Thank you for standing by and welcome to the Autosomal Dominant Hypocalcemia Type 1 Investor Webinar. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number 1 on your telephone keypad. If you would like to withdraw your question, again press star 1. Thank you. I'd now like to turn the call over to Ananth Sridhar. You may begin.
Thank you, operator, and good morning, everyone. We're pleased to have you join us as we provide a presentation to discuss Incalerit, a small molecule that we're developing for Autosomal Dominant Hypocalcemia Type 1, abbreviated as ADH1, throughout this presentation. On our next slide, you'll see our forward-looking statements. This presentation will include forward-looking statements. Actual results may differ due to various factors. On this call, I'm privileged to be joined by Dr. Rachel Gaffney, a Senior Research Physician at the NIDCR of the National Institutes of Health, who will present an overview of ADH1 and of Incalerit. I'm also joined by Dr. Scott Adler, the Chief Medical Officer of Cosphletics Therapeutics, the BridgeBio affiliate that is dedicated to the development of Incalerit. Dr. Adler will provide a review of the Incalerit clinical development program.
I will also provide our perspectives on the market opportunity for ADH1, and we will conclude the presentation with a question and answer session. Before I hand the call to Dr. Gaffney, we wanted to illuminate the patient experience with ADH1, and by doing so, we thought the best way was to start with a video featuring Jessica, an individual living with ADH1, and her story.
I actually was diagnosed minutes after I was born. I was already showing low calcium symptoms. I'm not sure if I was intentionally or my blood work was flagged because they already had the neonatal doctor team involved because I was born a month early. They were doing more of the panels and things like that, checking, and they saw that my calcium was dangerously low. They called the endo team immediately over. She pretty much diagnosed me without even seeing me because she saw the parathyroid hormone level and then the calcium, which were both nonexistent. Pretty much my mom was getting stitched up and she was being told that, yeah, your daughter has this condition. She's going to be in the NICU probably for six weeks because there was so much not known about ADH1 in babies, and at that time they thought it was just hypoparathyroidism.
This is all that we know right now. I was constantly getting labs done, and then I was on the Roccotril orally, which is just to help increase my calcium, and I was on that at pretty large doses as a baby, and that worked out really well up until about two or three. That's when I passed my first kidney stone. My doctor realized it's not just the normal hypoparathyroidism. It's not just the blood calcium that we got to be worried about now. The kidney doctor, she pretty much told my mom that there's nothing we can do. She's not eligible for a transplant. You might as well just prepare to say goodbye because there's nothing that we can do.
Thankfully, the NIH called, and within two weeks after getting the call, I was flown up to Maryland, and I had to stay there for about three weeks inpatient at the hospital. I remember I thought I was really cool flying into Maryland every two weeks. They knew us. The NIH is just an amazing place and the history and all the innovations that are happening. Plus the endocrinologist that was doing the study at NIH, she was phenomenal, and I honestly owe her so much of just my well-being because if it wasn't for her, I don't even know where I would be now. Thinking about there being a specific treatment for ADH1, I think gives me so much hope. It finally feels like there is a light at the end of the tunnel.
I think it would allow all of us to have normalcy and to actually put the puzzle pieces back that we've been missing with treatment. I think that gives me hope.
Thank you for inviting me to join this call. My name is Dr. Rachel Gaffney, and I'm a Senior Research Physician at the National Institutes of Health and a Principal Investigator and co-chair of the Calibrate Steering Committee. Under 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, liberating calcium into the bloodstream. In the kidney, PTH increases renal calcium reabsorption and promotes conversion of 25-hydroxyvitamin D to the active 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 is doing much of the work, it is in fact the calcium-sensing receptor that is 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 receptors lead to decreased calcium reabsorption to rid the body of the excess calcium. Heterozygous activating variants in the calcium-sensing receptor cause a rare form of hypoparathyroidism called autosomal dominant hypocalcemia or ADH1. These variants in the 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 hypocalcemia, which can include significant neuromuscular irritability, manifesting symptoms ranging from mild paresthesia, which is the sensation of pins and needles or tingling in the hands and feet and face, to severe muscle cramps, seizures, and even death. The long-term complications are often treatment-related and include nephrolithiasis, nephrocalcinosis, and chronic kidney disease. It is important to note that the high urine calcium 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. As the name indicates, ADH1 is an autosomal dominant condition. What does that mean?
Humans have 23 pairs of chromosomes, and 22 of these pairs are called autosomes, while the 23rd pair are the XY chromosomes, also called sex chromosomes. The gene for the calcium-sensing receptor is found on the third chromosome, with each parent contributing one of the pairs to their child. When a parent has ADH1, there is a 50% chance with each pregnancy that they will pass on the pathogenic variant to their child. Unlike autosomal recessive disorders like sickle cell disease and cystic fibrosis, where the child needs an abnormal gene from both parents to have the condition, ADH1 is a dominant condition, meaning that you only need one altered copy of the calcium-sensing receptor to manifest the disorder. It is also common for someone with ADH1 to have a de novo or spontaneous variant, which means that they are the first person in their family to have the disease.
Moving forward, that individual still has a 50% chance of passing it along to their children and future generations. For decades we have suspected the diagnosis of ADH1 based on family history, along with clinical and biochemical findings, genetic testing is important to make a definitive diagnosis and conduct genetic counseling. At present, the prevalence of ADH1 is estimated to be 1 in 25,000. In some cases, ADH1 can be difficult to diagnose based on symptoms alone, and patients may experience a prolonged delay before receiving a final diagnosis. When you do identify that first individual with ADH1, family screening is recommended to both identify and rule out ADH1 in other family members. This can be done through biochemical and/or genetic testing.
According to a systematic literature review, the median age of a diagnosis of a hypocalcemic-related disorder is four years, but a genetically confirmed diagnosis of ADH1 is delayed with a median age of 25 years. Currently, the standard of care for individuals with ADH1 is conventional therapy with calcium and active vitamin D supplementation given in divided doses throughout the day. Some patients also require magnesium and potassium supplements. The goal of this treatment is to increase the blood calcium enough to alleviate the symptoms of hypocalcemia. However, increasing the blood calcium in these patients also increases urine calcium, so we are forced to titrate the medications to the lower limit of the normal range for blood calcium, or even frankly below normal, to minimize the rise in urine calcium and its associated comorbidities. As a result, patients often continue to experience hypocalcemia-related symptoms.
What about using parathyroid hormone replacement in patients with ADH1? First of all, the data are quite limited, as most industry-sponsored studies of PTH analogs have deliberately excluded patients with ADH1 from their trials. Secondly, unlike other causes of hypoparathyroidism, where the parathyroid glands are either missing, damaged, or underdeveloped, patients with ADH1 have normal parathyroid glands with the capacity to produce PTH in response to the appropriate stimulation. Finally, we know from small investigator-sponsored studies that while PTH 1 to 34 can raise the blood calcium in patients with ADH1, it will not necessarily correct the hypercalciuria, not only because intermittent short-acting PTH 1 to 34 does not recapitulate normal physiology, but also because patients with ADH1 still have altered calcium sensing at the level of the kidney.
For example, in a study of twice-daily PTH 1 to 34 therapy that we conducted in 31 patients with hypoparathyroidism, including four participants with ADH1, we found that nephrocalcinosis was not prevented in this patient. The image on the left is the normal renal ultrasound of a 40-year-old man with ADH1. One year later, he had developed nephrocalcinosis while on PTH 1 to 34, despite maintaining his blood calcium at the lower end of the normal range. In our drive to provide more precision medicine, it made sense to pursue a therapy for ADH1 that directly targets the underlying genetic cause and restores normal physiology, rather than applying a band-aid of PTH analogs that incompletely addresses the problem at hand. This led us to Incalerit, which is an investigational oral medication from the class of drugs called calpholytics.
Calpholytics are negative allosteric modulators of the calcium-sensing receptor, which decrease the receptor sensitivity to extracellular calcium, essentially shifting the response of the parathyroids and the kidneys to the right, which should in turn lead to increased PTH secretion and increased renal calcium reabsorption. It should be noted that these drugs were originally developed and studied in large clinical trials for the treatment of postmenopausal osteoporosis, with the hope that increasing endogenous PTH secretion would increase bone density. Unfortunately, these drugs were not effective in osteoporosis, and further study for this indication was abandoned. However, results from these osteoporosis studies did demonstrate a rise in both PTH and blood calcium levels in these patients with osteoporosis, leading us to hypothesize that normalizing calcium-sensing receptor sensitivity with Incalerit has the potential to correct the hypocalcemia, hypercalciuria, and low PTH in individuals with ADH1. Thank you.
Thank you, Dr. Gaffney. I will now describe the Incalerit clinical development program. As Dr. Gaffney has described, activating variants in the calcium-sensing receptor increase the sensitivity to calcium, causing the parathyroids and the kidneys to behave as if the blood calcium concentration is higher than it actually is. As a result, patients with ADH1 have decreased PTH secretion, decreased blood calcium, and increased urinary calcium excretion. Incalerit is an investigational oral medication from the class of drugs called calpholytics and acts as a negative allosteric modulator of the calcium-sensing receptor. Through this mechanism, Incalerit decreases the sensitivity of the calcium-sensing receptor to extracellular calcium. Correcting the sensitivity of the calcium-sensing receptor is able to restore PTH secretion, increase serum calcium, and decrease urinary calcium excretion into their normal ranges. Incalerit is the first and only investigational treatment targeting ADH1 at its source.
By targeting the calcium-sensing receptor, mineral homeostasis can be restored in patients with ADH1. Incalerit addresses the common clinical markers of disease, namely low PTH, low serum calcium, and its associated symptoms of hypocalcemia, and the high urinary calcium excretion. Incalerit is also dosed orally. I'd like to briefly review the design and the results from our Phase IIb study of Incalerit in ADH1. On this slide, the Phase IIb open-label study was divided into four periods. During period one, six patients with ADH1 received Incalerit in escalating doses over five days while undergoing frequent blood and urine sampling. Period two was an inpatient period that included those six patients plus an additional seven patients. During period two, patients received individualized dose titration for five days. These 13 patients then entered period three, a 24-week outpatient period with scheduled assessments occurring every one to eight weeks.
Participants then entered a fourth period, which was a long-term extension with assessments every three months. The key study objectives were safety and tolerability and calcium metabolism. Additional secondary measures are listed here. Calcitriol, or calcium supplements, were discontinued upon Incalerit administration, and patients were instructed to consume at least 1,000 milligrams of dietary calcium per day. I will next present the results from 42 months of continuous outpatient treatment with Incalerit. On this slide, the baseline characteristics of the study participants are shown. Thirteen 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, namely hypocalcemia, low PTH, and inappropriately normal or frankly elevated urine calcium. Three quarters of the patients had nephrocalcinosis by renal ultrasound. The baseline kidney function was variable in the group, with a mean estimated glomerular filtration rate of 84.
All study participants were being managed with calcium and calcitriol supplements in fairly typical doses divided throughout the day. On the next slide, I show to you the safety and tolerability for the study, as these were primary endpoints. Incalerit was well tolerated with few adverse events. Two serious adverse events occurred very late in the long-term extension and were unrelated to Incalerit. The only treatment-related adverse events were instances of transient low blood phosphate concentrations and some instances of mild hypercalcemia with no patient exceeding an albumin-corrected calcium over 10.9 milligrams per deciliter. All treatment-related adverse events resolved either spontaneously or with adjustment of the Incalerit dose. No other concomitant therapies were required. On the next slide, these figures display the mean pharmacodynamic responses to individualized twice-daily dosing of Incalerit.
The first 24 weeks of treatment are shown on the left half of each graph, followed by an additional 36 months of treatment as part of the long-term extension on the right half of each graph. The upper panels show robust responses of blood and urine calcium, with increases in the albumin-corrected blood calcium into the normal range on the left and decreases in the urine calcium excretion into the normal range on the right. In the lower panel, you can also see robust increase of PTH into the normal range. These responses were maintained throughout the 42 months of treatment.
In the next slide, when we evaluated the blood and urine calcium responses to Incalerit, we observed that nearly 70% of the patients were able to achieve both a blood and urine calcium within the normal range, when none of them were able to achieve that while on standard of care. This finding led us to select this composite endpoint for the ongoing Phase III study in patients with ADH1. In this slide, to summarize, in 13 patients with ADH1, Incalerit administered twice daily for 42 months restored mineral homeostasis, as demonstrated by an increase in PTH, correction of hypocalcemia, and normalization of mean 24-hour urine calcium excretion. The 13 participants continue on Incalerit in a long-term extension study. I will next briefly discuss the ongoing Phase III study in patients with ADH1. The Phase III Calibrate study is ongoing.
The last patient last visit occurred at the end of the summer, and top-line results are anticipated this fall. The study design is outlined here on this slide. After a screening and standard of care optimization period, patients 16 years of age and older entered a four-week standard of care maintenance period. They were then randomized two to one to Incalerit or standard of care for 20 weeks. Those randomized to receive Incalerit had standard of care discontinued, and then Incalerit or standard of care was titrated to maintain blood calcium in the target range. Once titration was completed, the participants entered a four-week maintenance period when doses of drug were kept stable. After completing the 24-week study, all study participants were given the option to enter a long-term extension study when all participants received Incalerit.
The primary endpoint of the study is the proportion of participants achieving blood and urine calcium within the target range at week 24. The secondary endpoints are as listed. We are looking forward to top-line results in the fall. This past weekend, our collaborators at the NIH presented data from a study of Incalerit in patients with postsurgical hypoparathyroidism. In this proof of principle study of 10 participants, urine calcium excretion rapidly decreased following Incalerit administration, and importantly, the albumin-corrected blood calcium also increased into the mid-normal range. We believe that the mechanism of action is through a PTH-independent effect on the calcium-sensing receptor expressed in the kidney. An important observation is that none of these study participants had both blood and urine calcium within the normal range while on standard of care, but 80% were able to achieve this endpoint within five days of Incalerit administration.
These findings suggest a potential path for improved calcium control in an oral medication. Additionally, Incalerit will have a benefit in controlling 24-hour urine calcium excretion and potentially avoiding long-term PTH-mediated effects on bone health. We look forward to initiating additional clinical studies of Incalerit in patients with chronic hypoparathyroidism. I'll now turn it back to Ananth for the market opportunity.
Thank you, Scott. Now to present some of our perspectives on the ADH1 market opportunity, we wanted to start with our estimate of the disease prevalence. We've evaluated various genetic databases, and what started as an initial query of the Geisinger cohort, we evaluated about 1 in 25,000 individuals carry variants associated with ADH1. We replicated that work in a broader cohort, including the UK Biobank, the All of Us cohort, and the Mass General Biobank, which accounted for over 700,000 individuals of genetic data. In assessing the CASR genotypes associated with ADH1, we found a very similar prevalence of about 1 in 25,000. If we apply this rate to the U.S. population, we estimate there are about 12,000 individuals with ADH1 who are prevalent in the U.S.
Of those 12,000, we currently believe about 3,000 to 5,000 are currently addressable based on their symptom presentation and their current diagnosis rates. Turning to the next page on slide 28, we wanted to recap some of our genetic data from our sponsored testing program, which we have presented at recent medical meetings. In this program, we are testing for all known genetic causes of hypoparathyroidism, included in a 26-gene panel. Within this panel, we have learned that about 40% of non-surgical hypoparathyroidism cases are genetic in their etiology. Of those genetic cases, the majority are associated with CASR variants associated with ADH1. This work is illuminating that ADH1 is the most common isolated cause of non-surgical hypoparathyroidism, and the proportion of non-surgical hypoparathyroidism patients with genetic hypoparathyroidism or genetic etiology is quite high.
Turning to slide 29, we believe there's a few features of this marketplace that serve as tailwinds to accelerate diagnosis. In one element, we are sponsoring a genetic testing program, which I covered evidence from in the last slide. This is a no-cost testing program for providers to identify potential genetic variants causative of hypoparathyroidism. There's also a newly established ICD-10 code that is dedicated to ADH1 and ADH2. Finally, new management guidelines for hypoparathyroidism are recommending the need for genetic testing in all patients with idiopathic hypoparathyroidism, especially patients with a family history. These elements provide a tailwind to the broader ecosystem that we believe will accelerate diagnosis rates alongside our active development program. Turning to the next page, when we look at the Calibrate study that Scott presented, we believe that there's an opportunity for Incalerit to become a first-in-class medicine for ADH1 patients.
In our base case, we believe that any significant benefit over standard of care will really be practice-changing, especially when paired with a safety profile consistent with current standard of care. The upside home runs narrow that would really be paradigm shifting. We believe that if a majority of patients respond to therapy at the week 24 time point, as assessed by target blood and urine calcium within the normal range, we would be blown away. Additionally, we would hope to see mean parathyroid hormone within the normal range, which would be reflective of restoration of the endogenous axis of parathyroid hormone synthesis and secretion. This result would be practice-changing and would drive meaningful utilization and adoption based on our understanding of the market opportunity. With that, we'll conclude our call and open up to question and answer.
Thank you. We will now begin the question and answer session. If you'd like to ask a question, please press star 1 on your telephone keypad to raise your hand and join the queue. Your first question today comes from the line of Selim Said from Mizuho. Your line is open.
Hi, this is Bennett for Selim. Thanks for taking our question. Regarding the potential in chronic hypoparathyroidism, broadly speaking, could you discuss how Incalerit could differentiate versus hormone replacement therapy? Could we expect to see the same endpoints used in the proof of concept study and Incalerit in the upcoming pivotal? If I may, how important would it be to get the benefit on urinary calcium in the level? Thank you.
Thank you, Bennett. Scott, I will defer to you for that answer.
Thank you for the question. In order for differentiation, first of all, Incalerit is an oral medication, and I think would provide convenience for patients in avoiding daily injections. I think, importantly, the focus would be for Incalerit to decrease urinary calcium excretion in the patient population, which in doing so will also increase the blood calcium. Again, focusing on the effects in the kidney and preventing long-term complications, including kidney stones and the development of chronic kidney disease. I think it's a really important point that any decrease in urinary calcium excretion is beneficial to patients, and that's been well demonstrated in the patients with recurrent calcium stone formation. The differentiating points would be maintaining blood calcium, decreasing urine calcium, and then having an oral medication for this patient population.
Thank you.
Our next question comes from a line of Tyler Van Buren from TD Cowen. Your line is open.
Great. Thanks so much for hosting the webcast. Very clean data, obviously, in Phase II, especially for only 13 patients. Just to follow up, as we think about the probability of success for the ongoing Phase III, can you just confirm that the way you're measuring the primary endpoint of serum and urinary calcium levels and normalization, that it's the exact same as what you did in Phase II, and also what you would expect the standard of care control arm to do based upon historical data? Finally, can you talk about the enrollment pace, how it evolved throughout the study, the number of centers involved, and how that experience might enable commercial uptake upon a potential approval and launch?
Thank you, Tyler. I heard three questions there. One is how the Phase III assessment may differ from Phase II, what the standard of care response may be, and the overall study dynamics and enrollment. I'll let Scott answer the first question and the last regarding the Phase III study, and I'll defer to Dr. Gaffney on her perspective of standard of care response, the primary endpoint.
As far as the primary endpoints, they are measured in the same way. We'll receive both blood and urine calcium collected around the same time as each other. The patients will collect 24-hour urine collection and have a blood sample measured within a day or so of that collection. It is the same as was done in the Phase II study. We had 25 centers globally in the Phase III study. It's a rare disease. The patients that were being seen at that center were included in the trial, and additional patients in surrounding areas were referred into those centers. It did take us 18 months to enroll the study, but we had very good participation from those active tertiary care centers that see patients with this condition. Dr. Gaffney is going to address the standard of care response rate.
Thank you, Scott. Just to add to what Scott was saying, the primary endpoint for the Phase II study, which was a single-site study done at the NIH with the 13 patients, the primary endpoint was actually safety and tolerability because this drug had not been given to patients with ADH1. It had only been used in healthy volunteers and people with osteoporosis. Yes, we were collecting everything the same, but the primary endpoint was different between the two studies. In terms of standard of care response, I can't speak to the entire Calibrate protocol, but at our site, where we have 17 patients plus other patients who screen failed, really nobody on standard of care treatment has normal blood calcium. If they do have mid-normal blood calcium, then they're being overtreated.
Their doses have not really been optimized because we target their blood calcium for safety reasons at the lower end of the normal range or even slightly below. Some patients might not have frankly elevated urine calcium on standard of care, but it's certainly inappropriately elevated for the level of blood calcium that's targeted. Did that answer your question?
Yep, that's perfect. Thanks so much, guys.
One addition to the enrollment dynamics just to clarify for the audience here is that we were able to exceed our enrollment target by about 20% given the demand for this study, and we enrolled 71 participants, as noted in our presentation.
Our next question comes from a line of Byron Emmett from Piper Sandler. Your line is open.
Yeah, hi, guys. Thanks for taking my questions. In the Phase III, what type of a treatment difference would you need to see to achieve statistical significance? The second question, on the Phase II long-term follow-up, about the 42 months, are you looking for renal outcomes and measuring of renal outcomes on the long-term follow-up for both, I guess, the Phase II as well as the Phase III? What do you hope to see there?
Thank you for your questions. Scott, would you like to address these?
Yes, happy to do that. The statistical power of this study, we expect to see a, we're powered to see a difference of 30% between standard of care and the active treatment. We are well-powered, over 90% powered to see that difference. That's in the Phase III study. From the Phase II perspective, yes, we are following up on all renal endpoints. We are looking at both estimated glomerular filtration rate as a measure of kidney function over time, as well as looking at renal ultrasounds over the course of the study. Dr. Gaffney is the Principal Investigator of the Phase II study, and I'll defer to her if she would like to comment on the renal ultrasound findings from that Phase II study.
I hope you can hear me. Somebody just started drilling very loudly directly above my office. Okay, it went away. Yes, we are following the renal ultrasounds as well as the urine calcium and other urine metabolites and creatinine and glomerular filtration rate and cystatin C, as Dr. Adler referred to. As of now, we're not really seeing any changes in the renal ultrasound. Some patients who had a history of frequent kidney stones, some of them have continued to have intermittent kidney stones, while others haven't had kidney stones at all. We're not seeing progression of existing nephrocalcinosis on ultrasounds, keeping in mind that this is usually a permanent finding. It doesn't regress once you have it. Our goal is really to avoid progression and worsening of renal calcifications. I hope that answered you properly.
Our next question comes from a line of Josh Shimmer from Cantor Fitzgerald. Your line is open.
Great. Thanks so much for taking the questions. There's a case report at ESPE this year evaluating Yorvapath in a patient with ADH1. Maybe you can comment on that experience, and then specifically also indicate what gives you confidence that Incalerit would normalize urine calcium for a patient with such a high baseline. Separately, are there other settings in which Incalerit has clinical advantages over PTH replacement that go beyond just the convenience of an injectable, like you've illustrated for ADH1?
Thank you, Josh. Rachel, would you like to address the question on PTH replacement, given your clinical experience using that modality in ADH1 patients?
Yes, certainly. What we generally observed with, it's very hard to say anything about the Yorvapath study because that was a single case, and we have not personally treated any of our ADH1 patients with Yorvapath. With short-acting PTH 1 to 34 given twice daily, you see a drop in the urine calcium in all patients initially, maybe four hours after the injection, but because the pharmacokinetics of short-acting PTH do not recapitulate normal physiology, it's more of a spike in PTH that gradually goes away. The urine calcium starts to rise again after about four to six hours after the injection. It doesn't translate to a reduction in 24-hour urine calcium.
In that PTH 1 to 34 studies that have been done at the NIH also by investigators prior to me, patients with calcium-sensing receptors required higher doses of short-acting PTH, even just to get the blood calcium to the lower end of normal. It really wasn't correcting the physiology in patients with all types of hypoparathyroidism, including patients with ADH1 at our center. I think it's really hard to speak to the Yorvapath data because these are just individual case reports, and patients may have very high urine calciums that decrease, but perhaps don't go into the normal range. I can't really comment on that study, but certainly in our patient population, we are seeing in most patients normalization of 24-hour urine calcium while on Incalerit, and if not complete normalization, dramatic reduction in urine calcium excretion. Did that answer your question?
To some extent, I got the other part was, are there other settings like ADH1 where having calcium-sensing receptor antagonists would confer clinical advantages beyond just the convenience of an oral pill?
I think the only other population that we've given it to, as Dr. Adler presented, were these 10 patients with postsurgical hypoparathyroidism. It's hard to predict, but one could envision that even using this maybe as adjuvant therapy, it has the potential to be beneficial because it's going to act at the kidney to decrease urine calcium excretion, even if you don't have parathyroid glands present. It's a little difficult to predict who will respond to this, but based on that preliminary data in 10 patients, it seems that the renal effects of Incalerit alone are already quite substantial. Because with injectable PTH historically, you still had to keep the blood calcium at the lower end of the normal range because PTH injections did not completely ameliorate the hypercalciuria.
I think that there's potential to use this and improve the physiology overall in the patients, either as complete replacement therapy or adjuvant therapy, but obviously, further study is required.
May I comment on the use of PTH in ADH1? I think that it's important to recognize that ADH1 is not a PTH problem. The problem in ADH1, it's a calcium-sensing receptor problem. Incalerit fixes the disease at its source, both in the parathyroid glands and in the kidneys. Just using PTH, any PTH replacement alone is not necessarily the drug that will fix both components of the problem in patients with ADH1, and that is in the calcium-sensing receptor.
I can add anecdotally that some of the patients in the current Calibrate study at our site were also in previous PTH trials, and as they report to me, they really feel much better on the Incalerit than they did on the PTH, possibly because their 24-hour urine calcium have normalized, but also because they don't have that variability in pharmacokinetics and pharmacodynamics. It's more of a sustained normal range of calcium rather than sort of having a spike that then wears off over time.
Our next question comes from a line of Emmanuel Walter from Leerink Partners. Your line is open.
Hey, guys. You have Ryan on from Moni. Thanks for taking our question and appreciate the presentation. Could you just talk a little bit about whether patients were optimized on standard of care to achieve their target ranges in the Phase II trial, and whether we should expect that to be consistent with the standard of care maintenance period for Phase III? Separately, I guess just wondering your expectations on the number of weeks it typically takes for a patient to titrate to the optimal dose for Phase II and for Phase III. Thanks.
Thank you, Brian. I'll let Scott address the question regarding the standard of care maintenance period, and Dr. Gaffney address the question regarding her experience with the Incalerit titration.
I think Dr. Gaffney can comment on the standard of care maintenance in the Phase II population before they got put in the study. Certainly, for our standard of care optimization in Phase III, the patients were well optimized during that optimization period prior to period one. While the study is currently masked and blinded, we don't have results from that standard of care maintenance period, but we would anticipate having results similar to what was seen in the Phase II study. During the titration expectations, we are seeing patients titrated over approximately eight weeks with minimal adjustments in their drugs after an eight-week period of time. Dr. Gaffney, can you comment further on your experiences?
Yes. Regarding the optimization of care prior to initiation of Incalerit in the Phase II study, the majority of the patients enrolled in that study were known to me and were already established as patients at the NIH prior to enrollment. I was able, even though there wasn't a formal optimization period written into the Phase II study, I knew most of the patients and had optimized them before they started Incalerit. Again, optimization of treatment of standard of care requires targeting a blood calcium to the lower end of the normal range or just below. Everybody was pretty much well optimized by standard of care recommendations prior to entering into Phase II. Titration in general was pretty quick. In the Phase II study, period two was an inpatient phase for five days. We were really able to start titrating patients within that five-day period before they went home.
When they were in the outpatient phase, a few patients needed some additional adjustment over the subsequent weeks, but we got people pretty much to a standard dose, individualized standard dose for that patient within two months. In the Calibrate phase, it was about the same. We only had one patient at our site that randomized into Calibrate for the phase, into Incalerit for the Phase III study, but I feel very comfortable getting patients to their dose. I can't really predict it when I start the Incalerit, but within two days, I already have a sense of which way they're going to go, and I can get them into their final dose pretty quickly.
Super helpful. Thank you. Our next question comes from a line of Corey Kasimov from Evercore ISI. Your line is open.
Hi, this is Adi on for Corey. One question from us. One of the major differences between Phase II and Phase III is the broader genetic eligibility. Do you have a sense of relative severity across different genotypes and how this might impact the Phase III outcomes? Thank you.
Adi, I can address that question. There are no broader genetic criteria for eligibility in either of the Phase II or the Phase III study. Both studies were open to gain-of-function variants of the calcium-sensing receptor associated with a clinical feature or a clinical presentation of hypoparathyroidism.
Ananth, may I add, though? In the Phase II study, we only had nine different variants, and it's well known that there's over 120 genetic variants of ADH1. Clearly, in the Phase III study, we are enrolling additional variants to those nine. We'll probably have 50 or so different variants assessed of the calcium-sensing receptor, gain-of-function variants in the calcium-sensing receptor. We'll have a broader knowledge about variants and their location in the calcium-sensing receptor in response to the drug.
Our next question comes from the line of Andrew Sy from Jefferies. Your line is open.
Good morning. Thanks for taking my question. A big picture question is, can you describe the kinds of discussions you've had with the FDA over the years on this program, and what exactly has the FDA agreed to as it relates to the regular pathway? Can you file on this data, and do you actually have buy-in from ex-US regulators as well? Thank you.
Thank you for that question. Scott would be best positioned to address this.
Sure. We've had multiple discussions with the FDA over the design of the trial, and we have gotten agreement to move forward with the study that we have in hand, and that was assessed at the beginning of our program. We've also had multiple discussions with ex-U.S. regulators in Europe as well as in Japan. I've had very fruitful discussions with them about our path forward, and the study is well designed to address concerns. We feel very confident in our ability to file, you know, and just waiting for results of the Phase III program to move forward with regulatory submissions.
Thank you.
Our next question comes from a line of Danielle Brill from Chardan Securities. Your line is open.
Hi, good morning. Thanks for hosting this event, and thanks so much for the questions. I guess I have a couple. A follow-up for Dr. Gaffney on expectations for the standard of care arm. I guess maybe asking just a slightly different way from the prior questions. In standard clinical practice, how often are you able to achieve eucalcemia, and how often are you having to tweak patients' doses to get there? On the genetic front, are there any mutations permitted in the Phase III, like transmembrane mutations that might not respond as well? How should we think about the proportion of the overall population that will benefit from Incalerit? Thank you.
Dr. Gaffney, would you like to address the first question? I can start with the second question and pass it to Scott.
Yes, thank you for your question. In terms of managing patients with standard of care, you can get anybody's blood calcium level into the normal range, you know, between 8.5 and 10.2 milligrams per deciliter with oral calcium and calcitriol. You can definitely achieve that, but that is not the best goal for patients with ADH1 because that will cause the urine calcium to be quite elevated. The same is true for PTH. I can get anybody's blood calcium level normal with injections of PTH, but again, at the expense of renal calcium and the risk for renal calcifications. In terms of the adjustment of medications, standard of care in patients with ADH1 and all forms of hypoparathyroidism as well, in my opinion, and I'm a pediatric endocrinologist, so I treat children from birth with this disorder as well as other genetic causes of hypoparathyroidism.
Very frequent monitoring is required to adjust standard of care medications at a minimum in older children and adults every three months because you really don't want that patient to be running at a high blood calcium. If I wait six months to check their labs and their blood calcium is high, I don't know if that's been going on for one month or five months, and that can really cause damage to the kidneys. Anytime patients on standard of care medications on calcium and calcitriol get sick, get a gastrointestinal illness, or have to have even surgery, often they need to go to the hospital or even be admitted for IV calcium infusions because maybe they're not absorbing their calcium and calcitriol well, or maybe they're not allowed to eat or take medications because they're having surgery.
I will tell you that I haven't had a single patient in this study who has needed a calcium infusion while on Incalerit or needed any special care during elective surgeries. They just take their Incalerit in the morning, go have their surgery, and, you know, live their lives and do quite well. Even when they're ill with an intestinal condition, I haven't had to send anybody to the emergency room for IV calcium. It's really dramatically different. There's also just adjustments, particularly in children as they're growing, where we're constantly adjusting their calcium and calcitriol because, again, of illness, of puberty, of growth. This Phase III study is the first time that I have spaced out blood testing and urine testing to every six months in a patient population with hypoparathyroidism, and they've just been incredibly stable.
Once they get to the dose they need, it pretty much doesn't seem to change. Did that answer your question?
It does. Thank you.
Danielle, on your second question regarding the genetic variants that are enrolled in our Phase III, I can just comment briefly, and then I'll pass it to Scott on the specific study dynamics. Broadly, our assessment of the genetic landscape for the calcium-sensing receptor is that the majority, 60% to 70% of the known variants, are in the extracellular domain. This is related to the conformation of the protein with most of the protein sitting in the extracellular domain. As Scott mentioned, we do anticipate a broader heterogeneity of enrolled variants in our Phase III. I'll let him comment on any potential differences in response based on what we know.
It's a really, really interesting question, and you raised the transmembrane domain region of the calcium-sensing receptor. We know that in that transmembrane domain, there is a binding pocket for chemicals that bind to the calcium-sensing receptor, including some calcimimetics and calcilytics. We also know that there are amino acid residues within that transmembrane domain that are important and critical for binding of those drugs. We expect Incalerit to have some similar binding properties, and there will likely be variants within that transmembrane binding pocket in which Incalerit won't be able to bind. Again, we won't know that until we unmask our Phase III study and analyze all of the variants that were in our study.
As far as the frequency of the number of variants that occur in the transmembrane domain in that chemical binding pocket, we don't know what the relative frequency of that is in the general population. As Ananth pointed out, 60% to 70% of the variants are in the extracellular domain and outside of that binding pocket. We will basically have to wait and see.
Understood. Thank you.
Your final question today comes from the line of Anupam Rama from JP Morgan. Your line is open.
Hey, guys. Thanks so much for taking the question. For the KOL on the line, in the pivotal Calibrate Incalerit study, what's the minimal threshold on the primary endpoint of sort of blood and urine calcium proportion normalization that you think would be meaningful relative to standard of care? We've heard on this call it's powered to show 30% kind of delta. We've heard from the company that 50% is a home run. What are your perspectives on the threshold and the minimal that it would need to be clinically meaningful in your eyes? Thanks so much.
Dr. Gaffney?
I'm not sure this question is for me because it's about study design, statistical calculations.
The question?
I can only tell you my experience.
The question, Dr. Gaffney, to reiterate my understanding of it, is your perspective of a clinically meaningful responder rate on target blood and urine calcium in your perspectives?
Do you mean my perspective of what percentage of the urinary calcium needs to come down, or are we talking about general sort of quality of life issues? I'm sorry, I still don't really understand the question that you're asking from my perspective because I haven't seen the data from Calibrate, so I can't. Maybe ask the.
Rachel, if there's like a 20% response rate on standard of care, what is a meaningful difference in patients on Incalerit? Is it 50%, 80%, 90%? What's the difference between standard of care and Incalerit response rate that you would find clinically meaningful?
I think if I'm answering this correctly because this is just me guessing, I think 100% of our patients at our site have responded with blood calcium levels into the normal range. They, you know, while I haven't analyzed the questionnaires, anecdotally report to me a much better quality of life, not just from having a normal calcium and a normal PTH level, but also from just a pill burden status as well as the decrease in urine calcium. I'm not really sure how to speculate what percentage would be acceptable to me. Obviously, the more that respond, the better, but I'm not sure I can give you a percentage because I've had a 100% response rate at my site. I'm really sorry. I'm just a little bit flummoxed on what you want me to estimate still.
You mean if I saw only 25% people responded and 75% had to stay on standard of care, that would, in my mind, be a failure? Is that what you're asking me?
Hi, this is Anupam from JP Morgan. What is the minimal proportion delta that you think would be clinically meaningful? If standard of care does 10% responder rate, would it be 25%, 35%, 45%, 50%? What is that minimal threshold that you would be like, "Hey, this is still super, super interesting, but it doesn't have to be 100% clearly like what you're seeing"?
Yeah. I mean, I don't think in my experience, I don't see a response rate to the normal ranges with standard of care because, as I mentioned, if you're treating to that, you're usually overtreating the patient. I think even a 25% difference is significant. In some patients, particularly those that might be more brittle, more severely affected, switching them from standard of care to Incalerit would be very meaningful. I think from a physiologic standpoint and from a clinical standpoint, even 25 to 30% improvement or meeting the endpoint to me would be beneficial.
Great. That's awesome.
Is that what you're asking me for? I'm sorry.
Yeah, totally. Sorry. It was probably my bad.
No, it's okay.
Thank you.
Okay.
I'll now turn the call back over to Ananth for some final closing remarks.
Thank you for joining us this morning. Have a great rest of your day.
This concludes today's conference call. Thank you for your participation, and you may now disconnect.