Good morning, ladies and gentlemen, and welcome to BridgeBio Pharma's call to discuss proof of concept data for encaleret in ADH1. 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. 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, 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 week at the ENDO, detailing the latest in our efforts that many of you know about to treat autosomal dominant hypocalcemia 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. We owe our participants a huge thank you. 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 these data is that we can do something profound for patients going forward.
I'll make my comments brief here at the top, and I'll refer to just one slide, which is our so-called mountaintop slide on page three, for those of you following along in the slide deck, before I turn it over to my colleagues, Cameron Turtle and Jonathan Fox. Of course, if those names sound familiar, it's because they lead our cardiorenal division, which is presented in other forums such as these, mostly on our ATTR cardiomyopathy efforts. They sit alongside other names that you know about, like Uma Sinha, as a central skilled group ready to work with focus 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 three years. In other cases, as you know, it's led to INDs from hit to lead in less than three years and to phase III efforts from discovery in less than six 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 first of our major readouts this year, as you can see from this mountaintop slide. The readouts are united, I'd say, by the size of the unmet need they address. They're all large, 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 our ability to be a partner of choice when thinking about how to drive an idea forward into a therapeutic. The next readout after this one will be our phase III ATTR cardiomyopathy readout toward the end of the year. In ADH1, just as in ATTR, we have targeted a well-described genetic disease at its source, as I mentioned earlier, and in doing so, hewed 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. 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. As we flip to slide page four in the deck, we can see the summary of the approach and design criteria for ADH1. Specifically, there 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. 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 variant 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. 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 six of the deck, this is a schematic of the disease mechanism in a little bit more detail. As Cameron mentioned, there are variants 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 affects changes in hormones like PTH, to change that level either up or down. It's over-sensing the calcium levels, so it sees low calcium as normal.
As you can see, the result 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 but has a big leak at the bottom. 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. The acute symptoms and the long-term complications are laid out there to the right. 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. The long-term complications are actually related mainly to the inability to regulate the amount of calcium that's lost in the urine. Nephrolithiasis or kidney stones, nephrocalcinosis, which is actual calcification of the kidney tissue itself. This, of course, both of these can lead to or exacerbate chronic kidney disease and loss of renal function. As Cameron laid out a moment ago, the therapeutic hypothesis is that by dialing back the sensitivity or normalizing the calcium-sensing receptor's activity to extracellular calcium will normalize blood calcium and urine calcium and regulate PTH levels to its normal range in ADH1, potentially resolving all of these symptoms.
If we move to slide seven, just to 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. Those do raise blood calcium, but it's at the expense of increasing or exacerbating the urinary loss of calcium. It actually suppresses PTH secretion rather than encouraging it. The key disease measures you see there are blood calcium to the left, with the normal ranges indicated by the dashed lines. In the absence of therapy, these people have blood calciums in the sort of 6-7 range, which is quite low. Even with supplementation therapy is to get them to just about the lower limit of the laboratory reference range in order to minimize the spilling of calcium into the urine.
The middle shows you the best efforts of experts like Dr. Gafni and her colleagues at other institutions. Even with very careful regulation of the amount of oral supplementation, there's almost always going to be an 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. 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 who are participating in the study bear this out. There are two main places where the calcium-sensing receptor does its work.
It's at the level of the 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 has a G protein-coupled receptor that then tells the nuclear apparatus whether to express the PTH gene or not. That leads to PTH secretion or not. In the abnormally high sensing receptor as in ADH1, it's basically telling the 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, as depicted in the cartoon, directly regulates the reabsorption of calcium from the ultrafiltrate back into the blood. Again, in the presence of an abnormal receptor, that calcium does not get reabsorbed properly and is lost in the urine, again, with the consequences that I mentioned.
We did obtain proof of mechanism in a mouse model of ADH1 and in humans with the wild type receptor in a prior program designed to develop encaleret for a different disease indication. What you see on the left is a calcium-sensing receptor variant knock-in mouse. These are genetically modified mice that are carrying an over-sensing human calcium-sensing receptor. You can see that compared to their control littermates in white, in the gray bars, the ADH1 mice respond to encaleret with an increase in blood calcium and a decrease in urinary calcium as is predicted by the molecular mechanism. 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.
This gave us a lot of encouragement that this drug, in fact, could be, in a way, a perfect match for the underlying molecular defect in ADH1. The phase II-B study that is currently ongoing will continue as we plan the phase III program. Here you see a schematic of the program overview. We're right now in the dark blue part of the study that Dr. Gafni's going to present to you momentarily. We're continuing on to the second period in the phase II study as well as the Period 3. The differences here is that in the Period 1, this is basically a dose exploration phase. Period 2 is a dose consolidation phase, both inpatient at the NIH Clinical Center, and Period 3 follows directly out of Period 2 as an outpatient maintenance phase.
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. Now I'd like to turn it over to Dr. Rachel Gafni. Dr. Gafni is the 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. Hey, Dr. Gafni.
Thank you very much. I am 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. 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. 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 his hypercalciuria.
In 2010, he came to the NIH to participate in a clinical trial using twice-daily PTH(1-34) 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 his 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. After one 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. After one 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 five 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-encaleret studies performed while on conventional 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 for period one that Dr. Fox mentioned previously. As a reminder, period one 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 given escalating doses of encaleret for five days, once daily for the first three days and twice daily for the last two days, while undergoing intensive blood and urine sampling. During these five days, patients were instructed to consume at least 1,000 mg of dietary calcium per day.
Five of the patients were able to do that and received no calcium supplementation. One patient had a low dietary intake and was given a small calcium supplement to ensure that she consumed 1,000 mg per day. Next slide. The table on slide 17 shows the baseline characteristics of the study participants. Six subjects, three men and three women, with a mean age of 40 years, bearing four 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. Two-thirds had nephrocalcinosis on renal ultrasound. Not shown here is baseline renal function, which was variable in the group with a mean eGFR of 83 ± 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 in 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 two instances of transient asymptomatic blood phosphate levels below 2 mg per deciliter in two subjects. Next slide. The upper panel on slide 19 represents the mean pharmacokinetic response to escalating doses of encaleret over five 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 one hour.
On days four and five, when the drug was given twice daily, drug levels continued to be detectable throughout the time 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. In the upper panel, we see the mean albumin corrected blood calcium gradually increase into the normal range by day four. Of note, one patient developed a blood calcium level just over 10 mg per deciliter, and her day five dose was reduced to 120 mg. 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 EKGs 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 one blood calcium and PTH values, shown by gray hashed 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 five, 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. Four patients maintained an average PTH value within the normal range on day five, while two had an elevated mean value. Although not shown in this presentation, each subject's mean day five blood magnesium and phosphate levels were also in the normal range. Next slide. 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 rising and staying within the normal range by day four, 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 four and five. 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 five 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 Urocit-K. 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. I did want to just pause on slide number 25. Dr. Gafni is being too modest, but I think credit due, this is just an acknowledgment to the patients and the investigators and all of their staff who have been taking such great care of patients at the Clinical Center . There's Dr. Mike Collins and Rachel prominently displayed and some of the more key individuals participating in this study. We thank them. 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 with encaleret that is enrolling additional participants into that also then Period 3. 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. 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. 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. 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 encaleret in the treatment of non-genetic forms of hypoparathyroidism.
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 analysts' questions.
As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Salim Syed with Mizuho. Your line is open.
Great. Good morning, guys. 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 three and four for a second here. It looks like patients three and four had above the normal range in parathyroid hormone. They were also within the normal range of blood calcium, but on the lower end of normal. I'm just curious how you're thinking about the dosage level here, given that, in the pharmacodynamics slide, patients didn't achieve the blood calcium normal until about 180 mg BID, at least on the mean. 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?
How are you thinking about that? The second question here is just speaking to the last point that I think you guys had mentioned about the broader population of hypoparathyroidism. I'm 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? Thank you.
Great. Thanks, Salim. Dr. Gafni, please go ahead on the first question. I think maybe Jonathan, why don't you start on the broader hypoparathyroid population?
Sure. It's a very good question. I think it's important to remember that it's a little bit unpredictable how high the parathyroid hormone level will go when they're first exposed to this drug. We ramped up the dose pretty rapidly. Parathyroid hormone takes a little bit of time to raise blood calcium. It has a different effect. 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. It also activates vitamin D to take the storage form of vitamin D to make endogenous calcitriol. A very high spike, for example, in parathyroid hormone doesn't necessarily translate to an immediate rise in PTH.
I think that in this very short study, just over the course of five days, this does not really tell us what the dose for this patient is going to ultimately be. That's why we need to do Period 2 and Period 3 of the study to do more dose titration and adjust it out. 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. 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.
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? I can clarify it more if you need.
Yeah. In terms of being able to maintain the blood calcium, why wouldn't it be when you lower the dose, why would the blood calcium levels still stay in that lower end of the normal range for those patients, for example?
One of the main sources of calcium in our body is the bone. Patients with hypoparathyroidism, all forms, including ADH1, have low bone turnover because their parathyroid hormone levels are low. It takes time for the bone to reestablish a new steady state when it starts to be exposed to parathyroid hormone. This does take a little bit of time for all of the systems that contribute to the normalization of blood calcium to be re-regulated and find their new set point.
Okay. Got it. Thank you.
Thanks, Rachel. Jonathan, do you want to tackle a question for-
Yeah
...non-genetic causes of 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 nine and you look at the right-hand panel, these are people with a non-variant calcium-sensing receptor receiving encaleret on a chronic basis. It didn't take much encaleret, that 15 mg a day was the highest dose that was well-tolerated in terms of the blood calcium response in people with a normally functioning receptor. In Dr. Gafni's patients, it's a little hard to predict given the differences in penetrance and the differences in clinical expressivity in terms of how severe their hypocalcemia is. It can be quite variable, 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 post-surgical 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, 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. 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.
The key thing being in the post-surgical patients, either because of ischemic damage related to what is usually neck surgery or trauma, it's not clear how much residual gland there may be. Because of the mechanism of action, encaleret would probably require some residual tissue. Again, the magnitude of the contribution by the direct effects of encaleret on the kidney are not looking at different ways of establishing that.
Got it. Thanks, Jonathan. Thanks, guys, and congrats on the data again.
Thank you. Our next question comes from Eun Yang with Jefferies. Your line is open.
Thank you. Congrats on the data as well from me. A few questions. One, the prevalence is at 12,000 patients. Based on this phase II data, understanding that it's a small number of patients, what percent of patients represents the 12,000 prevalence, what percent of those is being represented in current study? That's question number one. Second, about two-thirds of patients have a nephrocalcinosis. From the treatment, how long do you think that you would, I don't know if it's going to reverse, but stabilize the condition in those patients and restoring mild to moderate kidney impairment?
Thirdly, when you meet with the FDA in the second half of this year, do you think a phase III study would be similar to hypothyroidism, hypoparathyroidism study, where you're only looking at calcium normalization in the serum and in urine, or do you think you may need to show some improvement in acute symptoms as well as long-term complications? Thank you.
Thanks, Eun. I'll take the first question. Rachel, I ask 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 four different mutations in the calcium-sensing receptor that were seen in this study. 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 P221L mutation is the most common mutation that's found in the literature. Together, those four mutations account for a little over a quarter of the total prevalent pool that are described in the literature.
Certainly, it's still a small proportion, and there may be additional variants that have different responses to encaleret. We did see variants that occur in both the extracellular domain and the transmembrane domain, and as you saw in the data, had very similar responses. 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. 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 resolve, at least on ultrasound, not necessarily on renal biopsy. 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 nephrocalcinosis and ideally prevent further decline in renal function. There is really no way to predict that just from these five days of data. That, of course, is the hope.
Thanks, Rachel. Jonathan, do you want to handle the last question regarding the phase III?
Sure. 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. The safety profile is pretty well established with the dose-limiting issue for people with a normal calcium-sensing receptor being, in fact, high calcium. No other safety issues were identified. When we filed our Investigational New Drug application with the FDA, they opened the IND without any serious concerns expressed on their part. That's all good news. We did obtain orphan drug designation as well, 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.
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. Again, we haven't had those discussions yet.
Thank you.
Thank you. Our next question comes from Anupam Rama with JP Morgan. Your line is open.
Hey, guys. Thanks for taking the question. Congratulations on the data. Maybe just a quick one, just following up on a couple of the last questions on granularity on timelines for meeting with regulators. Do you think you can do this based on the data you have now, do you need to learn more from phase II and III before you can have the regulatory interactions, particularly as it relates to dosing, which has been asked about a couple times? Thanks so much.
Sure, I'll take that one on as well.
Go ahead, Jonathan. Yeah.
Yeah. 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 five-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 a steady rise in blood calcium that was sustained was really quite encouraging. Does, again, point out the need for individualizing the dose. The period two carries on and, if anything, is confirming a lot of what we've seen so far with respect to the measures and the observations made.
It's really important that Period 3, that we learn more about how to manage the use of encaleret in the outpatient setting, which, of course, will be its chronic use as a marketed product should we get there, should we be successful. 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.
Got it. Thanks for taking our question.
Thank you. Our next question comes from Tara Bancroft with Piper Sandler. Your line is open.
Hi, guys. Good morning. Quick question on the PTH levels that you saw. In those two 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 even looked at that, and what the potential downsides of that may be if they do have sustained above normal elevations. For the urinary calcium, I was wondering how soon you saw that happen. For the three that still had detectable levels under the normal range, 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'd ask that you address those if you're able.
Yes. Thank you. What we don't show you here is after the 5th day, when the patients had their final dose of encaleret on Friday night. Saturday morning, they completed their 24-hour urines and were restarted on their conventional therapy. They had blood work done on Monday. Just over about 48-58 hours, depending on the timing after they took their last dose of encaleret and were back on their conventional therapy, all of their biochemical markers have returned to baseline pretty much. The PTH levels were undetectable again just two days after stopping the encaleret. The elevation in PTH was definitely not sustained. I think you can see on slide 19 that the rises that we saw in PTH were very sharp and then rapidly dropped, for most of the patients did remain within the normal range.
It was sort of this initial spike after the increase in encaleret levels. 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. 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.
Again, I think that additional titration of the dose in both Period 2 and Period 3 will answer those questions in the long term.
Thanks, Rachel. Tara, just as a reminder, these are 24-hour urinary calcium measures, so it is just one measurement per day as opposed to calcium and some of the other measures where it's being measured 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 at five 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. We did, of course, see a decrease in fractional excretion of calcium that correlated with this decrease in 24-hour urine excretion. 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.
Mm-hmm. Great. Thank you.
Thank you. Our next question is from Tom Shrader with BTIG. Your line is open.
This set. I'm looking at slide 20 and wondering if I'm taking it too literally. Some suggestion of collapsing to one or two doses. Is that no longer realistic? Is slide 20 kind of how you would expect to use the drug?
Apologies. I'm not sure if everyone had the same challenge as I did. I think I missed a few words there, Tom. The question was whether or not we expected the doses to consolidate over a longer period of time instead of going up to 180 mg BID. Is that correct?
No, whether every patient will eventually need a detailed titration or whether you will in fact eventually get to one or two doses that fit most patients.
I've got the question. Dr. Gafni, can you address that question?
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 yet. Is that correct?
That's correct. Yeah.
Yeah. Obviously we are into those phases. One 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. Subjects 1 and 2 also had the same genotype. 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.
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.
Okay, great. Thank you.
Thank you. Our next question comes from Paul Choi with Goldman Sachs. Your line is open.
Hi, thanks. 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 Dr. Gafni or Dr. Fox, can you perhaps envision a maintenance scenario where the dosing ends up being QD at either the 180 mg or some alternative dose? Secondly, I think one 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? Thank you very much.
Thanks, Paul, maybe we'll go in that exact order. Dr. Gafni, do you want to start by addressing the questions about QD versus BID dosing and the QT interval? Then Jonathan, please feel free to add.
Yeah, I might ask Dr. Fox to talk a little bit also about the QD versus BID dosing. Based on the previous pharmacokinetic profiling and the understanding of the terminal half-life of this drug, which is 10-12 hours, the expectation is that patients most likely would require twice-daily dosing. In terms of There were a couple 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. As I mentioned before, because the patients have low bone turnover. 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. In that case, the patients in this disorder would also have hypercalcemia.
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 am 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 the QTc here, either on the cardiovascular or other side of potential comorbidities? Thank you.
Yeah. I'm not aware of intrinsic increased cardiovascular risk per se. There's certainly exploratory things that one could consider looking at. For example, patients with hypocalcemia are at risk for laryngospasm and perhaps sleep apnea could be a comorbidity that's associated with it. That's never been reported in the literature. I'm just sort of making this up as possibilities that one could think about. I don't believe that there are specific cardiovascular diseases that are linked to ADH1 or other forms of hypoparathyroidism.
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.
Again, this was only a five-day period. The participants in the study are people with lives and jobs and kids and 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. We did what we could in terms of a rapid dose escalation, as Dr. Gafni mentioned earlier. If you look at the middle of these paragraphs on page 19, with the 180 mg given once, you see the rapid rise in blood concentration of encaleret, which drops off in a monoexponential fashion, a first-degree elimination pattern. This is typical for small molecules. 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 mg once daily for several more days if we might have seen something different. Again, given the half-life of 10-12 hours, it seems unlikely since this drug does not accumulate to any extent upon steady-state dosing. 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. Based on some modeling that was done from the prior development program lab values, it seems that there may be a minimum blood concentration of drug that is required to sustain a concentration of PTH in the blood, as is reflected in the day 4 pattern that you see on that slide.
If you go then back to slide 20, you can see that, again, if we had continued the 180 mg once a day, might we have seen a continued rise in the blood calcium to 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.
The thing about the QT interval, yes, it is a form of long QT syndrome, although it is not usually described that way because with proper therapy, at least to bring in the blood calcium up towards the normal level, should not precipitate heart rhythm problems. 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-
Great. Thank you for the call and taking our questions.
Could I make one 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. Obviously, that's a different drug, but you see a peak in PTH soon after giving the injection. What happened with parathyroid hormone therapy when it was given only once daily was that bone turnover was much more stimulated. 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.
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. Thanks.
Thank you. Our next question comes from Mani Foroohar with SVB Leerink. Your line is open.
Yes. Thanks for taking the question. Obviously, there's been a lot of discussion around doses in this study. When considering non-genetic causes of hyperparathyroidism and evaluation of encaleret there, obviously different causes between genetic and non-genetic can require very different levels of drug activity. How are you thinking about potential dose ranges? Would there potentially be the opportunity to create novel formulations or formulation IP as we saw in QED, or will it just be really difficult to find that wide of a gap between required doses? Secondarily, more specifically on this study and 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 monitor patients' serum calcium and urine calcium on an outpatient and ongoing basis.
Thanks, Mani. 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. Jonathan, maybe you can comment as much as we know at this point in terms of the potential dosing in the non-genetic hypoparathyroidism.
Yeah. To answer that question, 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 one 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.
My patients are at minimum getting their labs done on conventional therapy every three months, and in some patients, I actually get labs on them monthly. 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 into situations where the urine calcium is very, very elevated when we can avoid it. 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 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.
My feeling is that once they were on the correct dose, you could probably check them, go back to the monitoring of every three months, which is what I typically do, and then possibly after a 6-month period, if they were very stable on that dose, you could space it out to every six months. I would never envision any patient with hypoparathyroidism going more than six months without routine monitoring. 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 3-6 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.
Maybe if this drug is really fantastic over time, you could monitor it once a year, 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. 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 six-month monitoring in the long term for these patients, which would be an improvement over what they're doing now.
Thanks, Dr. Gafni. Jonathan, do you want to take the question or speculate on how we might think about dosing for the non-genetic 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 non-variant receptor, as was studied in the prior development program, even small doses of encaleret were 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. I think we did make that educated guess and hit on it pretty well.
Again, it's 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. Now we go on to other forms of hypoparathyroidism, and the main focus, of course, being on the largest subset, being the post-surgicals. Those people have, they might have some gland left, they may have no gland left, but they otherwise have a non-variant receptor in the main. 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 its ability to reabsorb calcium.
It may well be that it's sufficient to correct the hypocalcemia of post-surgical hypoparathyroidism, but that's an unanswered question, but it is a testable hypothesis.
Thanks, Jonathan. 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.
Thanks, guys. That's really helpful.
Thank you. Our next question comes from Geoff Meacham with Bank of America. Your line is open.
Hi, this is Greg Harrison on for Geoff. Thanks for taking our question, and congratulations on the data. 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 asymptomatic or less severe? How should we think about the balance between pricing for the benefit that patients are seeing versus accessing patients who have less severe disease?
Thanks, Greg. 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. 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 asleep all the time or to have this sort of tingling in your face or your fingers. 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.
This drug is so targeted to correct the defect at the level of the calcium-sensing receptor, and it's given as a pill, it just seems so tolerable and so to be able to completely normalize their physiology. 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 and ADH1. In general, I don't see a reason to not treat all ADH1 patients with this drug.
Thanks, Dr. Gafni. 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 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. 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 individuals who are carrying the ADH1-causing mutation.
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, that hopefully we could identify moving forward, particularly if a treatment is available for them.
Great. Thank you.
Thank you. I'm currently showing no further questions at this time. I'll 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 the continuance of this program and continued Q&A with many of you throughout the day. Thanks again.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.