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

Good morning, ladies Ladies and gentlemen, and welcome to BridgeBio Pharma's call to discuss proof-of-concept data for encaleret and ADH1. [Operator Instructions]. As a reminder, today's conference call is being recorded. I'd now like to turn the conference over to your host, Dr. Neil Kumar, Founder and CEO of BridgeBio Pharma. Please go ahead.

Thank you, operator, and thanks, everyone, for joining today's call. Before I dive in, I have to do the customary forward-looking statement here. So before we begin, I'll remind everyone that this presentation is being webcast and includes forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements. You all know the rest. So let's dive in. The purpose of today's call, which I hope is clear, is to discuss the positive and extremely encouraging data that were released this weekend at ENDO, detailing the latest in our efforts that many of you know about to treat autosomal dominant hypercalcemia type 1 through targeting the disease at its source, as we always do, in this case, directly targeting its causal driver, which is the hyperactivated calcium-sensing receptor. Maybe I'll say at the outset, whenever we're lucky enough to generate data, these compelling, we know we owe it to a broad group of individuals, starting with patients and physicians that participate in our trials. I'd say it always takes guts to participate in an experiment, but it took special courage this past year given the COVID backdrop, and so we owe our participants a huge thank you. And as I'll also discuss in a moment, we owe the whole team at the NIH. Certainly, Dr. Mike Collins, Dr. Rachel Gafni, who's on the phone with us today and their entire NIH team, a huge thank you for their vision and for bringing this idea to us. It's a very compelling idea. Our hope with this data is that we could do something profound for patients going forward. All right. So I'll make my comments brief here at the top, and I'll refer to just one slide, which is our so-called mountain top slide on Page 3. For those of you following along in the slide deck. Before I turn it over to my colleagues, Cameron Turtle and Jonathan Fox. And of course, if those names sound familiar, it's because they lead our Cardiorenal division, which is presented in other forms, such as these, mostly on our ATTR cardiomyopathy efforts. They sit alongside other names that you know about like Uma Sinha central skilled group ready to work with focused teams on very specific diseases. In this case, the capable Calcilytix team of less than 20 people and their partners at the NIH to turbocharge R&D efforts. In this case, it led to the transformation of an idea from Dr. Collins into proof-of-concept data in under 3 years. In other cases, as you know, it's led to INDs from hit to lead in less than 3 years and to Phase III efforts from discovery in less than 6 years. In all cases, I believe it's good evidence that a decentralized hub-and-spoke model that prioritizes focus at the level of each asset and hooks it up to a central chassis that provides speed does work. ADH1 is the major readout for us -- is the first of our major readouts this year, as you can see from this mountain top slide. The readouts are United, I'd say, by the size of the unmet need they address. They're all large and they're high probability of technical success. They're also late stage. They're also united by what I referred to earlier, which is that they wouldn't be projects actually. If it weren't for the vision of specific academics who, in turn, chose to partner with us. That says a lot about these academics and hopefully, something about the -- our ability to be a partner of choice when thinking about how to drive an idea forward into therapeutic. The next readout after this one will be our Phase III ATTR cardiomyopathy readout towards the end of the year. In ADH1, just as an ATTR, we have targeted a well described genetic disease added source, as I mentioned earlier. And in doing so, [ due ] to a set of design criteria designed really from the patient or marketplace backwards. In this case, something that works to rectify all key molecular symptoms, both serum and urine calcium without trade-offs, something that's efficacy spans all mutations. We tested in this trial, both transmembrane and extracellular mutations and something that is potentially convenient for patients. So I'm going to turn it over now to Cameron to walk us through the opportunity and then Jonathan to walk us through a bit more about our approach here. And I'll come back during Q&A. Thanks so much. Cameron, take it away.

Thanks, Neil. And as we flip the slide Page 4 in the deck, we can see the summary of the approach and design criteria for ADH1. Specifically, they are estimated to be 12,000 individuals in the U.S. who have any of over 100 variants in the gene that encodes the calcium-sensing receptor, causing ADH1. These variants hyperactivate the calcium-sensing receptor, resulting in decreased blood calcium levels, increased urine calcium levels and decreased parathyroid hormone levels, each of which can lead to a range of downstream symptoms. As Neil mentioned, there are no approved therapies indicated for the treatment of ADH1 and the current standard of care, which is supplementation with calcium and activated vitamin D or calcitriol do not correct the fundamental hyperactivity of the calcium-sensing receptor and are generally unable to normalize blood and urine calcium levels simultaneously. Our investigational therapy called encaleret, aims to match our design criteria that Neil outlined for a treatment for ADH1. Specifically, it's an orally available small molecule that aims to treat ADH1 at its source by directly antagonizing the calcium-sensing receptor. Ideally, normalizing the sensitivity of the receptor regardless of the variance that the individual inherits. The hypothesis that we're testing is that this approach could simultaneously correct the blood calcium, urine calcium and parathyroid hormone levels in ADH1 patients and ameliorate the downstream symptoms associated with the disease. From here, I'll turn it over to Dr. Jonathan Fox, the Chief Medical Officer across our cardiorenal programs to go over the molecular pathophysiology of ADH1, the rationale underlying our development of encaleret and the design of the ongoing Phase IIb study, which Dr. Gafni will present. Jonathan?

Thanks very much, Cameron. And welcome, everyone, to our program here this morning. It's a pleasure and honor to be able to share these data with you. Starting on Page 6 of the deck. This is a schematic of the disease mechanism in a little bit more detail. And as Cameron mentioned, there are a variance in the gene encoding the calcium-sensing receptor that lead to a hyperactivity so that the receptor, which basically tells all the calcium sensitive cells in the body. What the calcium level is on the outside and effect changes in hormones like PTH to change that level either up or down, it's oversensing the calcium levels, so it sees low calcium as normal. As you can see, the results of that is that in the middle box of the slide, you have decreased blood calcium, increased urinary calcium and decreased parathyroid hormone secretion from the parathyroid gland. You can think of it as a tank of water that you're continually trying to fill, that has a big leak at the bottom. So the filling is happening by taking supplementations by mouth. And the leak at the bottom is calcium spilling into the urine because in the absence of a normally functioning calcium-sensing receptor. And in the absence of PTH you don't reabsorb calcium that's otherwise lost in the urine. So the acute symptoms and the long-term complications are laid out there on to the right, they often can -- patients can present with hypocalcemic seizures, especially in infancy. They experience loss of consciousness, paresthesia or tingling of the fingers and toes, tetany or abnormal muscle contractions and muscle cramps. And the long term, complications are actually related mainly to the inability to regulate the amount of calcium that's lost in the urine. So nephrolithiasis or kidney stones, nephrocalcinosis, which is actual calcification of the kidney tissue itself. And this, of course, both of these can lead to or exacerbate chronic kidney disease and loss of renal function. So as can -- as Cameron laid out, a moment ago, the therapeutic hypothesis is that by dialing back the sensitivity of normalizing the calcium sensor receptors activity to exercise calcium, will normalize blood calcium and urine calcium and regulate PTH levels to its normal range in ADH1 potentially resolving all of these symptoms. So if we move to Slide 7, just a review in a little more detail about what is the current way to manage people with ADH1, and it's rather simple, oral calcium and activated vitamin D, which is a prescription medication. And those do raise blood calcium, but it's at the expense of increasing or exacerbating the urinary loss of calcium, and it actually suppresses PTH secretion rather than encouraging it. So the key disease measures you see there are blood calcium to the left with the narrow ranges indicated by the dashed lines. And in the absence of therapy, these people have blood calciums in the sort of 6 to 7 range, which is quite low. But even with supplementation therapy is to get them to just about the lower limit of laboratory reference range in order to minimize the spilling of calcium into the urine. It'll we[indiscernible] shows you that the best efforts of experts like Dr. Gafni and her colleagues at other institutions, even with very careful regulation of the [indiscernible] oral supplementation, there's almost always going to be in excess of calcium spilled into the urine with its consequences that I already mentioned. Finally, the parathyroid hormone secretion pattern in the presence of supplements, as you can see, is quite suppressed, and as Dr. Gafni will show you in a few minutes. The pattern of baseline measures in the patients that she's been taking care of and who are participating in the study bear this out. So there are 2 main places where the calcium-sensing receptor does its work. It's at the level of a parathyroid cell, which is schematically represented on the left that the calcium-sensing receptor, again, in a way reads the extracellular concentration of calcium. And as the G protein coupled receptor that then tells the nuclear apparatus, whether to express the PTH gene or not, and that leads to PTH secretion or not. So [indiscernible] is in the abnormally high sensing receptor as an ADH1, it's basically telling parathyroid cell to go to sleep and not to put out PTH. In the renal tubule, which is responsive both to PTH and directly to calcium, the calcium-sensing receptor is depicted in the cartoon directly regulates the reabsorption of calcium from the ultra filtrate back into the blood. So again, in the presence of an abnormal receptor that calcium goes -- does not get reabsorbed properly and is lost in the urine, again, with the consequences that I mentioned. We did obtain proof of mechanism and a mouse model of ADH1 and in humans with a wild-type receptor in a prior program designed to develop encaleret for different disease indication. So what you see on the left is a calcium-sensing receptor variant knock-in mouse. So these are genetically modified mice that are carrying an oversensing human calcium-sensing receptor. And you can see that compared to their control littermates in white in the gray bars and ADH1 mice have -- respond to encaleret with an increase in blood calcium and a decrease in urinary calcium, as is predicted by the molecular mechanism. In the human for the prior indication on the right, you can see that increasing doses of encaleret given to human participants in this study that compared to placebo, there was a dose-related increase in blood calcium in response to encaleret. So this gave us a lot of encouragement that this drug, in fact, could be in a way, a perfect match for the molecular -- the underlying molecular defect in ADH1. So the Phase IIb study that is currently ongoing will continue as we plan the Phase III program. So here you see a schematic of the program overview. We're right now in the dark blue part of the study that Dr. Gafni is going to present to you momentarily. And we're continuing on to the second period in the Phase II study as well as the period III. And the differences here is that in the period one, this is basically a dose exploration phase. Period 2 is a dose consolidation phase, both in patient at NIH clinical center and period 3 follows directly out-of-period 2 as an outpatient maintenance phase. And you can see that the key study objectives are listed down there on the bottom left. Those are the main things we're measuring and assessing. And the additional measures are a variety of biomarkers of calcium metabolism and related phenomena. So now I'd like to turn it over to Dr. Rachel Gafni. Dr. Gafni is a senior research physician of the Skeletal Disorders and Mineral Homeostasis section at the National Institute of Dental and Craniofacial Research at the National Institutes of Health in Bethesda, Maryland. Dr. Gafni is a pediatric endocrinologist and recognized [indiscernible] of bone and neck [indiscernible]. Dr. Gafni?

Thank you very much. I am very, very excited to present our early results from this Phase II trial using a drug that takes a novel and physiologically centered approach to the management of this unique form of hypoparathyroidism. Slide 12 lists my disclosures, and moving on to Slide 13. Before we jump into the data, I'd first like to introduce you to one of our patients. I met this gentleman in 2010 when he was 40 years old. He had a history of tetany as a newborn, seizures during childhood and ongoing muscle cramps and paresthesia. But despite these symptoms, he never underwent any evaluation or treatment until he was 24 years of age when hypocalcemia was noted on routine laboratory testing. At that time, he was diagnosed with idiopathic hypoparathyroidism and started on conventional therapy with calcitriol and calcium supplements. He also received intermittent hydrochlorothiazide to manage this hypercalciuria. In 2010, he came to the NIH to participate in a clinical trial using twice daily PTH 1 to 34 injections for hypoparathyroidism. During the course of the study, we performed genetic testing, which identified a pathogenic calcium-sensing receptor variant, confirming the diagnosis of ADH1. The table below summarizes is biochemical findings prior to and on treatment with PTH 1-34. As you can see, prior to PTH treatment, he had the classic features of ADH1, hypocalcemia, low PTH, high normal phosphate and inappropriately high normal urinary calcium. His eGFR, which reflects kidney function showed mild impairment. And after 1 year of PTH 1-34, without any concurrent calcitriol or calcium supplementation, his blood calcium remained just below the lower limit of normal, while the phosphate and 24-hour urine calcium levels were still elevated. Change to the next slide, please. Additionally, as part of our PTH study, we performed annual renal ultrasounds. The image on the left shows -- a normal scan on our patient at baseline. However, after 1 year of treatment with PTH 1-34, he had developed calcium deposits within the kidney, this is known as medullary nephrocalcinosis and is seen in the right panel. It therefore, appeared that both conventional therapy and PTH 1-34 were inadequate in managing his biochemical abnormalities or preventing renal morbidity. Next slide. After almost 5 years of PTH 1-34 treatment, he was transitioned back to conventional therapy. In 2020, at age 50, he returned to the NIH to participate in the encaleret study we are discussing today. This table includes the data from the previous table and adds his pre and encaleret studies performed while unconventional treatment this past October. Most of his laboratory studies have not changed, except for his renal function, which has continued to decline. Next slide. I am now going to present some of the data for this study in which our patient was a participant. Slide 16 shows the schema of for period 1 that Dr. Fox mentioned previously. As a reminder, period 1 consisted of a cohort of 6 patients. After assessing for eligibility, patients were admitted to the NIH. Their final dose of calcitriol was taken approximately 36 hours before the first dose of encaleret. They were then given escalating doses of encaleret for 5 days, once-daily for the first 3 days and twice daily for the last 2 days, while undergoing intensive blood and urine sampling. During these 5 days, patients were instructed to consume at least 1,000 milligrams of dietary calcium per day. 5 of the patients were able to do that and received no calcium supplementation. 1 patient had a low dietary intake and was given a small calcium supplement to ensure that she consumed 1,000 milligrams per day. Next slide. The table on Slide 17 shows the baseline characteristics of the study participants. 6 subjects, three men and 3 women with a mean age of 40 years, bearing 4 different calcium-sensing receptor variants were enrolled in the study, and they all had typical biochemical features of ADH1, hypocalcemia, hyperphosphatemia and inappropriately normal or frankly, elevated urine calcium, 2/3 had nephrocalcinosis on renal ultrasound. Not shown here is baseline renal function, which was variable in the group with the mean eGFR of 83, plus or minus 20, consistent with mild to moderate impairment in some of the subjects. On electrocardiogram, the mean QTC time was prolonged, as is seen with hypocalcemia. All were being managed with calcium and calcitriol supplements in fairly typical doses divided throughout the day. Next slide. Safety and tolerability were the primary endpoints for this study. As can be seen on the table on Slide 18, encaleret was well tolerated with very few adverse events and no serious adverse events reported. The only events deemed to be related to the drug were 2 instances of transient asymptomatic blood phosphate levels below 2 milligrams per deciliter in two subjects. Next slide. The upper panel on Slide 19 represents the mean pharmacokinetic response to escalating doses of encaleret over 5 days with the dosage listed along the top of the graph. Encaleret was rapidly absorbed with plasma levels rising as soon as 30 minutes after taking the dose and peaking at about 1 hour. On days 4 and 5, when the drug was given twice daily, drug levels continue to be detectable throughout the time, of course. The mean intact PTH levels shown in the bottom panel mirrored the encaleret levels, rising sharply in a dose-dependent fashion after each administration, generally peaking 30 to 90 minutes after dosing and transiently exceeding the upper limit of normal at the highest dose. Next slide. The figures on Slide 20 display the mean pharmacodynamic responses to escalating doses of encaleret it. In the upper panel, we see the mean albumin corrected blood calcium gradually increase into the normal range by day 4. Of note, one patient developed a blood calcium level just over 10 milligrams per deciliter and her day 5 dose was reduced to 120 milligrams. Concurrently, the mean 24-hour urine calcium excretion, shown in the bottom panel, decreased into the normal range. Next slide. The figure on Slide 21 demonstrates the sharp reductions in blood phosphate seen after each dose administration, which then stabilized and remained mostly within the normal range, with the exception of occasional asymptomatic decreases below the normal range at the highest BID dose. In addition, blood magnesium, which was low or low normal prior to encaleret normalized, and importantly, the prolonged QTC seen on baseline EKG is resolved, consistent with reversal of hypocalcemia. Next slide. On Slide 22, we see the individual and mean responses on days one and five. The day 1 blood calcium and PTH values, shown by gray hatched bars were drawn just prior to administration of the first dose of encaleret, while the urine calcium reflects the 24-hour excretion over the course of that first day. By day 5, shown by solid 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 an elevated mean value. Although not shown in this presentation, each subject's mean day 5 blood magnesium and phosphate levels were also in the normal range. Next slide. So what about the patient I described at the very beginning? As you can see on Slide 23, he had an impressive response to encaleret, with the top left panel showing calcium levels gradually arising and staying within the normal range by day 4 and the top right panel showing 24-hour urine calcium levels very elevated but then dropping into the normal range and then becoming undetectable. In the bottom left panel, this patient's PTH values rose from undetectable and were maintained within the normal range on days 4 and 5. Blood phosphate also declined into the normal range. Next slide. In conclusion, encaleret was well tolerated when administered in escalating oral doses once or twice daily over 5 days with no serious adverse events reported and no adverse events of moderate or severe intensity. Blood calcium, PTH and phosphate were normalized while maintained within the normal range on average by day five. Urinary calcium excretion was reduced to below the upper limit of normal or undetectable in all participants while on encaleret and eucalcemic. So we saw these consistent changes from baseline in blood and urine mineral measurements, which provide proof-of-concept data that encaleret may be an effective treatment for ADH1, and data support further development of encaleret in this disorder. Thank you very much.

Jonathan, we'll turn it back to you to cover the next steps.

Sure. So I did want to just pause on Slide #25. Dr. Gafni is being too modest. But I think credit to you, this is just an acknowledgment to the patients and the investigators and all of their staff who have been taking such great care concept [ with others ] Mike Collins and Rachel prominently displayed and some of their -- some of the more of the key individuals participating in this study. So we thank them. So if we go to Page 27, the next steps here, really, the main focus right now is to generate further evidence in the ongoing Phase IIb study. As I mentioned, we have a second period of inpatient treatment within encaleret that is enrolling additional subjects -- additional participants into -- that also then participate 3. And we look forward to similarly exciting data coming from those participants as they move through the study. We did receive the orphan drug designation from the FDA for ADH types 1 or 2 earlier this year, and we plan to have some interactions with the agency as we continue to generate data and shape the rest of the registration program. In terms of planned activities, we're working on different options for designing the Phase III program. And importantly, we're also paying attention to the pediatric development program, which by necessity as in many other drug development programs lags a bit behind the adult development program because of the special considerations around treating children. But as this disease often presents early in life with quite severe manifestations like seizures. We are putting a high priority on moving this along as quickly as we can. Finally, we are also looking at opportunities to evaluate and color in the treatment of nongenetic forms of hyperparathyroidism. So I'll now I'll turn it back over to Cameron for the Q&A.

Great. Thanks, Dr. Gafni and Dr. Fox. Operator, please now open the queue for Q&A, and we'll address analyst questions.

[Operator Instructions] Our first question comes from Salim Syed with Mizuho.

Congrats on the data. I just had a couple of questions, if I can. One for maybe Dr. Gafni and then maybe one for maybe Neil or the team. The first, Dr. Gafni, on Slide 22, I wanted to talk about patients 3 and 4 for a second here. So it looks like patients 3 and 4 had above the normal range in parathyroid hormone. And they were also within the normal range of blood calcium, but on the lower end of normal. And I'm just kind of curious how you're thinking about the dosage level here given that in the pharmacodynamics slide, patients [ who didn't ] achieve the blood calcium normal until about 180 mg bid at least on the mean. So if you were to take -- if you were to take these patients down in dose, do you suspect that they would still be in the normal range for blood calcium level? And how are you thinking about that? And then the second question here is just speaking to the last point that I think you guys had mentioned about the broader population of [ hypo-para ]. Sort of curious what you guys are thinking about there, which populations you plan on pursuing. Any concerns on any or anywhere you feel more confident?

Okay. Thanks, Salim. And Dr. Gafni, please go ahead on the first question. And then I think maybe, Jonathan, why don't you start on the broader hypoparathyroid population?

Sure. It's a very good question. And I think it's important to remember that it's a little bit unpredictable how hypoparathyroid hormone level will go when they're first exposed to this drug. And we ramped up the dose pretty rapidly. But parathyroid hormone takes a little bit of time to raise blood calcium. It has a different effect. So it acts at the bone to increase bone resorption, which releases calcium from the bone. It also acts at the kidney to stimulate bone reabsorption. And it also activates vitamin D to take the storage form of vitamin D to make endogenous calcitriol. So it's a very high spike, for example, in parathyroid hormone doesn't necessarily translate to an immediate rise in PTH. And so I think that in this very, very short study, just over the course of 5 days, this does not really tell us what the dose for this patient is going to ultimately be. And that's why we need to do period 2 and period 3 of the study to do more dose titration and adjust it out because I do suspect that we won't require doses of 180 twice daily in many of these patients to achieve PTH levels that stay within the normal range and calcium levels within the normal range. So I think this is a little bit of snapshot. What it does tell us, which is really exciting is that these parathyroid glands are completely normal. They have all the machinery to make parathyroid hormone. They're ready to go. They just need a drug like encaleret to alter the signaling so that they can do their job. And once we better titrate the dose in the individual patients, I think that we will be able to normalize all of the parameters over a sustained period of time. Did that answer your question? Or I can clarify it more if you need?

Yes. So in terms of being able to maintain the blood calcium, so why wouldn't it be when you lower the dose, why would the blood calcium levels stay -- still stay in that lower end of the normal range for those patients, for example?

Because -- so patients with one of the main sources of calcium in our body is the bone. And patients with hypoparathyroidism all forms, including ADH1, have low bone turnover because their parathyroid hormone levels are low. And it takes time for the bone to reestablish a new steady state when it starts to be exposed to parathyroid hormone. So this will -- this does take a little bit of time for all of the systems that contribute to normalization of blood calcium to be reregulated and find their new set point.

Got it, thank you.

Thanks, Rachel. Jonathan, do you want to tackle the question for non-genetic hypoparathyroidism?

Sure. I'd be happy to. Just one small comment to follow-on to Dr. Gafni's comments to the last question. If you go back to Slide 9 and you look at the right-hand panel, these are people with a non variant calcium-sensing receptor receiving in encaleret on a chronic basis. So it didn't take much encaleret, at 15 milligrams a day was the highest dose that was well tolerated in terms of the blood calcium response in people with a normally functioning receptor. So in Dr. Gafni's patients, it's a little hard to predict, given the differences in penetrants and the differences in clinical exclusivity in terms of how severe their hypocalcemia is, it can be quite variable. And so it just highlights the need for individualized dosing of encaleret in the patient population we're talking about today. Moving to the other question about other forms of hypoparathyroidism. Just recall that in addition to ADH1 and other genetic [ forms ], we have the postsurgical population, which is probably the largest single subgroup. There are people with autoimmune causes of hypoparathyroidism and the so-called idiopathic, which is just a fancy way of saying we don't know. In fact, illustrating -- illustrated very well by Dr. Gafni's case history patient who was diagnosed with that label at age 24. And it wasn't until he came under her care that the proper diagnosis was made in terms of genotyping. But going back to those other subsets, we're exploring the opportunities in those subsets, especially in the post surgicals, it's not yet clear to what extent encaleret works -- its good effects on blood calcium and urine calcium, either directly through the effects on the kidney or indirectly through stimulating PTH secretion. So the key thing being in the postsurgical patients, either because of ischemic damage related to what is usually a neck surgery or trauma, it's not clear how much residual gland there may be. And because of the mechanism of action encaleret would probably require some residual tissue. But again, the magnitude of the contribution by the direct effects of encaleret on the kidney -- are not -- looking at different ways of establishing [ them ].

Our next question comes from Eun Yang with Jefferies.

Congrats on the data as well for me. So a few questions. One, so the prevalence is 12,000 patients. Based on this Phase II data, understanding it's a small number of patients, what percent of patients kind of like represents the 12,000 prevalence. So percent of those is being represented in the current study? That's question number one. Second, about 2/3 of the patients have nephrocalcinosis. So from the treatment, how long do you think that you would kind of I don't know if it's going to reverse, but kind of stabilize the condition in those patients and kind of restoring mild to moderate kidney impairment? And thirdly, when you meet with the FDA in the second half of this year, do you think a Phase III study, would it be kind of a similar to the hypothyroidism -- hypoparathyroidism study where you're only looking at calcium normalization in the serum in -- in urine? Or do you think you may need to show some improvement in acute symptoms as well as long-term complications?

Thanks, Eun. I'll take the first question. But Rachel, I'd asked you to potentially comment on the timing related to urinary calcium and nephrocalcinosis. And then Jonathan, regarding the interactions with the FDA. Regarding the proportion of the prevalent population that is represented by this study, as you saw on the first page, we saw 4 different mutations in the calcium-sensing receptor that we're seen in this study. That -- there were actually a few of those that are some of the most common mutations that cause ADH1, even though there's over 100 mutations that have been described, the P221 L mutation is the most common mutation that's found in the literature. And together, those 4 mutations account for a little over 1/4 of the total prevalent pool that they've described in the literature. So certainly, it's still a small proportion, and there may be additional variants that have different responses to encaleret. But we did see variants that occur in both the extracellular domain and the transmembrane domain. And as you saw in the data, had a very similar response. So Rachel, I'll let you comment further on that question and then as well the question regarding urinary calcium and the time to nephrocalcinosis.

Thank you. So nephrocalcinosis is defined as really microscopic calcium deposits within the tissue parenchyma, and traditionally, they do not go away. It's not reversible, though there are some reports in the literature of people who develop nephrocalcinosis acutely because of a hypercalcemic event that then do result at least on ultrasound, not necessarily on renal biopsy. So it's not expected that correcting the biochemical parameters in these patients would cause reversal of nephrocalcinosis. But it is our hope that reducing the urine calcium into the normal range as well as normalizing the blood phosphate for a prolonged period of time would stabilize existing metro calcinosis and ideally prevent further decline in renal function. But there is really no way to predict that just from these 5 days of data. But that, of course, is the hope.

Thanks, Rachel. And Jonathan, do you want to handle last question regarding the Phase III?

Sure. So the short answer is we've not yet had that discussion with the agency. I will say that given the fact that prior to the initiation of the ADH1 program, with our collaborators at the NIH, encaleret had been administered to almost 1,200 people in prior research studies. So the safety profile is pretty well-established with the dose-limiting issue for people with a normal calcium-sensing receptor being, in fact, a high calcium. So no other safety issues were identified and when we filed our investigation on new drug application with the FDA, they opened the IND without any serious concerns expressed on their part. So that's all good news. We did obtain orphan drug designation as well. So there's recognition at the FDA that this is a rare and serious disease that merits further investigation and development of targeted therapies. That could be disease modifying. And to your question about endpoints, since the immediate acute, chronic and renal consequences of the disease are, in fact, all directly tied to blood calcium levels and urine calcium excretion. I don't see any reason why those wouldn't serve as endpoints, either separately or as a composite. But again, we haven't had those discussions yet.

Our next question comes from Anupam Rama with JPMorgan.

Congratulations on the data. Maybe just a quick one, just following up on a couple of the last questions on granularity on time lines for meeting with regulators. Do you think you can do this based on the data you have now? Or do you need to learn more from period 2 and 3 before you can have the regulatory interactions, particularly as it relates to dosing, which has been asked about a couple of times?

Sure. I'll take that one on as well.

Go ahead, Jonathan. Yes.

Yes. So thanks, Anupam. I described the periods of the Phase II study as exploration consolidation and maintenance for a reason. As Rachel illustrated by her discussions around the initial 5-day period, we didn't really know what to expect in terms of how much encaleret these people with an abnormal receptor might require what the excursions in blood calcium might be. And the fact that we observed quite steady rise in blood calcium that was sustained. It was really quite encouraging. But does, again, point out the need for individualizing the dose. The period 2 carries on if anything, is confirming a lot of what we've seen so far with respect to the measures and the observations made. But it's really important that period 3 that we learn more about how to manage the use of in colored in the outpatient setting, which, of course, will be its chronic use as a marketed product should we get there. Should we be successful. So I think all of those data are going to be important to share with the agency with respect to how we go about confirming all of this in a Phase III program.

Our next question comes from Tara Bancroft with Piper Sandler.

So quick question on the PTH levels that you saw. So in those 2 patients that you said that had elevated PTH slightly above normal levels. I was just wondering if those elevations were sustained after the treatment period, if you had looked at that? And what the potential downside to that may be if they do have sustained above normal elevations? And then for the urinary calcium, I was wondering how soon you saw that happen. And for the other -- for the 3 that still had detectable levels under the normal range? Did it like what were the kinetics of those? And did it appear that maybe they were on their way to becoming undetectable as well?

Dr. Gafni, I'll ask if you address those, if you're able?

Yes. Thank you. So what we don't show you here is at the conclusion of the 5th after the 5th day, when the patients were -- had -- they had their final dose of encaleret on Friday night, Saturday morning, they completed their 24th or [ year-end ] and were restarted on their conventional therapy, and then they had blood work done on Monday. So just over -- about 48 hours, 48 to 58 hours depending on the timing, after they took their last dose of encaleret and we're back on their conventional therapy, and all of their biochemical markers have returned to baseline pretty much. So the PTH levels were undetectable, again, just 2 days after stopping the enceleret. So the elevation in PTH was definitely not sustained. And even in, I think it was -- you can see on Slide 19, you can see that the rises that we saw in PTH were very sharp and then rapidly dropped and for most of the patients did remain within the normal range. So with sort of this initial spike after the increase in encaleret levels. So there's no evidence to suggest that these PTH levels would be sustained. And of course, with titrating of the drug, they should return into the normal range when the correct dosing is achieved for the individual patient. Regarding the urinary calcium, the urinary calcium is going to a degree, reflect not only the drug but also the blood calcium levels. So there will be presumably a limit, if you continue at too high a dose of encaleret such that the blood calcium level continues to rise, the urine calcium level eventually will also continue to rise because you'll exceed the renal threshold for calcium reabsorption. It's a little bit hard to predict what was going to happen in those patients who did not achieve undetectable levels. But again, I think that additional titration of the dose in both period 2 and period 3 will answer those questions in the long term.

And Rachel, and Tara just as a reminder, these are -- there are 24-hour urinary calcium measures. So it is just 1 measurement per day as opposed to calcium and some of the other measures, where it's being entered multiple times.

Well, just to clarify because we didn't show this data, but we do have fractionated calcium excretions and fractional excretion of calcium throughout the day as fractions of these 24 hours, we measured that 5 different intervals throughout the 24-hour period, and we did see a decrease. All of the data in terms of statistical analysis hasn't been fully analyzed, this is all just preliminary. But we did, of course, see a decrease in fractional excretion of calcium that correlated with this decrease in 24-hour urine excretion. But the more important value over the 20 -- the fractional excretion of calcium shows you this immediate pharmacodynamic response, but the ultimate important value when you're assessing the long-term effects of the kidney is the 24-hour excretion.

And our next question from Tom Shrader with BITG.

I'm looking at Slide 20 and wondering if I'm taking it too literally. And I think [Technical Difficulty] some suggestion of collapsing to 1 or 2 doses. Is that no longer realistic? Is Slide 20 kind of expect -- how you would expect to use the drug?

Apologies. I'm not sure if everyone had the same challenges as I did. I think I missed a few words there, Tom. The question was whether or not we expect the doses to consolidate over a longer period of time instead of going up to 180 milligrams BID? Is that correct?

No, whether every patient will eventually need a detailed titration or whether you will, in fact, eventually get to 1 or 2 doses that fit most patients.

Got it. Good question. Dr. Gafni, can you address that question?

Well, I don't think I'm allowed to share any of the information that we're accumulating with our ongoing period 2 or period 3 data, yes, is that correct?

That's correct. Yes. Yes.

Because, obviously, we are into those phases. But I -- 1 thing to point out is if we look at the individual data on Slide'22, what I can tell you is that subjects 4 and subjects 6 had the same genotype, yet they had quite different calcium and PTH responses. And subjects 1 and 2 also have the same genotype. So I think it's a little bit too early to tell if we'll be able to settle out on a couple of doses. My intuition is that we'll be able to settle out on a reasonable starting dose with some titration in either direction, but it's really too early to speculate on this. But I suspect that based on the differences in calcitriol and calcium requirements that are required by patients. Even with the same genotype, where some patients are quite asymptomatic and some people need higher doses of calcium and calcitriol that more flexibility in dosing may be required for this drug as well.

Our next question comes from Paul Choi with Goldman Sachs.

And let me add my congratulations as well on the data. Just a couple of quick ones for us. Just as you get the normalization of the parathyroid hormone and this is for either at Dr. Gafni or Dr. Fox. Can you perhaps then envision a maintenance scenario where the dosing ends up being QD at about either the 180 or some alternative dose? And then secondly, I think 1 of the interesting signals in terms of the data was the normalization of the QTC prolongation. In addition to this and perhaps for women, can you maybe just speak to any other comorbidities that could be potentially addressed, such as the QTC prolongation or perhaps downstream for women, things like osteoporosis?

Thanks, Paul. And maybe we'll go in that exact order. Dr. Gafni, if you want to start by addressing the questions about QD versus BID dosing and the QT interval. And then Jonathan, please feel free to add?

Yes. I might ask Dr. Fox to talk a little bit also about the QD versus BID dosing. But based on the previous pharmacokinetic profiling and the understanding of the terminal half-life of this drug, which is 10 to 12 hours, the expectation is that patients most likely would require twice daily dosing. And then in terms of the -- there were a couple of different questions. One was regarding specifically effects in women. One thing to keep in mind is that patients with hypoparathyroidism have elevated bone density, osteoporosis is not a component of hypoparathyroidism. So -- and because, as I mentioned before, because the patients have low bone turnover. So the risk for low bone density could occur if you were to over treat the patient such that they had persistently elevated parathyroid hormone levels. So -- and -- but in that case, the patients in this disorder would also have hypercalcemia. So I think with adequate monitoring, you would be able to prevent the development of osteoporosis. Keeping in mind that these patients are already starting at an elevated bone density compared to their peers. What was the question exactly about the EKG? I mean, I'm not certain what the question was on that.

Sure. Just with regard to the normalization of the QTC prolongation, are there any additional comorbidities that could potentially be addressed besides of QTC here either in the cardiovascular or other side of potential comorbidities? .

Yes, I'm not aware of intrinsic cardiovascular risk per se. I mean, one, there's certainly exploratory things that 1 could consider looking at, for example, patients with hypocalcemia tend to have -- are at risk for laryngospasm and perhaps sleep apnea could be a comorbidity that's associated with it. But that's never been reported in the literature. I'm just sort of making this up as possibilities that 1 could think about. But I don't believe that there are specific cardiovascular diseases that are linked to ADH1 or other forms of hypoparathyroidism.

So if I could just add to Dr. Gafni's comments. I want to take you back to Slide 19 on the once daily, twice daily question. So if you -- so again, this was only a 5-day period. These are the participants in the study are people with lives and jobs and kids in school and what have you, and asking them to spend a week of their lives at the NIH Clinical Center is quite a dedicated commitment on their part. So we did what we could in terms of a rapid dose escalation, as Dr. Gafni mentioned earlier. And if you look at the middle of these paragraphs on Page 19, with the 180-milligram given once you see the rapid rise in blood concentration with encaleret, which drops off in a mode exponential fashion or first degree elimination pattern. This is typical for small molecules. And while you got the PTH up to the upper limit of normal, right after that dose, it did tend to drift down to the lower limit of normal over the course of the 24 hours. Now it's hard to know if we had continued 180-milligram once-daily for several more days, if we might have seen something different. But again, given the half-life of 10 to 12 hours, it seems unlikely since this drug does not accumulate, to any extent, upon steady state dosing. And then when we gave it twice daily, you can see that the nadir of encaleret concentration is quite a bit higher than it is with the once daily dosing, as you would expect, given the half-life. And based on some modeling that was done from the prior development program, lab values, it seems that there may be a minimum concentration, blood concentration of drug that is required to sustain a concentration of PTH in the blood as is reflected in the day for pattern that you see on that slide. And if you go then to slide -- back to Slide 20 you can see that, again, if we had continued the 180 once a day, might we have seen a continued rise in the blood counts into the normal range. It seems as likely as not, but given the prior comments I made about maintaining sort of a more steady blood concentration or at least above a minimum value of encaleret seems to result in a smoothing out of the PTH profile and more importantly, the blood calcium and urine calcium profiles. When it comes to some of the related effects of hypocalcemia and its correction, it is known that severe hypocalcemia can cause muscle weakness, including cardiac muscle. And so it is recognized as an unusual, but reversible form of heart failure, especially in people who may be presenting with extremely low calciums who have not yet been properly diagnosed. And the thing about the QT interval, yes, it is a form of long QT syndrome, although it's not usually described that way because with proper therapy, at least to bring in the blood causing up towards the normal level should not precipitate heart rhythm problems, but these have been associated with people who, for reasons related to if they run out of their calcitriol or they have an intercurrent illness with nausea and vomiting and that sort of thing that might lead to an abrupt lowering of the blood calcium that can lengthen the QT interval even further and potentially precipitate cardiac rhythm problems.

Could I make a -- could I make 1 additional comment just that might help elucidate this once-daily versus twice daily, based on some of our experience previously with using parathyroid hormone injections in hypoparathyroidism, it was much more difficult to maintain -- and obviously, that's a different drug, but you see the same sort of -- you see a peak in PTH soon after giving the injection. And what happened with parathyroid hormone therapy when it was given only once-daily was that bone turnover was much more stated. You had a rapid rise in calcium and had to give higher doses to achieve a blood calcium into the normal range, which then fell and then the patients were hypocalcemic. So the dosing, if you -- my expectation would be that if you wanted to try to use this drug in a once-a-day dose, you would have to give a higher dose resulting in a higher PTH peak to keep the blood calcium level into the normal range for the most of the 24-hour period, whereas you could probably have more physiologic dosing with less rises and undulation in PTH levels, if you were to give it in a BID dosing based on the figures on Slide 19.

Our next question comes from Mani Foroohar with SVB Leerink.

Obviously, there's been a lot of discussion around doses in this study. But when considering nongenetic hypoparathyroidism and evaluation of encaleret there. Obviously, different causes between genetic and nongenetic, can require very different levels of drug activity. How do you think about potential dose ranges? Would there potentially be opportunity to create novel formulations or formulation IP as we saw in QED? Or will it just be really difficult to [ fund ] that wide of a gap between required doses? And then secondarily, most specifically on this study in this patient population, obviously, normalizing serum urine calcium is at the very center of what you're trying to do for these patients and normalizing their blood chemistry. How do you think about integrating ongoing monitoring into the study and into what might wind up in a label, given it's relatively straightforward to [ moderate ] patients, serum calcium and urine calcium, on an outpatient and ongoing basis?

Thanks, Mani, and maybe we'll take those questions in actually the reverse order. Dr. Gafni, if you could comment on how you think about the long-term usage of a drug like encaleret in the outpatient setting? And then, Jonathan, maybe you can comment as much as we know at this point in terms of the potential dosing in the nongenetic hypoparathyroidism?

Yes. So to answer that question, I think you first -- I just want to give you an idea of what monitoring goes into a patient on conventional therapy because I monitor a lot of patients, and they all have standing orders for laboratory values so that if they're having symptoms of high calcium or low calcium, they can go directly to a lab, without even having to call me, they can go to the lab and just say because we don't have home calcium monitoring because most patients with hypoparathyroidism, if you ask them for 1 thing that they wanted, they would want a finger stick home calcium measure, just the same way diabetics do because the calcium levels can really vary a lot. So my patients are at minimum getting their labs done on conventional therapy every 3 months. And in some patients, I actually get labs on them monthly. So these patients are already used to having to be monitored pretty frequently because we don't want them to get hypercalcemic, and we don't want them to get to situations where the urine calcium is very, very elevated when we can avoid it. So in terms of starting a patient on encaleret for long-term outpatient monitoring, my expectation would be that we would have some sort of starting dose. And there would be a monitoring period, probably for the first couple of months of the drug where they might need to get their labs done once a week or twice a month, just to make sure the dose is established. But then my feeling is that once they were on the correct dose, you could probably check them, go back to the monitoring of every 3 months, which is what I typically. And then possibly after a 6-month period, if they were very stable on that dose, you could space it out to every 6 months. I would never envision any patient with hypoparathyroidism going more than 6 months without routine monitoring. It just -- at this point, it seems a little cavalier to trust any situation, drug or otherwise. Because if a patient doesn't get labs, at least every 3 to 6 months, and they're in a condition of hypercalcemia, and you're not aware of it, you could be doing irreversible damage to the kidneys. Now maybe if this drug is really fantastic over time, you could monitor it 1 here. But we don't even do that for most other drugs. We're usually monitoring thyroid medication, at least twice a year, that sort of thing. So I think that if you could get a patient on a real stable dose and have very set evidence that their dose isn't changing that you could potentially go to an every 6-month monitoring in the long-term for these patients, which would be an improvement over what they're doing now.

Thank Dr. Gafni. And Jonathan, do you want to take the question or speculate on how we might think about dosing for the nongenetic forms of hypoparathyroidism?

Sure. With the caveat that this is entirely speculative. I guess I'll start out by, again, observing that in people with a nonvariant receptor as was studied in the prior development program. Even small doses of encaleret we're able to stimulate quite a bit of PTH secretion because those people have both a normal receptor and a fully intact parathyroid gland or set of parathyroid glands. We had to sort of make an educated guess as to what the dose of encaleret might be that would be required to have a beneficial effect on the parameters in the present study, and I think we did make that educated guess and hit on it pretty well. But again, it's a -- the unique combination of a variant receptor, but otherwise an intact gland and everything else being relatively normal with the caveat that some of Dr. Gafni's patients, in fact, already had evidence of some diminished renal function. So now we go on to other forms of [ hypopara ] -- and the main focus, of course, being on the largest subset being the post surgicals. And those people have -- they might have some glands left. They may have no glands left, but they otherwise have a non variant receptor in the [ main ]. And what we don't know, but we would like to know, and we have to design the right experiment to know is what is the quantitative contribution of the calcium-sensing receptor's direct effect on the kidney, and it's ability to reabsorb calcium. And it may well be that it's sufficient to correct the hypocalcemia of postsurgical hypoparathyroidism, but that's an unanswered question. But it is a testable hypothesis.

Jonathan. And then Mani, to the follow-up question is after we know the answer in terms of what the appropriate dose would be for that population, then, of course, we would consider different formulations and intellectual property for that use.

Our next question comes from Geoff Meacham with Bank of America.

This is Greg Harrison on for Jeff. Congratulations on the data. So when we're looking at the ultimate patient population, how should we be thinking about that in terms of the proportion of patients that would be addressed by encaleret those that have severe enough disease versus those that are maybe a symptomatic or less severe? And then how should we think about the balance between pricing for the benefit that patients are seeing versus accessing patients who have less severe disease.

Thank Greg. Maybe Dr. Gafni, I'll ask you first to comment on how you would select patients for use of this therapy if we were successful in having it registered? And then I'll handle the second question?

Well, I think that my inclination would be to treat all ADH1 patients with this drug because even patients who are asymptomatic or feel somewhat asymptomatic, are still running at an abnormally low blood calcium. And oftentimes, these patients who are diagnosed late in life don't realize until you put them on conventional therapy and raise their blood calcium a little bit that they actually maybe did have symptoms that they weren't recognizing. They didn't realize that it wasn't normal for your feet to fall sleep all the time, or if you have this sort of tingling in your face or your fingers. So my general feeling is that all patients with ADH1 would benefit from this drug because the alternative therapies, the conventional therapy with calcitriol and calcium can really cause more problems at the renal level. And this drug is so targeted to correct the defect at the level of the calcium-sensing receptor. And it's given us a pill, it just seems so -- so tolerable. And so to be able to completely normalize their physiology. I mean there are other issues with having chronically elevated phosphate levels as well as chronically low magnesium levels that we haven't really discussed in detail, but that are well described with hypoparathyroidism in ADH1, in general, I don't see a reason to not treat all ADH1 patients with this drug.

Thank Dr. Gafni. And then to the second question, it's certainly too early to comment on how we think about pricing for this molecule. As we said at the outset, we estimate that there's approximately 12,000 individuals in the U.S. that that have the mutations that cause ADH1. However, based on our understanding of the current diagnosis rate today, the number is quite a bit smaller on the order of 3,000 or so patients. And so there's clearly an unmet need here, not just in terms of developing a therapy, but also helping to promote the diagnosis of this disease and move it from something that's rarely diagnosed to where we're finding a higher proportion of the individuals who are carrying the ADH1 causing mutations. And like Dr. Gafni's case, it's quite likely that there are a number of individuals who don't know that they have ADH1 who are idiopathic hypoparathyroid patients, then hopefully, we could identify moving forward, particularly if a treatment is available for that.

And I'm currently showing no further questions at this time. I'd like to turn the call back over to Dr. Neil Kumar for closing remarks.

Just like to thank everyone for taking the time, and we look forward to continuing to this program and continue Q&A with many of you throughout today. Thanks again.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.