Thank you for standing by, and welcome to the BridgeBio Pharma to discuss phase 2b data and phase 3 trial design for encaleret in ADH1. At this time, all participants are in a listen-only mode. As a reminder, this conference is being recorded. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Dr. Neil Kumar, Chief Executive Officer of BridgeBio. The floor is yours.
Thanks so much, operator, and thanks to everyone joining us for your time. Before I dive in, I just wanted to remind everyone that I will be making forward-looking statements today, and if you need additional details, please refer to our SEC filings. It's my privilege to kick this call off and to introduce our most recent data from our phase 2 ADH1 or autosomal dominant hypocalcemia type 1 program. Doctors Rachel Gafni and Mary Scott Roberts will provide the bulk of what's gonna be useful today, on this call. I wanted to take a moment to set up the discussion and provide a bit of perspective. Before I do that, though, I wanted to thank the investigators and patients that participated in this trial, along with the patient advocates at the HypoPara Association.
It's always true, but even more so during COVID, and we've seen this across many of our clinical trials, that a biotech relies on its partnership with those who are on the front lines of care and caring, and so we thank them for their inspired effort here. I want to start on slide 4, if we could go there, by highlighting, first, this program's efficiency. In a little under three years, this capable team took this program from IND to the doorstep of a well-designed phase 3. This was also accomplished in a little under $100 million. This is the same Cardiorenal team that here at Bridge accomplished something very similar with our ATTR cardiomyopathy program, and we anticipate more data points like this.
Analogous to what we did in LGMD 2I, where as many of you recall, we had positive phase 2 data that was announced earlier this year, and we expect more of this type of thing to come in the next 12 months. Given current market constraints, as you all know, efficient prosecution of late-stage programs is the only way to build value for patients and investors in rare disease markets, and we think we can reproducibly execute on that and are building a track record to prove it. So maybe if we advance to the next slide, we can drill into the program of interest today. I'll begin by reiterating that we're taking our normal BridgeBio approach to trying to help patients here, which is to target a well-described disease at its source.
In this case, as will be discussed in greater detail later, this involves negative allosteric modulation of the calcium-sensing receptor to counteract disease-causing heterozygous gain-of-function mutations occurring in that receptor's gene. That's the good news, that this disease, thanks to pioneers like Dr. Michael Collins and others, is well-described. The bad news is that there is a large unmet need that warrants our immediate attention. Against any of the two axes against which we understand disease burden, that is patient numbers or disease severity, we can see that ADH1 exacts a significant toll. On slide 5, we see the estimated prevalence of ADH1 in the U.S. at a little over 10,000. A large unmet need analogous to the XLH unmet need that was addressed by Ultragenyx and others in their program over the past couple of years.
Many ADH1 patients are likely currently under- or misdiagnosed in the hypopara community. An estimated 3,500 patients are diagnosed today. If you flip to slide 6, you can see also that a majority of these patients identified experience moderate to severe symptoms, which include both acute symptoms like seizures or tetany and others that you'll hear about, and longer-term complications like nephrocalcinosis and CKD. Importantly, even mild patients that don't appear to have appreciable acute burden often go on to experience longer-term kidney complications. Against this diaspora of symptomatology, current standard of care is able to do very little. As shown on the right-hand side of this chart here, you can see that it normalizes fewer than 5% of patients on both serum and urine calcium.
Okay, we have a program here addressing a large and severe unmet need by targeting this well-described disease at its source and being prosecuted by a group of very experienced drug developers and academic partners who have efficiently led the development of the program to its doorstep into a high PoTS, or probability of technical success, phase 3 clinical trial. In doing so, hopefully, we can provide some hope for ADH1 patients and provide a stellar example of how the BridgeBio model can work. I'm gonna turn it over to Dr. Gafni now to get into the more interesting stuff. As you can see here, she heads the Mineral Homeostasis Studies Group at the NIH, and is a senior research physician there as well. We're privileged to be working with her and learning from her. Rachel.
Thank you very much. It's really exciting to present our data from this novel therapy, which really takes a precision medicine approach to treating a rare form of hypoparathyroidism. I have a disclosure slide up there, I think. Or no. Okay. We're gonna start with. I don't see a slide number. We're gonna start with the slide that has 9. Slide 9. Thank you. In normal circumstances, blood calcium levels are kept within a narrow physiologic range, and this tight control is mediated by four organs under the regulation of parathyroid hormone. When the calcium level is low, the parathyroid glands respond by synthesizing and secreting PTH, which in turn acts to increase calcium levels by several mechanisms. In the bone, PTH stimulates bone resorption, and this liberates calcium into the bloodstream.
In the kidney, PTH increases renal calcium reabsorption and promotes conversion of 25-hydroxyvitamin D to the active form of vitamin D, 1,25-dihydroxyvitamin D, which in turn promotes intestinal absorption of calcium. PTH also inhibits renal phosphate reabsorption. Now, while PTH is an important circulating hormone that's doing a lot of work, it's in fact the calcium-sensing receptor that's controlling this complicated dance. In the parathyroid, when the calcium-sensing receptor senses high levels of calcium, PTH synthesis and secretion are decreased. Likewise, in the renal tubule, high levels of calcium sensed by the calcium-sensing receptor leads to decreased calcium reabsorption to rid the body of the excess calcium. Go to the next slide, please. Heterozygous activating variants in the calcium-sensing receptor cause a rare form of hypoparathyroidism called autosomal dominant hypocalcemia, or ADH1.
These variants in the calcium-sensing receptor increase tissue sensitivity to extracellular calcium, essentially tricking the parathyroids and the kidneys into thinking that the blood calcium level is higher than it actually is. As a result, patients with ADH1 have decreased PTH secretion, decreased blood calcium, and increased urinary calcium. The clinical manifestations of ADH1 are similar to other forms of hypoparathyroidism, and long-term complications may include nephrolithiasis, nephrocalcinosis, and chronic kidney disease. It's important to note that hypercalciuria may be worse in ADH1 compared with other forms of hypoparathyroidism because these patients experience both decreased PTH as well as altered calcium sensing, leading to reduced calcium reabsorption. Treatment is often difficult, and conventional therapy with calcium and activated vitamin D does not correct the underlying pathophysiology and has the potential to worsen long-term complications. Next slide.
Encaleret is an investigational oral medication from a class of drugs called calcilytics, which are negative allosteric modulators of the calcium-sensing receptor. Through this mechanism, Encaleret decreases the sensitivity of the calcium-sensing receptor to extracellular calcium, effectively shifting the responsivity curve in the parathyroids and the kidney to the right. Restoration of the calcium-sensing receptor sensitivity towards normal has the potential to correct the hypocalcemia, hypercalciuria, and low PTH in individuals with ADH1. Next slide. Our study is a Phase IIb open-label design that is divided into four sections. During Period I, six patients with ADH1 received Encaleret in escalating doses over five days while undergoing frequent blood and urine sampling. Period II was a second inpatient period that included those six patients plus an additional seven patients for a total N of 13. During Period II, patients received individualized dose titration for five days.
The 13 participants then entered a 24-week outpatient phase with scheduled assessments occurring every 1- 8 weeks. The key study objectives were safety and tolerability and calcium metabolism, with additional secondary measures listed here. While taking encaleret, patients did not receive calcitriol and were instructed to consume at least 1,000 mg of dietary calcium per day. The 1 patient with a low dietary calcium intake was given a calcium supplement to meet that goal. Next slide. These are the baseline characteristics of the study participants. 13 subjects with a mean age of 39 years bearing nine different calcium-sensing receptor variants were enrolled, all with the typical biochemical features of ADH1, hypocalcemia, low PTH, hyperphosphatemia, and inappropriately normal or frankly elevated urine calcium. Three-quarters had nephrocalcinosis on renal ultrasound, and the renal function was variable with a mean eGFR of 84.
All were being managed with calcium and calcitriol supplements in fairly typical doses divided throughout the day. Next slide. This slide shows the dosing regimens for the study. In Period I, the dose escalation was fixed, with all subjects receiving once-daily dosing on days 1- 3, increasing from 30 mg- 90 mg to 180 milligrams, followed by 180 mg twice daily on days 4 and 5. Only one subject had the final dose decreased to 120 milligrams because of a calcium level slightly above 10 mg/dL . In Period II, the Day One starting dose was originally 180 mg twice daily but was then decreased to 90 mg twice daily as it became clear that individual dose requirements were quite variable.
Over the course of the five days, the mean encaleret sulfate dose decreased, with patients ultimately receiving between 10 mg-180 mg twice daily. The third graph shows the individualized dosing over 24 weeks in Period III. Most patients were maintained at doses similar to their dose at the end of Period II, again ranging from 5 mg-190 mg twice daily by week 24. Next slide. Safety and tolerability were primary endpoints for this study. Encaleret was well-tolerated with very few adverse events and no serious adverse events reported. The only treatment-related adverse events were instances of transient blood phosphate levels below 2 mg/dL and some instances of mild hypercalcemia, with no patient exceeding a corrected calcium level of 10.9 mg/dL. All treatment-related AEs resolved either spontaneously or with adjustment of the encaleret dose.
No other concomitant therapies were required. Next slide. These graphs show the individual and mean responses on day 1 and 5 for the six subjects in period one. The day 1 blood calcium and PTH values shown by the light blue bars were drawn just prior to administration of the first dose of encaleret, while the urine calcium reflects the 24-hour excretion at the screening visit. By day 5, shown by the dark blue bars, all subjects had average blood calcium levels that were in the normal range and normal or undetectable 24-hour urine calcium. Four patients maintained an average PTH value within the normal range on day 5, while two had elevated mean values. Next slide. These figures display the mean pharmacodynamic responses to individualized BID dosing of encaleret over five days in period two and 24 weeks in period three.
In the upper panel, we see the mean albumin-corrected blood calcium gradually increase into the normal range by day 2 and remain normal during period 3. Concurrently, the mean 24-hour urinary calcium excretion shown in the bottom panel decreased into the normal range within the first 24 hours of dosing and remained normal throughout. Next slide. Similar to period 1, the PTH response to encaleret in periods 2 and 3, shown in the top figure, was robust, increasing from a very low mean baseline value well into the normal range 30 minutes after the first dose on day 1 and remaining normal during period 3. Likewise, the mean blood phosphate level decreased from a high normal level into the mid-normal range. Mild hypophosphatemia was noted in several subjects, usually within a few hours of the morning dose.
However, these episodes were asymptomatic, transient, and resolved either spontaneously or with reduction of the encaleret dose. Next slide. Both the mean blood magnesium, shown in the top panel, and the 1,25-dihydroxyvitamin D in the bottom panel were low normal prior to encaleret and increased. Next slide. These graphs show the bone turnover markers CTX on the left and P1NP on the right during Period 3. Because the normal range is age and sex specific, we are presenting the values as a ratio of the level over the upper limit of normal for that patient. Thus, a value of 1 indicates a bone turnover marker at the upper limit of normal. As expected, the bone turnover markers increased significantly while on encaleret, consistent with the increase in PTH levels. While three or four subjects had slightly elevated levels, most subjects remained within the normal range. Next slide.
Same slide. Excuse me. At the bottom, you see a table showing the DEXA scans, which were obtained at screening and at the 24-week visit of period three. As we typically see in hypoparathyroidism, the mean BMD Z-score was elevated at screening for the total body, lumbar spine, and hip, and there were no significant changes in BMD Z-score except for a slight decrease in the total hip. Next slide. To summarize, in 13 patients with ADH1, encaleret administered twice daily for 24 weeks restored mineral homeostasis, as demonstrated by an increase in PTH, correction of hypocalcemia, normalization of the mean 24-hour urine calcium, reduction in blood phosphate, increase in mean magnesium and 1,25-dihydroxyvitamin D, and increase in bone turnover while remaining in the normal range in most participants. Encaleret was well tolerated over 24 weeks with no serious adverse events reported.
An outpatient evaluation of encaleret in the Phase IIb long-term extension is ongoing, with a Phase III study planned for later this year. Thanks very much, and I'm happy to answer any questions.
First, Dr. Roberts is going to present.
Thank you, Dr. Gafni. You can go to slide 23, please. Given the data that Dr. Gafni presented from our phase II study, we are very excited to initiate the CALIBRATE phase III pivotal trial, which will be a global randomized open label two-arm study that is informed by our learnings from phase II. We are looking to enroll patients with genetic and biochemical evidence of ADH1 aged 16 years and older. Following a screening period that includes standard of care optimization, approximately 45 participants will enter a 4-week standard of care maintenance period. Participants will be randomized in a 2-to-1 manner to receive either encaleret or to continue on standard of care treatment for a total of 24 weeks.
Following period 3, participants in the encaleret treatment arm can continue on encaleret treatment while patients in the standard of care arm can initiate encaleret in the long-term extension, which will last approximately 48 months. Our primary endpoint for this study consists of the proportion of participants who achieve a composite of both blood calcium in the target range and 24-hour urine calcium, either within the reference range or greater than or equal to 50% decrease from their baseline value. The secondary endpoints can be seen on the right-hand bottom portion of the screen and include the effects of encaleret on other markers of mineral homeostasis, as well as following the renal function and renal ultrasounds in these patients with ADH1, as well as the impact of treatment on their quality of life. Next slide.
We are encouraged about our probability of success to meet the primary endpoint in the CALIBRATE phase 3 study by data from our phase 2 trial, which you can see here. No participants had blood calcium in the target range while simultaneously having 24-hour urine calcium in the normal range on standard of care at screening. While 69% of the participants in the phase 2 study met both of these parameters after 24 weeks of encaleret. I would just like to note here that for the urine calcium, we are only able to assess urine calcium in the normal range, which is only one part of the phase 3 endpoint criteria that I just shared with you for urine calcium. That's because we only had a single screening measure on standard of care, so calculating the change from baseline was not possible with this particular study data.
Next slide. To summarize what Dr. Gafni had shared previously, the phase 2 trial demonstrated that encaleret normalized mean corrected blood calcium and 24-hour urine calcium excretion, and this was maintained for 24 weeks. The increase in calcium was mediated by increased PTH secretion, which also led to decreases in blood phosphate. Encaleret was well tolerated when administered twice daily for 24 weeks, with no serious adverse events reported. These consistent improvements in mineral homeostasis suggest that encaleret may be an effective treatment for ADH1. We're thrilled to study this further in our phase 3 CALIBRATE study that is set to initiate in the second half of this year. We anticipate completing enrollment early in 2023 and having top-line data available at the end of next year.
As we look into 2023 and beyond, we'll have additional long-term safety and efficacy data as Dr. Gafni continues to follow phase 2 participants in the long-term extension. As you can see in the timeline below on the bottom right, we have some other exciting work ahead of us, including clinical studies in pediatric patients with ADH1, as well as assessing the potential for encaleret treatment of other non-genetic forms of hypoparathyroidism. Thank you.
With that operator, we can open the line for Q&A.
Thank you so much. As a reminder to ask a question, simply press star one on your telephone. To withdraw the question, press the pound key. Our first question comes from Eliana Merle with UBS. Your line is open.
Hey, guys. Thanks so much for taking the question, and, Matt, congrats on the update. Maybe first for Dr. Gafni, can you just elaborate a little bit on the titration period and thoughts on moving into the outpatient setting and thinking about this for the phase 3 as well as potentially long term in the commercial sort of real-world treatment setting? Just a question for Dr. Roberts. When you guys are thinking about the phase 3 enrollment, any kind of color in terms of the site identification that you've done so far, that sort of informs some of the timelines that you guys are talking about? You alluded to this at the end, but sort of future plans for studying encaleret and other potential forms of hypoparathyroidism, if you could just elaborate there. Thanks.
Thanks for those questions, Ellie. We'll pass it to Dr. Gafni for your first question and then to Dr. Roberts for your second.
Hi. I'm not 100% sure you were asking about the titration period from period 2 into period 3. Is that correct? Or how
Yeah
We do it or how we foresee doing it in the real world. I mean, it was actually pretty straightforward. We did monitor patients on a weekly basis initially after they left the inpatient unit to adjust their doses. In cases where we needed to make adjustments more frequently, we monitored their labs more frequently. It was actually pretty straightforward for most of the patients. They stayed on this. It took, again, a few days to figure out their dose, and for the most part, they stayed quite stable, so it was very easy to adjust. I'm not sure if that's answering your question.
Yeah, that's helpful. I guess maybe just implications, I guess, in the real world outside of a clinical trial setting. I mean, do you expect this to need to be sort of any type of inpatient monitoring or how this can be sort of monitored on an outpatient visit as you get to sort of this maintenance dose?
Yeah. I definitely think this can be done on an outpatient dose for the most part. It would be really very speculative because I've never actually started anybody as an outpatient. It's a little hard for me to know for sure, but I've managed a lot of other hypoparathyroid patients and with PTH and conventional therapy. In general, unless there's really an acute situation, I generally don't need to check labs more than twice a week.
When I make an adjustment, that's sort of a maximum twice a week. It's doable as an outpatient, but I can't say specifically for this because I've never actually done it with this drug.
Okay. Got it. That's helpful.
Eliana, this is Dr. Roberts. Just to add to that, in case it wasn't clear when I went through the phase 3 study design, our intention for the phase 3 pivotal trial is that it will be all based on an outpatient basis. We've taken our learnings from the dosing range in the phase 2 study and chosen a dose that we think will be safe for most patients, and then the ability to titrate up or down as needed, just as Dr. Gafni was suggesting. We'll learn more when we have the data from phase 3.
Great. Makes sense. I guess last question from me. Just any color you can give in sort of the real-world identification or any patient registries in terms of the number of patients actively diagnosed today with ADH1?
Yes, great question. We've taken a multifactorial approach in trying to identify patients as well as centers, physicians that might have these patients. You know, one of them is reaching out to thought leaders across the world, having, you know, conversations on where these patients might be located. The second is through a sponsored Invitae testing panel, in which any patient that has nonsurgical hypoparathyroidism in the United States can be tested for free. We've already had quite a bit of uptake with the use of that panel in the past year or so that it's been in effect. The second is through patient advocacy.
There's a number of patient advocacy groups in the US, in Europe, and in other parts of the world, that we have team members that are reaching out and working with them to really try to find these patients where they are and then to have a study site that is convenient to their location. Because as you know, in rare disease, every patient counts.
Got it. Thanks so much.
Okay. Your next question comes from Mani Foroohar with SVB Securities. Your line is open.
Hi, good afternoon. This is Rick on the line for Mani. Congrats on the great data here. Just a couple questions from us. First, what, if anything, did the data say about the interaction between patient genotype and response to encaleret? Did you notice any trends based on patient genotype, either in response to encaleret or the ability to normalize blood or urine calcium? For the second question, this is probably directed more for Neil. Given a pretty large spread between final doses that patients received in the study, how are you currently thinking about potential pricing models for encaleret, as well as any downstream impact for commercialization that these wide range in doses might have?
Thanks for those questions, Rick. We can pass it to Rachel Gafni, Dr. Gafni, for the first question on the association between genotype and the encaleret dose in the study.
Yeah. It's really a great question. So we can't say anything definitively on the effects relative to genotype, but what we do know is we have 13 subjects enrolled in the phase 2 study, and they have nine different calcium-sensing receptor variants. So the ones that have the same calcium-sensing receptor variant are related, either siblings or parent-child, cousin. So as it turns out, those family members tended to require approximately the same dose. So there is a suggestion that perhaps the genotype does correlate with the effectiveness or the dose requirement for the drug, but it's also possible that there are other genetic factors at play that affect the responsivity to the drug. So it's a little too early to know based on this very small cohort.
I think that there is consideration of perhaps doing bench research with cells, for example, that can bear these mutations to look at responsivity with the different variants, but that has not been yet done to date.
Yeah. Hey, Rick. Maybe on the pricing question, I'll turn it over to Ananth, who leads operations and strategy for this program.
Thank you, Neil. It's a great question, Rick. It is preliminary to comment deeply on pricing, and we can get more into details as we approach potential registration in this program. I think in a general sense, we are definitely gonna approach pricing with a responsibility perspective and intend to price encaleret responsibly for this condition if we're successful. In terms of how we would manage the large dose range and the individualized dosing, we intend to interrogate packaging formats to enable titration in the outpatient setting that will enable individuals to get to their optimal dose in a rapid and pragmatic fashion, and we'll adopt a pricing approach that will enable that sort of titration.
All right, great. Thanks for taking the questions.
Okay, your next question comes from Anupam Rama with JP Morgan. Your line is open.
Hey, guys. Thanks so much for taking the questions. Two from me, just quickly. For the few patients that had bone turnover markers outside of the normal range, is there anything in the baseline characteristics to consider there for those patients? I guess anything to consider when it comes to inclusion, exclusion criteria for the phase 3 related to bone turnover. Another question, which is the safety exposure period gonna have to go beyond 24 weeks for a filing, or can you file on the 24 week data in the phase 3? Thanks so much.
Thank you, Anupam. For the first question on the predictive nature for the bone turnover markers, we'll have Dr. Gafni address that question.
Yeah, thanks for the question. The bone turnover markers are back on slide 20, and there's a couple. There's basically three patients who seem to have persistently high bone turnover markers above the normal range during period three, and two of those are fraternal twins. They have the same, a very, you know, they share obviously not 100% of their genetics, they're fraternal, so there may be a genetic implication in there that we don't know about. They also are starting at the highest baseline, and that also could be reflective of their age because they're 22, so they're in the younger part of our cohort. It's a little bit unclear, but it make sense that those siblings might be sorting out similarly.
The third patient is actually, they were on medium doses of the drug, so not on the highest doses of the drug. The third patient who's up above the normal range is actually one of our patients on one of the lowest doses of the drug. It's really unclear why some of the patients have higher bone turnover markers, but this is still a fairly brief period of time, and I think we're gonna get a lot more information from this in the long-term extension as we continue to monitor the bone turnover markers every six months, as well as the bone density studies annually. It's a good question, and I don't really have an answer for it right now.
Sure. To Dr. Roberts, on your second question, Anupam, on the exclusion criteria, inclusion criteria in the phase three study and the 24-week data package.
Sure. Most of these patients with hypoparathyroidism, including those with ADH1, have a low bone turnover state when they are not being treated with drugs that replace or increase parathyroid hormone. Since we were unable to identify anything in the three patients, as Dr. Gafni just mentioned, that would have predicted their increase in bone turnover markers on study, we don't plan to include any inclusion or exclusion criteria focused specifically on the bone turnover markers. For your safety question, we have completed our end of phase two interaction with the FDA and received scientific advice or feedback from the European Medicines Agency, and 24 weeks of safety data should be sufficient for filing.
Just keep in mind that we'll have supplemental data from our phase 2 study as patients continue on treatment, some of which have been on treatment for up to 12 months at this point in time.
Thanks so much for taking our questions.
Your next question comes from Paul Choi with Goldman Sachs. Your line is open.
Hi. Good afternoon, and thanks for taking our questions. Let me add my congratulations on the data as well. My first question is for Dr. Gafni, and it's regarding the change in PTH over time. I think as we looked at the data last year, you know, there was some concern about spikes and outliers. With additional patients and additional follow-ups, can you maybe, you know, speak to your level of comfort about risks and, you know, potential downstream risks from the changes in PTH over time?
Go ahead, Dr. Gafni.
Thanks. Thanks for your question. Yeah, I think that the spikes that we saw in the earlier periods were due to the dose-finding studies because obviously we were giving patients up to 180 mg twice daily, when some of them really needed much lower doses. The responsivity of the PTH was somewhat expected. Certainly in period three, once we figured out the best dose for the patient, which was actually pretty close to the end of period two or even at period two for most of the subjects, the PTH levels were quite stable, and we weren't seeing those types of excursions. We're not showing all of the data at 8, 16, and 24 weeks, but we did do 24-hour sampling on the patients during those visits.
While we did sometimes have PTH values that exceeded the upper limit of normal, you know, within a period of time after the dose, none of them were exceptionally high that they would be concerning in the long term.
Okay. Thank you for that. And just a quick one as a follow-up to Anupam's earlier question, for Dr. Roberts. Will you exclude patients with renal dysfunction or CKD from the phase 3? One from Neil is, how concentrated is this market, you know, as you think about commercialization down the road? Is this primarily a center of excellence model, or do you think you'll have to have some more feet on the street to promote encaleret? Thanks for taking our questions.
Go ahead, Dr. Roberts.
Sure, happy to do so. For the phase 3 study, we plan to include patients with a minimum eGFR of 30 or higher. Definitely looking at some individuals with altered renal function as far as the study group goes.
Yeah, thanks, Paul. I can address the final question. You know, today I think with a launch, we would concentrate on COE-driven launch. In the future, I'd imagine that we would expand out into the community footprint, especially given some of the earlier comments around finding some of these patients within the HP community. That sales footprint could be broader, and we'd look to flex that as we find more and more of those patients in the community setting. I might also come back to an earlier commercial question that was asked just around pricing just for models. I think we do anticipate having a flat pricing model, whereby we take all of those different parameters that Ananth mentioned and introduce them.
I think you can imagine, just given prevalence of this disease, a flat pricing model for any financial projections.
Thank you. Your next question comes from Salim Syed with Mizuho. Your line is open.
Hey, guys. Congrats on the data. I have four questions, but if it's easier for you can think of it as 1 question, four parts, all on the phase 3 trials, if that's okay. You know, part 1 or question number 1, just curious, for whoever attended the end of the phase 2 meeting with the FDA, just what was the FDA's primary concern coming out of that meeting why a phase 3 trial was necessary in the first place. Seems like there is an incredible unmet need here, and yet 70% of the patients in this particular trial achieve normal range blood calcium and urine calcium. Was it a particular safety issue or what was it that they are really trying to get at? Part two here.
I think I know the answer to this question, but just the 2-3 patients that we're still not seeing get into those normal ranges for blood calcium and urinary calcium, was there anything particular about those patients that seems to make them more difficult to treat? Is that criteria being excluded from the phase 3 trial design? Third, is there any interim or built-in into the phase 3 design given its open label, and you will be getting data in-house as it comes? Lastly, for the phase 3 study, the titration period seems to be, you know, pretty much most of the duration of the trial, with a short-term maintenance period.
Just curious how confident we are that we won't need to have ongoing titration in a real-world setting. Thank you.
Hi, this is Dr. Roberts. Thank you for your question. I'm going to answer three of the four, and then I'm gonna pass it to Dr. Gafni for your second question on the individual patients in the phase two study. For the end of phase two meeting, the conversation around the need for a phase three study was really focused on the number of patients that have been exposed to the drug and generating enough safety data to ensure that we're, you know, not seeing any safety signals in a larger patient population. The other aspect of that conversation was the lack of a concurrent control. As Dr. Gafni reviewed in our phase two study, we only had baseline data on standard of care.
For the phase three study, we are not planning for an interim analysis given that the length of the study is relatively short, a total of 24 weeks on drug. Then your last question on the titration period. As Dr. Gafni showed in phase two, it really was around two weeks for almost all patients to reach the dose that they stayed on for the majority of the 24 weeks in period three. If they needed a dose adjustment, it was a minor change. We anticipate that in that period two of the schema that you saw, that most patients will actually be on their optimal dose early in that period, and then we can make minor adjustments over the remaining 20 weeks, so that when we get to period three, we don't anticipate that dosing adjustments will be needed.
We didn't actually see that for the individuals in our phase two study as well. I'll pass it over to Dr. Gafni.
Okay, thank you. Just regarding endpoints because I didn't present the individual data for the phase 2 study, but I just wanna make sure that it's clearly understood that all 13 patients maintained blood calcium levels within the normal range for the entire 24-week period. That was achieved in all patients. Eleven of the patients also maintained normal 24-hour urine calcium, and there were two patients who intermittently had normal and sometimes elevated 24-hour urine calcium. These two patients happened to also have the highest 24-hour urine calcium excretion at the screening visit. Both of them decreased their 24-hour urine calcium more than 50% during period 3. They didn't always enter the normal range on every assessment. I think what you were looking at with Dr.
Roberts' interpretation of what percentage of the patients achieved the primary endpoint, it was an incompletely calculated endpoint because we didn't have the same information collected in the phase 2 study that we plan to collect in the phase 3 study. Everybody maintained a normal calcium, and most of the vast majority had persistently normal 24-hour urine calciums on every measure.
Got it. Super helpful. Thank you.
Okay, thank you. Your next question comes from Yun Zhong with Jefferies. Your line is open.
Thank you. I have several questions. First, Neil, you mentioned that out of estimated 12,000 prevalence, about 3,500 patients have been diagnosed. That's less than about 30% of estimated prevalence. Are those diagnosed patients severe or they also include mild and moderate? Second question is, based on phase 3 entry criteria, would you be targeting mostly severe patients? The third question is on bone density. During the period of three, based on the bone turnover markers, there was minimal short-term effect on bone density, but how do you think about the long-term use of the drug there? Lastly, where will the phase 3 trial be conducted, and what % of estimated 45 patients to be enrolled would be coming from the US?
Thank you.
Yeah, thanks. I guess I can kick it off. I missed the second part of the question. The first part on the 3,500 patients, those are mostly moderate to severe patients since the fact that they are getting picked up today. I don't know what the split is between moderate and severe. Yeah.
Okay.
Go ahead.
Second question was based on the phase 3 entry criteria. Would you be targeting mostly severe? I mean, I guess it's going to be moderate severe based on your comment.
Yeah.
I can take this question. My name is Ananth here. The market opportunity probably is expands and is broad enough to include all symptomatic ADH1 participants or patients. The reason being is the symptom presentation as a result from hypocalcemia can vary from individual to individual, and some of the events can be sporadic in nature. What can be characterized as a severe symptomology, something like a loss of consciousness, acute event or a seizure, is hard to predict and in many cases is difficult to manage against.
We understand that diagnosis is probably picked up best by symptomology and symptomatic presentation, but we anticipate that NKAR will be studied in a broad symptomology population and anticipate that the eligible population will include mild to severe individuals with symptoms.
Thank you. Bone density. Potential long-term effects on bone density and where the phase 3 trial will be conducted?
Sure. Dr. Gafni can likely best address the question on bone mineral density.
Yeah, it's a great question. These patients at baseline are in a low turnover state, and that's why patients with hypoparathyroidism tend to have high bone density a priori prior to treatment with PTH or a calcilytic. What has been seen with medications such as PTH when they're given intermittently is a mixed anabolic catabolic effect, where you see increases in bone density in some compartments and decreases in bone densities in other compartments. This is true even for post-menopausal women that are treated with PTH because it's not being given in a physiologic way. Now where you give an injection and you see a spike in PTH and then it decreases very rapidly after that. What we're seeing with this drug is restoration more of normal physiology with the PTH levels being fairly stable.
My anticipation based on our initial Phase 3 data would be that I would hope not to see the significant changes in bone mineral density that are seen with intermittent PTH therapy. It's hard to know for sure, but I think if we're trying to, as best as possible, restore normal physiology, then yes, the bone density might change, and it might even go down as we go from a low turnover state to a normal turnover state. But I wouldn't necessarily expect it to become abnormally low. It may just more approach normal because we're starting with it in an abnormally high state.
This is Dr. Roberts. I can answer your question about the location of phase 3 trial sites. We're looking for sites in North America, the United States and Canada, and then in Europe as well as in Asia Pacific.
Do you have any estimate what percent of the 45 patients to be enrolled would be coming from the US?
At this time, we do not have that, but that information will be forthcoming as we do study start up in just a few months now.
Thank you.
Thank you. Your next question comes from Dane Leone with Raymond James. Your line is open.
Hi, guys. This is Sean on for Dane. Congrats on the pretty consistent data. Just a couple from us. First, can you give any color on the provenance of what appears to be somewhat of a jigsaw pattern in the blood calcium and the PTH? Then the second, maybe to put a finer point on the BMD discussion. In any of your preclinical models, did you see signs of elevated osteoclastogenesis like RANKL/OPG ratio changing?
Thanks, Sean. I'll pass it to Dr. Gafni to comment on the consistency of the parathyroid hormone and blood calcium profiles over time.
I think that certainly for phosphorus, there's a circadian rhythm that you expect anyway. I think that most of the I think what I'm understanding you're looking at is a zigzag pattern is mostly what we're seeing in Period 2, when we're rather rapidly adjusting the doses in a lot of patients over the course of the five days. Once we get them into a more stable place, we're seeing less of a zigzag pattern. Unfortunately, we're not showing the 24-hour sampling during Period 3 at 8, 16 and 24 weeks, where you could see that really this zigzag pattern that is more apparent in Period 2 is much less apparent when the patients are on a stable dose that's the most physiologic dose for them. Of course it is twice-daily dosing during Period 2 while we're sorting out the dose.
I think that.
I was actually.
I-
Sorry. I was actually talking about.
Okay.
Yeah, I was actually talking about period three, where at week eight and week 16, it appears to be closer.
Oh, okay.
to the lower limit of
Okay.
of normal.
I'm sorry.
Yeah.
That's actually. It's in the legend. The eight-
Okay.
I'm sorry, I misunderstood. The 8, 16 and 24 week measures were collected at the NIH, and those were collected prior to the dose in the morning. Whereas the outpatient measures, for the most part, were collected approximately four hours after the dose. That's that slight variation that you're seeing in the PTH there and the blood calcium.
Got it. Thanks for the clarification. Yeah.
Yeah. I'm sorry. I misunderstood your question.
All right.
The second question on the preclinical.
Sorry. Go ahead.
Sure.
The second question on any signs of elevated osteoclastogenesis in preclinical models.
Dr. Roberts, would you like to address this question?
That's an excellent question. Off the top of my head, I don't recall the specific preclinical data that you're asking about. I know that this drug has been tested in a number of preclinical models, but I don't recall the parameters of osteoclastogenesis . I'm sorry, I don't have an answer for you.
Okay. Thank you.
Your next question comes from Greg Harrison with Bank of America. Please go ahead.
Hey, good afternoon. Congrats on the data and thanks for taking our question. I have one question with one part. On the ex-U.S. commercialization plan, is this a situation where you would pursue a partnership or one where the patient population is maybe small enough that you could manage the effort yourselves?
Yeah, thanks for the question. Neil, I can take it. I think a little bit of it depends on how much or how extensive we build out our ex US infrastructure, based on the TTR data early next year. Yeah, I think you're right to say that if you're gonna do a de novo just for this drug, it's probably better to partner it.
Yeah. Thanks.
I mean, generally to make it NPV positive to build out European infrastructure, you would need, you know, something like $150 million per the region. Unless you have a super high price drug, which this wouldn't be, so I doubt we'd do it alone.
Great. Helpful. Thanks.
Thank you. Your next question comes from Ram Selvaraju with H.C. Wainwright. Your line is open.
Hi, this is Maz on for Ram. Congrats on the data. I was wondering what the gating items are for the phase 3 trial initiation, if you're expecting a Q3 or Q4 start. I was wondering about the quality of life questionnaire. Does this include acute symptoms of ADH1, such as seizures, paresthesia, and muscle cramps? Finally, in the long-term extension trial, are you evaluating long-term complications, such as nephrolithiasis, nephrocalcinosis, and chronic kidney disease. Thank you.
Thank you for your.
I'll pass it to Dr. Roberts. Go ahead.
Yes. Thank you. I'm gonna go from your last question backwards, if that's okay. In the long-term extension, we are planning to follow patients long term with renal ultrasounds to do it exactly as you suggest, monitor for nephrocalcinosis and potential changes in nephrocalcinosis over the long-term course of treatment as urine calcium is expected to decrease, as we've seen in our phase 2 study. We'll also plan to record, you know, events of symptomatic nephrolithiasis as well. From the quality of life questionnaire, the SF-36 or Short Form-36 is a nonspecific to ADH1 quality of life measure. The questions that'll be asked and assessed there are not specific to the symptoms these patients experience. However, out of all quality of life assessments, the SF-36 is the one that's been most robustly used in the hypoparathyroidism population.
We have, you know, data on different forms of hypopara to which we can compare this, and it also allows comparison to normal, individuals as well. We do plan to capture symptoms of ADH1 or hypocalcemia and hypercalcemia over the course of the study. Those will just be captured outside of a questionnaire. Finally, for your first question regarding gating of phase three initiation, we are waiting, or we're, awaiting and almost to the point of protocol finalization and then the typical site initiation activities that take some time with different various IRB ethics boards, whatnot, reviews to get the first site up and going.
Thanks very much.
Thank you. I'm not showing any further questions in the queue. I turn it back to management for any final remarks.
Thanks so much, everyone, for the time, and we'll look forward to following up on the one outstanding question and speaking with you all as this phase 3 gets underway. Thanks.
This concludes today's conference. Thank you for your participation, and you may now disconnect. Everyone, have a great day.