number of patients actively diagnosed today with ADH1?

Yes. Great question. And so we've taken a multifactorial approach in trying to identify patients as well as centers, physicians that might have these patients. So one of them is reaching out to thought leaders across the world, having conversations on where these patients might be located. The second is through a sponsored in vitae testing panel in which any patient that has nonsurgical hypoparathyroidism in the United States can be tested for free. And we've already had quite a bit of uptake with the use of that panel in the past year or so that it's been in effect. The second is through patient advocacy. So there's a number of patient advocacy groups in the U.S., in Europe and in other parts of the world that we have team members that are reaching out and working with them to really try to find these patients where they are and then to have a study site that is convenient to their location because, as you know, in rare disease, every patient counts.

Your next question comes from Mani Foroohar with SVB Securities.

This is Rick on the line for Mani. Congrats on the great data here. Just a couple of questions from us. First, what, if anything, did the data say about the interaction between patient genotype in response to encaleret? Did you notice any trends based on patient genotype either in response to encaleret or the ability to normalize blood or urine calcium? And for the second question, this is probably directed more for Neil. Given a pretty large spread between final doses that patients received in this study, how are you currently thinking about potential pricing models for encaleret as well as any downstream impact for commercialization that these wide range in doses might have?

Thanks for those questions, Rick. So we can pass it to Rachel -- Dr. Gafni for the first question on the association between genotype and the encaleret dose in the study.

Yes. It's really a great question. So we can't say anything definitively on the effects relative to genotype. But what we do know is we have 13 subjects enrolled in the Phase II study, and they have 9 different calcium sensing receptor variant. So the ones that have the same calcium sensing receptor variant are related, either siblings or parent-child, cousin. So it's -- and as it turns out, those family members tended to require approximately the same dose. So there is a suggestion that perhaps the genotype does correlate with the effectiveness or the dose requirement for the drug, but it also possible that there are other genetic factors at play that affect the responsivity to the drug. So it's a little too early to know based on this very small cohort. I think that there is consideration of perhaps doing bench research with cells, for example, that can bear these mutations to look at responsivity with the different variants, but that has not been yet done to date.

Yes, Rick, maybe on the pricing question, I'll turn it over to Ananth who leads operations and strategy for this program.

Thank you, Neil. So it's a great question, Rick. So it is preliminary to comment deeply on pricing. And we can get more into details as we approach potential registration in this program. But I think in a general sense, we are definitely going to approach pricing with a responsibility perspective and intend to price encaleret responsibly for this condition if we're successful. In terms of how we would manage the large dose range and the individualized dosing, we intend to interrogate packaging formats to enable titration in the outpatient setting that will enable individuals to get to their optimal dose in a rapid and pragmatic fashion, and we'll adopt a pricing approach that will enable that sort of titration.

Your next question comes from Anupam Rama with JPMorgan.

Two for me, just quickly. For the few patients that had bone turnover markers outside of the normal range, is there anything in the baseline characteristics to consider there for those patients? And then, I guess, anything to consider when it comes to inclusion/exclusion criteria for the Phase III related to bone turnover? And then another question, which is, is the safety exposure period going to have to go beyond 24 weeks for a filing? Or can you file on the 24-week data in the Phase III?

Thank you, Anupam. So for the first question on the predictive nature for the bone turnover markers, we'll have Dr. Gafni address that question.

Yes. Thanks for the question. So the bone turnover markers are back on Slide 20. And there's a couple -- so there's basically 3 patients who seem to have persistently high bone turnover markers above the normal range during period 3. And 2 of those are fraternal twins. So they have the same -- very -- they share obviously not 100% of their genetics, they're fraternal. So there may be a genetic implication in there that we don't know about. They also are starting at the highest baseline and that also could be reflective of their age because they're 22, so they're in the younger part of our cohort. So it's a little bit unclear, but they -- it makes sense that those siblings might be sorting out similarly. The third patient is actually -- and they were on medium doses of the drug, so not on the highest doses of the drug. The third patient who's in the -- above the normal range is actually one of our patients on one of the lowest doses of the drug. So it's really unclear why some of the patients have higher bone turnover markers, but this is still a fairly brief period of time. And I think we're going to get a lot more information from this in the long-term extension as we continue to monitor the bone turnover markers every 6 months as well as the bone density studies annually. But it's a good question, and I don't really have an answer for it right now.

Sure. And then to Dr. Roberts on your second question, Anupam, on the exclusion criteria or inclusion criteria in the Phase III study and the 24-week data package.

Sure. So most of these patients with hypoparathyroidism, including those with ADH1, have a low bone turnover state when they are not being treated with drugs that replace or increase parathyroid hormone. And since we were unable to identify anything in the 3 patients, as Dr. Gafni just mentioned, that would have predicted their increase in bone turnover markers on study. We don't plan to include any inclusion or exclusion criteria focused specifically on the bone turnover markers. For your safety question, we have completed our end of Phase II interaction with the FDA and received scientific advice or feedback from the European Medical Agency and 24 weeks of safety data should be sufficient for filing. And just keep in mind that we'll have supplemented data from our Phase II study as patients continue on treatment, some of which have been on treatment for out to 12 months at this point in time.

Your next question comes from Paul Choi with Goldman Sachs.

Let me add my congratulations on the data as well. My first question is for Dr. Gafni, and it's regarding the change in PTH over time. I think as we looked at the data last year, there was some concern about spikes and outliers. But with additional patients and the additional follow-ups, can you maybe speak to your level of comfort about risks and potential downstream risks from the changes in PTH over time?

Go ahead, Dr. Gafni.

Thanks. Thanks for your question. Yes, I think that the spike that we saw in the earlier periods were due to the dose-finding studies because, obviously, we were giving patients up to 180 milligrams twice daily were -- when some of them really needed much lower doses. So the responsivity of the PTH was somewhat expected. But certainly in period 3, once we figured out the best dose for the patient, which was actually pretty close to the end of period 2 or even at period 2 for most of the subjects, the PTH levels were quite stable, and we weren't seeing those types of [ excursion ]. We're not showing all of the data at 8, 16 and 24 weeks, but we did do 24-hour sampling on the patients during those visits. And while we did sometimes have PTH values that exceeded the upper limit of normal within a period of time after the dose, none of them were exceptionally high that they would be concerning in the long term.

Okay. And just a quick one as a follow-up to Anupam's earlier question for Dr. Roberts. Will you exclude patients with renal dysfunction or CKD from the Phase III? And then one for Neil is, how concentrated is this market as you think about commercialization down the road? Is this primarily a center of excellence model? Or do you think you'll have to have some more feet on the street to promoting encaleret?

Go ahead, Dr. Roberts.

Sure. Happy to do so. For the Phase III study, we plan to include patients with a minimum eGFR of 30 or higher. So definitely, looking at some individuals with altered renal function as far as the study group goes.

Yes. Thanks, Paul. I can address the final question. Today, I think with a launch, we would concentrate on COE-driven launch. But in the future, I'd imagine that we would expand out into the community footprint, especially given some of the earlier comments around finding some of these patients within the HP community. That sales footprint could be broader and we'd look to flex that as we find more and more of those patients in the community setting. I might also come back to an earlier commercial question that was asked just around pricing just for models. I think we do anticipate having a flat pricing model, whereby we take all of those different parameters that Ananth mentioned and introduced them. So I think you can imagine just given prevalence of this disease a flat pricing model for any financial projections.

Your next question comes from Salim Syed with Mizuho.

Congrats on the data. I have 4 questions, but if it's easier for you can think of it as 1 question, 4 parts, all in the Phase III trial, if that's okay. Part 1 or question #1. Just curious for whoever attended the end of the Phase II meeting with the FDA, just what was the FDA's primary concern coming out of that meeting? Why Phase III trial was necessary in the first place just given it seems like there is an incredible unmet need here. And you get 70% of the patients in this particular trial achieve normal range blood calcium and urine calcium with a particular safety issue. Or what was it that they are really trying to get at? Part 2 here, I think I know the answer to this question, but just the 2 to 3 patients that we're still not seeing get into those normal ranges for blood calcium and urinary calcium, was there anything particular about those patients that seems to make it more difficult to treat? And are those patients being -- and is that criteria being excluded from the Phase III trial design? Part 3, is there any interim in -- or built into the Phase III design, given it's open label, and you will be getting data in-house as it comes? And lastly, for the Phase III study, the titration period seems to be pretty much most of the duration of the trial with a short-term maintenance period. Just curious how confident we are that we won't need to have ongoing titration in a real-world setting?

This is Dr. Roberts. Thank you for your question. I'm going to answer 3 of the 4, and then I'm going to pass it to Dr. Gafni for your second question on the individual patients in the Phase II study. For the end of Phase II meeting, the conversation around the need for a Phase III study was really focused on the number of patients that have been exposed to the drug and generating enough safety data to ensure that we're not seeing any safety signals in a larger patient population. And then the other aspect of that conversation was the lack of a concurrent control. And as Dr. Gafni reviewed in our Phase II study, we only had baseline data on standard of care. For the Phase III study, we are not planning for an interim analysis, given that the length of the study is relatively short, a total of 24 weeks on drug. And then your last question on the titration period. As Dr. Gafni showed in Phase II, it really was around 2 weeks for almost all patients to reach the dose that they stayed on for the majority of the 24 weeks and period 3. If they needed a dose adjustment, it was a minor change. So we anticipate that in that period 2 of the schema that you saw that most patients will actually be on their optimal dose early in that period, and then we can make minor adjustments over the remaining 20 weeks. So that when we get to period 3, we don't anticipate that dosing adjustments will be needed, and we didn't actually see that for the individuals in our Phase II study as well. I'll pass it over to Dr. Gafni.

Okay. Just regarding end points because I didn't present the individual data for the Phase II study. But I just want to make sure that it's clearly understood that all 13 patients maintained blood calcium levels within the normal range for the entire 24-week period. So that was achieved in all patients. 11 of the patients also maintained normal 24-hour urine calcium, and there were 2 patients who intermittently had normal and sometimes elevated 24-hour urine calcium. And these 2 patients happen to also have the highest 24-hour urine calcium excretion at the screening visit. So both of them decreased their 24-hour urine calcium more than 50% during period 3, but they didn't always enter the normal range on every assessment. And so I think what you were looking at with Dr. Roberts' interpretation of what percentage of the patients achieved the primary endpoint, it was an incomplete -- incompletely calculated endpoint because we didn't have the same information collected in the Phase II study that we plan to collect in the Phase III study, but everybody maintained a normal calcium. And most of the vast majority had persistently normal 24-hour urine calciums on every measure.

Okay. Your next question comes from Eun Yang with Jefferies.

I have several questions. First, Neil, you mentioned that out of estimated 12,000 prevalence, about 3,500 patients have been diagnosed. So there's less than about 30% of estimated prevalence. Are those diagnosed patients severe? Or they also include mild and moderate? And second question is based on Phase III entry criteria, would you be targeting mostly severe patients? And the third question is on bone density. So during the period 3, based on the bone ton of markers day and there is a minimum -- there was a minimal short-term effect on bone density, but how do you think about the long-term use of the drug there? And lastly, where will the Phase III trial be conducted? And what percent of estimated 45 patients to be enrolled would be coming from the U.S.?

Yes. I guess I can kick it off. I missed the second part of the question. But the first part, on the 3,500 patients, those are mostly moderate to severe patients since the fact that they are getting picked up today. I don't know what the split is between moderate and severe.

Okay. Second question was based on the Phase III entry criteria, would you be targeting mostly severe? I mean I guess, it's going to be moderate, severe based on your comments.

Yes. So I can take this question, and this -- my name is -- Ananth here. So the market opportunity -- price -- expands and is broad enough to include all symptomatic ADH1 participants or patients. And the reason being is the symptom presentation as a result from hypocalcemia can vary from individual to individual and some of the events can be sporadic in nature. So what can be characterized as a severe symptomology, something like a loss of consciousness, acute event or a seizure. It's hard to predict and in many cases, it's difficult to manage against. So we understand that diagnosis has probably picked up best by symptomology and symptomatic presentation, but we anticipate that encaleret will be studied in a broad symptomology population and anticipate that the eligible population will be -- will include moderate to severe individuals with symptoms.

And then bone density, potential long-term effect on bone density and where the Phase III trial will be conducted?

Sure. So Dr. Gafni can likely best address the question on bone mineral density.

Yes. It's a great question. And these patients at baseline have -- are in a low turnover state. And that's why the patients with hypoparathyroidism tend to have high bone density a priori prior to treatment with PTH or calcilytic. And what has been seen with medications such as PTH, when they're given intermittently, is a mixed anabolic-catabolic effect where you see increases in bone density in some compartments and decreases in bone densities in other compartments. And this is truly even for postmenopausal women that are treated with PTH because it's not being given in a physiologic way. Now where you give an injection and you see a spike in PTH, and then it decreases very rapidly after that. What we're seeing with this drug is restoration more of normal physiology with the PTH levels being fairly stable. So my anticipation based on our initial Period 3 data would be that I would hope not to see the significant changes in bone mineral density that are seen with intermittent PTH therapy. It's hard to know for sure, but I think if we're trying to as best as possible restore normal physiology, then yes, the bone density might change, and it might even go down as we go from a low turnover state to a normal turnover state, but I wouldn't necessarily expect it to become abnormally low. It may just more approach normal because we're starting with it in an abnormally high state.

And then this is Dr. Roberts. I can answer your question about the location of Phase III trial sites. So we're looking for sites in North America, the United States and Canada and then in Europe as well as in Asia Pacific.

So do you have any estimate of what percent of the 45 patients to be enrolled would be coming from the U.S.?

At this time, we do not have that, but that information will be forthcoming as we start -- do study start-up in just a few months now.

Your next question comes from Dane Leone with Raymond James.

This is Sean on for Dane. Congrats on the pretty consistent data. Just a couple from us. First, can you give any color on the prevalence of what appears to be somewhat of a jigsaw pattern in the blood calcium and the PTH? Is it a function of a patient or 2 or more of a cohort-wide phenomenon? And then the second, maybe to put a finer point on the BMD discussion. In any of your preclinical models, do you see signs of elevated osteoclastogenesis like rank-OPG ratio changing?

Thanks, Sean. So I pass it to Dr. Gafni to comment on the consistency of the parathyroid hormone and blood calcium profiles over time.

I think that most -- they're -- certainly, for phosphorus, there's a circadian rhythm that you expect anyway. But I think that most of -- I think what I'm understanding you're looking at is the jigsaw pattern is mostly what we're seeing in period 2 when we're fairly rapidly adjusting the doses in a lot of patients over the course of the 5 days. And then once we get them into a more stable place, we're seeing less of the jigsaw pattern. Unfortunately, we're not showing the 24-hour sampling during period 3 at 8, 16 and 24 weeks, where you could see that really, this jigsaw pattern that is more apparent in period 2 is much less apparent when the patients are on a stable dose, that's the most physiologic dose for them. Of course, it is twice daily dosing during period 2, while we're sorting out the dose. But I think actually...

I was actually -- sorry -- I was actually talking about period 3, where week 8 and week 16, it appears to be closer to the lower abnormal.

I'm sorry, and that's actually -- it's in the legend. So the 8, 16 and that -- okay, that's -- I'm sorry, I misunderstood. The 8, 16 and 24-week measures were collected at the NIH, and those were collected prior to the dose in the morning, whereas the outpatient measures for the most part were collected approximately 4 hours after the dose. So that slight variation that you're seeing in the PTH there and blood calcium.

Got it. Thanks for the clarification.

Yes, I'm sorry. I misunderstood your question.

And then my second question on the preclinical. And then the second question on any signs of elevated osteoclastogenesis and preclinical models.

Dr. Roberts, would you like to address this question?

That's an excellent question. And off the top of my head, I don't recall the specific preclinical data that you're asking about. I know that this drug has been tested in a number of preclinical models, but I don't recall the parameters of osteoclastogenesis. I'm sorry, I don't have an answer for you.

Your next question comes from Greg Harrison with Bank of America.

Congrats on the data. I have 1 question with 1 part. On the ex-U.S. commercialization plan, is this a situation where you would pursue a partnership or one where the patient population is maybe small enough that you could manage the effort yourselves?

Yes. Thanks for the question. This is Neil. I can take it. I think a little bit of it depends on how much or how extensive we built out our ex-U.S. infrastructure based on the TTR data early next year. But yes, I think you're right to say that if you're going to do a de novo just for this drug, it's probably better to partner it. I mean, generally to make it NPV-positive to build out European infrastructure, you would need something like $150 million per the region unless you have a super high-priced drug, which just wouldn't be. So I doubt we'd do it alone.

Your next question comes from Ram Selvaraju with H.C. Wainright.

This is [ Miz ] on for Ram. Congrats on the data. So I was wondering what the gating items are for the Phase III trial initiation, if you're expecting a Q3 or Q4 start. And then I was wondering about the quality of life questionnaire. Does this include acute symptoms of ADH1 such as seizures, paresthesia and muscle cramps? And then finally, in the long-term extension trial, are you evaluating long-term complications such as nephrolithiasis, nephrocalcinosis and chronic kidney disease?

I'll pass it to Dr. Roberts. Go ahead.

Yes. Thank you. I'm going to go from your last question backwards, if that's okay. In the long-term extension, we are planning to follow patients long term with renal ultrasounds to do it exactly as you suggest, monitor for nephrocalcinosis and potential changes in nephrocalcinosis over the long-term course of treatment as urine calcium is expected to decrease as we've seen in our Phase II study. And we'll also plan to record events of symptomatic nephrolithiasis as well. From the quality of life questionnaire, the SF-36 or Short Form 36 is a nonspecific to ADH1 quality of life measures. So the questions that will be asked and assessed there are not specific to the symptoms these patients experience. However, out of all quality of life assessments, the SF-36 is the one that's been most robustly used in the hypoparathyroidism population. And so we have data on different forms of hypoparathyroid to which we can compare this and that it also allows comparison to normal individuals as well. We do plan to capture symptoms of ADH1 or hypocalcemia and hypercalcemia over the course of the study, those will just be captured outside of a questionnaire. And then finally, for your first question regarding gating of Phase III initiation, we are waiting or we are awaiting and almost to the point of protocol finalization and then the typical site initiation activities that take some time with different various IRB ethics, boards, whatnot reviews to get the first site up and going.

And I'm not showing any further questions in the queue. I turn it back to management for any final remarks.

Thanks so much, everyone, for the time, and we look forward to following up on the one outstanding question and speaking with you all as this Phase III gets underway. Thanks.

And this concludes today's conference. Thank you for your participation, and you may now disconnect. Everyone, have a great day.