Good evening, and welcome to this continuing medical education symposium on hypoparathyroidism. My name's Dolores Schoback. I'm from the University of California, San Francisco, and I want to welcome you to this, I think, very exciting program, Then, Now, and the Future, Preventing the Complications of Hypoparathyroidism. I'm joined here on the podium by Dr. Suzanne Jandabur, Professor of Medicine and Chief of Endocrinology and Metabolism at the University of Virginia in Charlottesville, and I'm also, we have two incredibly special guests with us today, who are our patient advocates and who are our leaders in the Hypoparathyroidism Association, Patty Keating, to the left of Dr. Jandabur, and Michelle Reyes, to Patty's left. And you will see that they will be providing some incredible insights into this disease and the impact it has on patients and families. So we're really thrilled to have these two very special visitors with us today. So we will start this program, really, with an introduction to this disease. We'll go through that quickly, because I know in an endocrine audience, there's lots of expertise already. I'll talk about some of the kidney complications of hypoparathyroidism and some ways that those might be affected by some of the therapies that we use. Suzanne will take over then and talk about what it means for patients and talk about quality of life and hypoparathyroidism, and then we'll have presentations from both Patty and Michelle throughout the program, and then we'll have some concluding remarks. So we'll start first with the background on this disease, what the definition is based on the second international publication in 2022. We'll talk about sort of the variety of body systems that are affected by this disease and the impact on the life of the patient. Patty will talk to us about that and share her personal timeline and her personal experience. Then we'll talk about renal complications, quality of life, and then Michelle will finish us up with some additional information on quality of life. So let's start with some of, really, some of the very basics about this disease. So the second international workshop, it took quite a while to hammer out what the definition of this disease is going to be going forward, and so there are three parts to that. Hypocalcemia, as this audience well knows, and you can do a total albumin-corrected calcium or an ionized calcium, either one is just fine, but the PTH level is critical. Along with that ionized or total calcium, it needs to be undetectable, low, or inappropriately normal for that serum calcium concentration. That needs to be measured twice, at least two weeks apart, to establish the definition. And this is really important for research as we go forward. The other abnormalities are valuable, but they are not essential. The elevated phosphorus, the reduction in 125D, and elevations in urinary calcium excretion. And then for patients who've had surgery, the surgery needs to be at least 12 months from the time you're trying to make that diagnosis. And this recommendation, because the evidence actually was not very strong for making any definition, was an ungrateful recommendation. So with regard to the causes of hypoparathyroidism, I think this audience well knows that the majority is caused by some kind of anterior neck surgery, and the other etiologies make up quite a few very heterogeneous ones, mainly dominated by genetic disorders and autoimmunity. So in terms of the genetic disorders, and we'll take those on first and not go into tremendous detail here, but these really divide themselves into disorders where the parathyroid gland doesn't form properly, or the cells, they might be there, but they don't function properly. And then there are the disorders of PTH secretion. So there's a lot of information on these slides, and there's no reason that you need to get into any detail, but know that there are a number of genetic conditions that need to be ruled out if you encounter a patient with non-surgical hypoparathyroidism. And they include the syndromes that are listed here, and many of us either have taken care of or have ruled out the DeGeorge syndrome. That's probably one of the most prominent, and that one, as well as other isolated forms of hypoparathyroidism. And the disorders of PTH secretion itself really lend themselves into a pretty straightforward classification, either hypocalcemia with hypercalciuria, the autosomal dominant type 1 hypoparathyroidism, and type 2 due to two different mutations in different signaling molecules in the calcium receptor pathway. There are quite a few, at least 10 different syndromes where magnesium is low, and that drives the hyposecretion, if you will, of PTH and low calcium. And then finally, damage to the glands through autoimmune mechanisms, either as part of APS1, the polyglandular syndrome, or as an isolated phenomenon where we know much less about the genetic predisposition there. We know a lot more about the risk of hypoparathyroidism after neck surgeries, and this is one series by Powers and colleagues where they took a good look at a very large insurance claims database. And they took that information, and they calculated, they estimated from the information they had from that database that about 7.5% of the anterior neck surgeries, and you can see the breakdown of the type of procedure that was being performed, led to either transient or permanent hypocalcemia and hypoparathyroidism. So it's somewhere between about a half to 2% of the operations that you see here lead to permanent hypoparathyroidism. The definition used here was six months. The current definition we use is 12 months, but probably these numbers are amongst the best that we will have for a while. What are some of the risk factors for post-surgical hypocalcemia and hypoparathyroidism? So this is a busy slide. You can see some of the details here, but there are quite a few patient factors. Obesity is one of them because of the way that the parathyroid glands need to be approached during a surgical procedure. So that'll approximately double the risk if the BMI is over 40. Being vitamin D deficient, so that puts the patient at risk for having post-op hypocalcemia about doubles the risk of post-op hypocalcemia. Being small, a pediatric patient, because the glands are harder to find, is going to raise the risk. Graves' disease, because the gland has got so much more vascularity, is going to raise the risk. And it depends on the series, but up to as much as fourfold versus the patient without Graves' disease. Cancer, as the basic diagnosis, is going to raise the risk. And in addition, if the surgeon is trying to resect a thyroid nodule and a parathyroid gland, double operations are going to raise risk. And then the more extensive the surgery, so sort of operative factors, lymph node dissections are going to raise risk. If it's a reoperation, that raises the risk of that patient coming out with hypoparathyroidism at the end of it. And then the longer the procedure ends up being, the greater the chance the parathyroids are going to be compromised during that surgery. And then finally, and probably one of the very most important, it ought to be in bigger print, is a surgeon who has less experience than a high-volume parathyroid or endocrine surgeon. And that's at least a threefold increased risk. So there's lots of factors for that. Hypoparathyroidism affects, as this figure, I think, tries to show you, pretty much every system in the body. I think we focus a lot on the central nervous system. We focus a lot on the peripheral nervous system. But it's important to recognize that the heart is affected, the eyes are affected, the skin can be affected, the muscle system can be affected, and we're going to focus here on the kidney. And the kidney can be affected with a whole host of different complications. All of this together, this is such a polysystem disease, can affect quality of life as our patients will talk to us and as Dr. Jandabor will present. So I'm going to turn the podium over to Patti Keating to tell us a little bit about her journey as a patient with hypoparathyroidism. Patti. All right. Thank you all for being here tonight and really learning what you can learn about this. Because as a patient, it's a tough thing to live through. After you live for many years normally, or I lived many years normally and then had a thyroidectomy and ended up in this condition, it definitely was life changing. So I had my surgery back in 2015. My sister had thyroid cancer at a young age, and she's no longer with us. So of course, when I get the diagnosis that I've got complex tumors and did the biopsy indeterminate, yeah, we need to take care of this. So I decided to go ahead and have the surgery done. And it was interesting because I think my biggest concern, because he talked about it often, was worried about the vocal cords. And I can tend to be a chatty patty. So I was like, oh my God, how am I going to, I got to be able to talk. Like I'm so worried about that. I wasn't, I remember them saying 1%, but I didn't know what the 1% meant. The 1% that he was talking about was my parathyroids. So afterwards, you know, they're trying to get things level with, I think they were focused more on the thyroid level that had gone wacky versus the actual calcium. Because I went for months and months with just take some calcium, just take some. I don't think you can overdose on calcium is what the words were said to me. So I believed and I just kept taking calcium. But what was happening is I really wasn't being controlled. I did a lot of travel. I got on a plane every week for work. I came back, went on Monday, came back on Thursday, every single week. And I was out traveling to an area and I was staying with a friend and she lived on the third floor apartment. And I remember trying to walk up the stairs and I'm like, my God, my legs, like I literally am telling my legs to move, like walk up these stairs, what's wrong with you? And I didn't realize that that night I laid there trying to go to sleep and my face was just buzzing off. Like I was like, that's what it feels like when you are low on your calcium. And I remember having it so much because it had built up for a couple days where I literally laid in the bed that night and I said, well, I've had a really good life. So if this is it, this, you know, okay, like just go to sleep, you'll be okay. And luckily I did wake up the next day, but a few days later, and it's interesting because I actually ended up with heartburn and I took Tums that evening. So I think that's why my actual like tingling went away was because I took the Tums, but I didn't know I was taking Tums to help it. So anyway, I, the next day I went home and a couple of days went by and I was like, man, my heart just starting to feel a little bit weird. And Easter, it was Easter day and we went to have dinner and everything. I came home and I was like, I think I'm going to go to bed. I just don't feel good. And I laid down and my heart started, it felt like it was going like all over. Well, I ended up having a heart attack from all of this. I got to the hospital and, you know, they're doing all the troponin and all these things and hooking me up and they're like, oh my God, she's having a heart attack. And so they did a heart catheterization, they're like, whoa, there's no issue. Why don't you have cloned arteries? Like what's going on? So I didn't, back then I didn't, didn't have that. So, you know, they treated me for that. We finally figured out we needed to take calcitriol, calcium, all those things. In the years going on, every time my heart would start flutter, it'd be like, emergency room, emergency room, everywhere. I was just like wanting to run to the, cause I was so afraid it was going to happen to me again. The brain fog was so bad that I went to visit a friend and I was driving and I had to stop and say, I don't know where I'm at. Like I literally don't know where I'm at. Call my husband. I'm like, he's like, well, where are you? I don't know where I'm at. Like I couldn't even talk to tell him where I was at. It was just, it was petrifying to think that I was out in a vehicle doing that. So obviously I'm still not controlled as I go through it. So we, I met with a nephrologist to help me understand how to spread out the medication. So I began taking the medication six, six times a day. Everybody knew when Patty's alarm went off, it was time to take medicine. That was so embarrassing. But you know, the alarms go off, medicine time, 2.30 medicine time. It would happen six times during the day. The one thing that was really, really hard for me is the level of pain as well. The deep down serious bone, bone, bone pain. It's just awful. And then the muscles like trying to really figure out, I'd sometimes I'd look at my hands and go, gosh, just move. Like don't drop this. I would drop things a lot. So I went through all of that. And then I recently did a study where the natural history study where they did a bunch of scans and everything and the incidental findings with the, the calcifications. In that nine years, I've now am diagnosed with severe, moderate to severe calcifications of my artery. And one could say, yeah, well, you're going to be 59 years old next month. You know, that happens to you. But remember nine years ago, I didn't have that. So in nine years, the amount of calcium, calcitriol and all the vitamin, everything that I was taking, I would say that we attribute part of that to this. I've been fortunate to participate in a clinical trial, and I will say that it's been going really well. It's fantastic. I mean, life has changed quite, quite a bit for me. So I'm really excited about that. And I'm really excited about the future of it. I just need to say, though, that as endocrinologists, we're treating the calcium retreat, because that's what we've been told for so many years. There's a difference. When we were treating my calcium, it would take away the tingling and take away some of the bone pain and all of that. But it didn't, I still felt like my body was going to break. And I still felt this brain fog and this sadness and this, this anxiety. Since I've been in a clinical trial over this last year or so, it's, it, I feel happy. I feel, I don't, I haven't had symptoms probably in about, I know, three or four weeks since we went to New Orleans to another conference and it was 100 degrees outside. And I haven't had symptoms since then. So it's been life changing. My body doesn't feel like it's going to break. Yeah, I got orthopedic issues, but not that deep bone, bone issue that is just so dreadful that comes with this. So really that's, that's my story and, and what I've been going through over the last nine years. And again, thank you for being here and learning from this. It has been a really tough nine years, really tough nine years, but I do think I'm on the other side of it. And I hope that it lasts forever for me. And for all of us as hypoparapatients, so yeah, thank you. Thank you so much, Patty. Wow, that was beautifully put and really just gripping. So what I, what I get to do now is run through some of the kidney complications for our discussion tonight. We'll start first with the role of PTH and regulating serum calcium, how that gets disrupted in hypopara, how conventional therapy, calcium and vitamin D, how those affect serum and urine calcium, some of the consequences of those actions on our kidney, and then how we might in the future have different ways to prevent some of these complications. So when PTH is absent in the kidney, you can see on this figure, there are several major impacts. First of all, serum calcium goes down because the ability of the kidney to reabsorb, and this is mediated through a whole host of proteins in the kidney. Calcium is reabsorbed. It's lost in hypopara. The ability to control serophosphorus gets lost because the transporters for phosphate reabsorption are altered when PTH is absent. And finally, the ability to make 125 vitamin D is also suppressed when PTH isn't present. So lots of very important consequences mediated through our kidney. And as you can see here, it's a busy slide, but it just shows you that really the effects of PTH on each different segment of the nephron are very important in maintaining calcium, phosphorus, and vitamin D metabolism in our bodies. So PTH plays a role not only by itself, but as you can see here, with the FGF receptors and the cloth-O protein, with the calcium-sensing receptors, and also with the vitamin D system. So incredibly important. What I want to do now is just review, and I've just picked four different lines of evidence to sort of paint the picture of the effects of this disease and its treatment on kidney function. So the first cohort to talk about briefly with you is one developed actually right here in the Harvard system of 120 patients with hypoparathyroidism that were followed and studied retrospectively. The second one is data out of Denmark and post-surgical and non-surgical hypoparathyroidism. And we'll see what we can learn from that population study. Then the managed care claims data, which has gotten a lot of press because it involves so many people that have this disease. And finally, an interesting cohort out of Germany of 160 hypoparapatients where they did do a systematic evaluation. So the study that came out about 10 years ago looked at, retrospectively, 120 hypoparapatients followed by endocrinologists within a university hospital system. The diagnosis was well-confirmed. It aligns with what we talked about for the most recent definition of the disease. These patients were very, very representative of people with hypopara, mainly women, post-menopausal, most of them surgical. And the follow-up, again, retrospective, was seven years. And they looked at whatever was accumulated in the chart in these patients. So these are some of the data from that cohort of 120 patients. And what you're looking at on your left is the serum calcium. In the middle is the serum phosphorus. And on the panel C is the calcium phosphate product. And the sort of gray areas on the top and the bottom are the abnormal areas. And I think you can see that the majority of patients in this cohort had a calcium within the target range, had a phosphorus within the target range, and had a product kind of within the target range. But there's plenty of outliers. And they did something interesting in this cohort. They did sort of a time-averaged calcium measurement for each of their patients. And each line in this green figure on your right represents one patient in the cohort. And green means these patients had a time-weighted average that was between 7 and 1⁄2 and 9 Okay? And those that are yellow were below. And those that were orange were above 9 and 1⁄2. So they calculated, it's kind of what we do with the CGM, the time in range for the serum calcium. They actually found that in this cohort, 86 percent of the patients actually were in this target range. You might argue, if that's the right range, that they should be in, but they were there. Less so in the patients that had autoimmune hypopara, and even less so in those with calcium receptor mutations. And in terms of urinary calcium measurements, again, this was not a systematic study. Just about half had had a 24-hour urine. And the gray is the abnormal, a level above 300 milligrams for 24 hours. And they had about 40 percent of the patients that were put together in this cohort had an abnormal urinary calcium. Again, not systematically obtained, but just what was done for clinical purposes. About 30 percent had renal calcifications by renal imaging, but again, not systematically done. It was what the clinicians following them decided to do. And then you can see in panel B that there's a rough relationship between serum calcium and urinary calcium, but really it's kind of, at least in this cohort, all over the shop. They then looked at the estimated GFR measurements in these patients, and they separated them out by quartiles of age. And you can see the 20- to 40-year-olds, the 40- to 60-year-olds, 60- to 70- and over basically over the age of 69. And as you march over to the right in this curve, the patients with hypopara are the gray ones, and this is the percent that had a GFR that was, estimated GFR, that was under 60. And this is markedly, statistically significantly increased for age-matched controls taken from NHANES data. So this was, to me at least, the first piece of evidence that we really have a significant problem as people get older with this disease. So just to summarize, seven years of follow-up, a well-defined cohort, an interesting calculation of time and range, but pretty much a high rate of complications despite the fact that these people were considered by their clinicians to be within range. And so the study emphasized that kidney function really needs to be thought about very carefully, and urinary calcium excretion needs to be monitored in these patients. These are some data very quickly out of Denmark. There, they have a registry for pretty much all people in Denmark. And over the period of time, 1988 to 2012, they uncovered approximately 700 post-surgical patients. They nicely matched them with age-matched controls and then looked at what went on over eight years in those people. And you can see by the ICD codes that the risk of renal disease was four-fold elevated in the patients with post-surgical, risk of kidney stones five-fold, and the risk of renal insufficiency five-fold versus age-matched population-based controls. They did the same kind of study in 120 patients with non-surgical hypopara. Again, a nice group of age, gender-matched controls from the general population. And you can see the age and the female prevalence in that disease. And again, renal insufficiency six-fold versus controls, and any renal disease about three-and-a-half-fold greater than controls. They did not have data that showed a statistical increase in either nephrocalcinosis or kidney stones. And you can see that the patients with hypopara, that's the dark line that's going down very quickly, versus the dotted line, which is the controls. It's the hazard ratio. It's greater survival to be free from having renal disease. And so they have it more red light three-fold elevated. When they then looked, and again, these are still the Danish data, different cohort of patients, 430 of them, where they actually looked at some of the biochemical parameters in detail and some of the clinical characteristics. And this is getting us closer to the present time. And they did a time-weighted, so they looked at a lot of things. But what was statistically significant was the time-weighted calcium phosphate product. And if that was above a certain level, and you can see it in SI units, so I calculated it for milligrams per deciliter squared, and that's only a 28 for the calcium phosphate product. And that doubles your risk of having renal disease. And any episode of hypercalcemia, even just one, triples your risk of being someone with an ICD code of renal disease. And disease duration over 20 years triples your risk of having renal disease. We take a look at some data from the US Managed Care Claims data. And a lot has been talked about, because this represents over 8,000 patients with hypoparathyroism followed in these managed care practices. And the control is, again, about 40,000. So you've got a lot of good data here. And I think what you can see in panel A is the percentage of patients with chronic kidney disease. And the hypopara in all of these figures is going to be the blue line. And in general, it lands on the top. In other words, higher than the gray line that controls. So the rate of chronic kidney disease and hypopara is about four to five times control in this population. The middle panel, panel B, represents those with at least a 30% decline in estimated GFR over the five years of the time period of this study. And that's about 25% to 30% greater than the control. And then those that end up with end stage kidney disease, ESKD, that's about double if you have hypoparathyroidism. They also looked at renal stones. And the percent of the cohort with renal stones was about threefold elevated if you had hypopara versus control over that five years. And if you developed a stone, if you acquired the new diagnosis of kidney stones, again, about threefold elevated. So pretty significant progression over time compared to controls and acquisition, if you will, of the diagnosis of kidney stones. These were not screened by ultrasound. This is clinical presentation of these complications. And finally, this German cross-sectional systematic study on renal complications looked at 160 adults. And we're getting closer to the current period. And I'll also just emphasize that all of these patients are managed with conventional therapy. These were periods of time when we didn't have anything but conventional therapy. And this population was mainly non-surgical. Again, good population-based controls. And here, they systematically performed biochemical analysis, dietary analyses, et cetera. And they tried to do a renal ultrasound in every single patient. And they accomplished that in 93%. So this is not self-selection or doctor selection. This is actually systematically performing the study. So what you're looking at on the left side is 24-hour urine on the y-axis and mean serum calcium on the x-axis. And you can see that line kind of shows a statistically significant relationship between the two parameters with an R-value of 0.3. But you can see there's plenty of scatter. So some patients have perfect or even low serum calcium and have elevated urinary calcium. So you've got to measure it. And if we take a look to the picture on the right, it looks a lot like the data from the Mitchell study. Again, looking at people based on quartiles of age in black are the patients with hypopara. And you can see the risk of having CKD, defined as an estimated GFR of less than 60, is markedly increased as you get older with hypoparathyroidism versus controls. They then also, as I said, systematically looked at renal calcifications. And panel A shows the RC stands for those patients who, by renal ultrasound, had calcifications. And it actually wasn't very many of the patients in this cohort, but there they are. And their estimated GFR in this cohort was actually not lower in those who had renal calcifications. And the others, you can see, didn't have any. But when they looked at the urinary calcium excretion, and that's in panel B, you can see that those with RC, or renal calcifications, did have a higher urinary calcium excretion for 24 hours compared to those without. Now, over on your right, you can see that the rate of picking up kidney stones, it was only 3% in this cohort, and nephrocalcinosis, only 7%. So this is really the most systematically ascertained cohort I could find. So that is really the main strength, that these patients were actually looked at carefully, regardless of what the clinicians thought. This was a real study. So disease duration, a high urinary calcium, a high serum phosphorus, those were the parameters that were associated with renal calcifications in this group of patients, and not, in this study at least, the calcium phosphate product. So I'd say, bottom line, less renal involved in here, perhaps, than some of the other studies, but very comparable when you actually sit down and put it together with the managed care data. So how do some of the newer treatments, beyond conventional therapy, affect the kidney? So 1 to 84, it's disappearing from clinical use, but at least it serves as a basis for us to think about PTH replacement. And I'll mention some data from the Open Label Extension and almost 50 people of six years of PTH therapy. We'll talk about the Phase III trial with transcon PTH 1 to 34. We'll talk about very early Phase II data with iniboparotide, a PTH receptor agonist. We'll talk about, just again, some early results with an oral medication that's a calcylytic called N-calorette in patients with one of those genetic forms of hypopara-ADH type 1. So we'll do that in the next bit of time. So the treatment with 1 to 84 comes from a study by Dr. Watts and colleagues, and it was an Open Label six-year extension of a placebo-controlled with PTH 1 to 84. At baseline, 65% of the subjects in this trial were hypercalciuric, and by the end of six years, 54% of them became normal calciuric. Calcium supplement use declined by almost 50%. Calcitriol use declined by 74%. So we're able to be tapered off most of conventional therapy to be replaced with PTH 1 to 84. And in this cohort, six patients did report kidney stones during that time. Now, what you're looking at here in the bottom panel on your left is where the serum calcium was maintained over that six years of this clinical trial. And you can see that it was quite stable and was within the target range for hypoparathyroidism. If you look over on the right, and it's difficult without a pointer to show you, but up at the top of that curve is where everybody started. And their urinary calcium levels were, on average, elevated when they entered this trial. And they slowly declined over the course of the trial, not in any rapid way, but over time. At baseline, 70% of the women and 67% of the men were hypercalciuric. And by 72 months, six years into the trial, a third of the women were hypercalciuric, and 40% of the men were hypercalciuric. There weren't statistics to go with this, because this was not a pre-planned analysis, but these are the data. And I think they move in a convincing direction. If we look at the 24-hour urine calcium excretion for the men, it was over 400 milligrams at baseline. And it went to, on average, 276 milligrams. And for the women, 344 to 216. And it's remarkable that the decrement is about 130 milligrams over that period of time for both men and women. So definitely a fall with PTH therapy. What you're looking at here are the serum calcium values over the six years of this trial. And you can see that these levels are stable. Looking at estimated GFR, it was 78 milliliters per minute per meter squared. At the beginning of the trial, and went to 81. So it was stable over six years of the trial. And two patients had CKD3A at baseline. And at the end of six years, four were in the range of CKD3A. And although I'm showing you six years of data here with this particular trial, the Columbia group have 12 years of data in a smaller number of patients. So 1 to 84 patients maintain serum calcium, as well as serum creatinine and estimated GFR. We'll look quickly now at some results from the studies with transcon PTH 1 to 34. And this molecule is over here. It's given by daily injection as an inactive drug. And the little tiny helix, a little orange helix in the middle of that blue molecule, is actually 1 to 34 buried in that carrier. At body temperature, at body pH, 1 to 34 is released. It goes to the receptor on your far right in the kidney and in the bone and does its job. And that carrier molecule is cleared. So the idea here is that you have a sustained source of PTH like a PTH infusion in patients after about five to six days of use of the compound. So the phase 3 trial randomized 3 to 1 patients to the active peptide versus placebo for six months. And while they were taking this peptide, standard of care medications were down titrated. And so the primary endpoint of the study at six months was a normal calcium, independence from conventional therapy, and being on a stable drug dose for four weeks. So there were sort of three parts to that primary endpoint. And it was met in 80% of patients receiving active treatment. And we'll take a look at urinary calcium and renal function in the next couple of slides. So here is just to show you that patients receiving in the blue line, patients receiving transcon PTH by daily injection had a average serum calcium within the target range. Patients on placebo couldn't be down titrated from their supplements. They maintained their serum calcium at the lower part of the target range. And then in the middle, at 26 weeks when the open label portion of the study started, everybody continued with an average calcium right in the middle of the target range. So serum calcium can be well-maintained with this kind of a treatment. Here we're looking at 24-hour urine calcium over the full year of the trial. And in the blue, you're looking at the patients who were randomized to the active transcon PTH. Their average urinary calcium was 390 milligrams per 24 hours. And by six months, it was down to 220. And by the end of the first year, it was down to 180. So a pretty rapid and pretty profound significant effect on urinary calcium. On your right, you can see the placebo, 329 at baseline. Didn't change very much during the placebo titration. But once those patients went on to open label in that blue curve on your far right, this was down to about 220. So they all came down into, on average, below the upper limit of normal, which was set at 250 for this study. Then they looked at estimated GFR over 52 weeks of the study. And on your far left, it's everybody in the study, both in the blue line, those who were randomized to transcon PTH, and in the lower line, those who got the placebo at the beginning. And you can see that on average, the estimated GFR went up by about 10 mLs per minute per 1.73 meter squared, statistically significant. And in that middle curve, what you're looking at are those people who entered the trial who had an estimated GFR below 60, and they actually benefited the most, if you will, by, I believe, about a 12 or 13 mL per minute change in estimated GFR. So it looks good for improvement in estimated GFR over 52 weeks. When this analysis and the trial was extended for another year, you can see that the increase in GFR also persisted through 104 weeks of treatment. And in the two middle lines here on this slide, you can see the change in urinary calcium. Those patients who were treated for 104 weeks went from about 10 millimoles per 24 hours to 3.8. That's a 60% drop. And those who had 26 weeks of placebo, followed by the rest of the time on transcon PTH, lowered their calcium by 44%. You can see the numbers. So the effects on urinary calcium and the effects on estimated GFR persists over the two years of the study. This new peptide, iniboparatide, and these are very early data here, is a PTH1 receptor agonist. It's kind of a chimeric molecule between PTH and PTHRP. These are data from an open-label study, phase 2, just 28 patients and just 84 days of use. And in that little upper curve where you see C1, that's one cohort of patients. And C2 is another cohort of patients. And what we're looking at there is the decline in urinary calcium over the course of really just three months of the study. And these were highly significant, both for the men and the women in this study. Both cohorts had a nice decrease in urinary calcium. And if we take a look at the ones, and this is on your far right, that were hypercalciuric at baseline in both of the cohorts, and there were 13 patients who were, and 12 out of those 13 normalized their urinary calcium in 84 days with use of this peptide. So similar rapid effects on urinary calcium, for sure, but very early data. This medication called Encaliride, it's under investigation now. And this is a calcilitic. That means it's a sort of antagonist, or what's called a negative allosteric modulator of the calcium receptor. And down on the bottom, you can see that in the genetic disorder, ADH1, where the calcium receptor is constitutively active because these patients have mutations in that receptor, their secretion of PTH is shut down because the body thinks the calcium is perfectly normal, or high even. And in the kidney, they are putting calcium out through the urine, even though their blood calcium levels are low because the receptor in the kidney thinks that it needs to get rid of calcium. So with this calcilitic, you shift to the right both the parathyroid and the kidney calcium sensing receptors. So how does this work in those patients with that disease? Well, these are from, again, a small study of only 13 patients. But on the top lines, you can see the blood calcium levels, and you can see that they started at about 7 milligrams per deciliter. Everybody was stopped from all their supplements. And this was done in the hospital. Don't try this at home. And blood calcium levels came up into the normal range. That's that gray area. It's really within a couple of days of administration of this small molecule. And then this is six months worth of data showing maintenance of serum calcium in the normal range off of conventional management. If we take a look in the bottom, you can see that PTH was practically at zero. Again, the gland is shut down because of this mutation. And as the medication is given, PTH levels become detectable and are in the normal range. And that's maintained over six months of the study. So this compound certainly worked with the biochemical efficacy, if you will. Here's what it did to the urinary calcium. You can see, on average, these people have a low blood calcium and marked hypercalceria. And they usually have kidney complications early in life. Urinary calcium came down from, on average, 400 at baseline, down to probably about 100 to 150 milligrams. And it was maintained over six months of this study. So just to conclude what we've tried to cover over the last 20 minutes or so, the studies that we've looked at, they vary quite a bit in the way that they were conducted. I think we can conclude that, overall, patients with hypoparathyroidism tend to have a higher urinary calcium. They tend to have more kidney stones. They tend to have renal calcifications and progressive chronic kidney disease, with varying numbers from the different studies. The age of the patient, the duration of the disease, those are really critically important in determining what kind of signal you're going to get from studying these patients. But again, in general, the natural history type of studies I shared with you are patients on conventional therapy. I think it's pretty convincing from a couple of sources that treatment with PTH, either 1 to 84 or some of the new peptides that are coming along, can elicit marked improvements in urinary calcium and can stabilize and perhaps even improve estimated GFR, whether that's due to the compound itself or whether it's due to the withdrawal of conventional therapy. We don't know the answer to that right now. And we have a couple of new peptides that are being tested in active trials now. And then finally, the N-calorite treatment of ADH1, again, very early results but looks promising and is in the process of being tested in other forms of hypoparathyroidism. So with that, I will stop and I will turn things over to Suzanne. You, Dolores. It's really a privilege to be able to share the stage with Dr. Schoback and with Patty and with Michelle. And thank you for your kind attention so far this evening. So now I'd like to turn a topic from the kidney and the parathyroid to the effect of hypoparathyroidism on quality of life. We're gonna talk a little bit about patients' quality of life and symptoms. We're gonna talk about quality of life studies, and we're gonna talk a little bit about the burden of standard of care. And then we're gonna finish it up with some words from Michelle and some moving testimony about what her journey's been like. So as Dr. Schoback pointed out, and as Patty told us, hypoparathyroidism is really characterized by many symptoms and it is truly a multi-system disease. And the symptoms are in the here and now, and people experience these symptoms quite often and they can be quite distressing. Central nervous system, peripheral nervous system, neuropsychiatric, and musculoskeletal, and then, as Dolores said, dental, dermatologic, and the eyes. So there's many symptoms that individuals with hypoparathyroidism experience. So not only the symptoms in the here and now, but then the long-term complications of hypoparathyroidism are part of that burden of disease. So the symptoms, but also the renal complications, hypercalceria, nephrocalcinosis, kidney stones, and CKD, as Dr. Schoback talked about, low bone turnover, cardiac and vascular calcifications, as Patty talked to us about, basal ganglion calcifications, cataracts, infections, and neuropsychiatric complications. So the daily symptoms, but then the long-term complications are part of this burden of disease. So this is a survey of individuals from the PARADOX study, 374 patients, and these were patients that were felt to be uncontrolled. 30% of this cohort self-rated themselves as severe, and 56% felt they were unprepared to manage their condition. And 60% really thought it was more difficult to control than they had anticipated. What really struck me about these data were that 75% were really concerned about what long-term complications were gonna be of the current treatment they were on, which was calcium and active vitamin D. And 72% of people experienced greater than 10 symptoms in the previous year on therapy. And 79% require hospitalizations or emergency department visits during the previous year. 85% indicated they cannot perform some household activities. So in this survey of 374 patients with a questionnaire, you can really feel what the burden of disease here. They're concerned about the medication they're on, they're ending up in the ED, they're requiring hospitalizations and they're having symptoms on a regular basis. In another study, this was an international chart review of 614 patients with hypoparathyroidism. The majority of these patients are post-surgical. 70% were adequately controlled based on the chart review criteria and 30% were uncontrolled by clinical guidelines. 59% of the uncontrolled and 49% of the controlled reported symptoms and comorbidities of hypoparathyroidism. So over 50% of this cohort, whether they were controlled or not controlled. 91% reported at least one hypoparathyroid health resource utilization event in the previous year. 58% of the uncontrolled and 43% of the controlled had a hypoparathyroid comorbidity. And 28% of the uncontrolled and 16% of the controlled had at least one hospitalization. 48% of uncontrolled and 39% of controlled had at least one ED visit. And they had an average of about 2.6 outpatient visits per year for the controlled and 3.6 outpatient visit per year for the uncontrolled. That just really gives you an idea of, in this population of 614 patients, what type of burden of disease they were bearing. In addition to the symptoms they feel in the healthcare utilization and ending up in the ED and having symptoms and being worried about therapy, there's also a burden of disease on work life. So this is a study looking at 397 patients with hypoparathyroidism and 207 caregivers. And these were questionnaires that were given to these patients. And you can see in the top line that before the diagnosis of hypoparathyroidism, about 58% of these individuals participated in full-time work. Whereas after the diagnosis of hypoparathyroidism, only 34% participated in full-time work. And about 60% of those individuals said it was because of their disorder, their disease, that they were not participating in full-time work. And you can see that also affects the caregivers. In the caregivers before the patient's diagnosis of hypoparathyroidism, 51% were participating in full-time work. Whereas after the diagnosis, only 41% were participating in full-time work. And if you look at the bottom box, when they measured work productivity, when they looked at work activity and productivity index, the WAPI, they found that those individuals that were diagnosed with hypoparathyroidism had about a 40% work impairment. And those that were the most severe had about a 76% work impairment. So it's really a heavy burden of disease and it affects people, not only their symptoms and their health, but also their ability to work. And it also affects their ability of their caregivers to work. So this is just a brief orientation to the SF-36 because we're gonna be talking about a lot of SF-36 data here. So the SF-36 is a 36 question questionnaire that puts things in eight domains. They're in physical functioning, in role physical, in bodily pain, general health, vitality, social functioning, role emotional, mental health. And then they take a subset of those domains and then put them together in a physical composite score and a mental composite score. So this is the study that we were just talking about before about burden of work. And this is looking at burden of disease correlating with the symptoms of severity. So this is self-reported severity of disease. And you can see this is a graph on the left of the SF-36 and the eight domains of the SF-36. Those that are most severe are the ones in the dark line with the triangles. And then the least severe are the ones in the purple crosshatch lines. And then the concentric circles are those with mild, moderate, and most severe. And you can see that the smaller the circle, the most severe and the worst the SF-36 score are. So the more reported severity of symptoms, the worse the quality of life measures. And then when they looked at both caregivers in panel B and patients in panel A, and looking at the major impact on their relationships of their disease, the ones that are the most severe are the ones to the far right. And you can see whether it be relationships with their spouse, their family, their friends, or their children, the more severe the disease is, the worse the impact and the major impact are on these different social interactions. And even the caregivers in the bottom area, you can see we're having, 30% of the caregivers felt like the disease had major impact on the spouse or the partner, on their relationships with their family, friends, and children. So the burden of this disorder is far beyond just the physical symptoms and spills over to people's work life and people's relationships. So let's look at the studies that we have on quality of life and people on conventional therapy with calcium and activated vitamin D. So there are five studies here that I just wanted to highlight. And it was gonna be important to look at, is gonna be important to look at how big the studies are, the comparator group, and then we can look at the outcomes. So in the ASTER study, this is a cross-sectional study of 283 patients with hypoparathyroidism. And again, they're gonna have that mix of hypoparathyroidism that Dolores talked about, the majority surgical and then genetic and autoimmune. This, they looked at these individuals against a normal population base. So they're gonna look at the SF-36 and they're gonna take it against the regular general healthy population. When they looked at the SF-36, there was reduction in all eight domains of the SF-36. And they also looked at a depression and anxiety score called the HADS. There's increased anxiety and depression compared to a normal population. In the Kusano study, this was an open-label uncontrolled trial of 54 individuals with hypoparathyroidism, again, against a general population. And they were reduction in all eight domains of the SF-36 compared to that general population. The SickCare study was a randomized controlled trial, 62 individuals, and again, looking at against the general population. And there was a reduction of seven of the eight domains of the SF-36. And looking at the WHO-5 score, which is a score that looks at depression and wellbeing, there was 20 of 62 had either depression or reduced wellbeing. Another study by SICTAR, they took 22 patients that were post-surgical with hypoparathyroidism and then matched them against well-substituted hypothyroid patients. So kind of matched them for that surgical piece. And when they did that, the cross-sectional study with the matched post-surgical hypoparathyroidism population, there was decreased physical functioning, role functioning physical, and physical component score compared to those individuals that had well-substituted post-surgical hypothyroidism. And then the ARLT study was a cross-sectional study of 25 women with post-surgical hypoparathyroidism. And they looked at, they compared them to 25 women with a history of subtotal thyroidectomy and age, sex, and time of surgery matched. And what they found here, that they had worse scores on psychological index, SCL-90, and physical symptoms, the GBB-24, and the BL-Zersen general well-being. So in individuals with hypoparathyroidism on conventional therapy, there does appear by SF-36 and other indices to be a reduced quality of life. So Dr. Stoback talked to you a little bit about the different types of new therapies that are available. So the PTH-1 to 84 that was approved by the FDA and EMA, but no longer available. And then palopegteroparatide, also known as transcon PTH, that's held by a linker that holds the PTH in a position so that it gets released and released over time. So it's a slower release PTH. And Calorette, again, this works on the calcium-sensing receptor, a negative allosteric regulator of the calcium-sensing receptor. And then ineboperatide, which is a PTH receptor agonist that has a longer-term mechanism of action. We have data for PTH-1 to 84 and palopegteroparatide on quality of life. We don't have data for the other two investigational agents. So let's look at the PTH-1 to 84. So this is the REPLACE trial, and this is PTH-1 to 84 versus calcium and activated vitamin D and looking at quality of life at week 24. And this is by SF-36. So I've put in red the domains that had a statistically significant difference between baseline in week 24 and PTH-1 to 84. And I put in blue the one that made a near miss. So what these data show is that there's a significant change in PTH-1 to 84 versus baseline in bodily pain, general health, vitality, and physical component score. And then there is a close to significance in physical functioning. What's important to note here is there's a difference in SF-36 between PTH-1 to 84 baseline versus 24 weeks. But when you look at PTH-1 to 84 against placebo, there was not a statistically significant difference. Also in the REPLACE trial, when we take a look at those that had the severe symptoms and the biggest magnitude of change on their SF-36. So the magnitude of change between zero and 24 weeks and the SF-36 score was negatively correlated with the baseline score. So this tells you that patients with the lower overall health-related quality of life at baseline experienced the most improvement in response to treatment. So the SF-36 is a more general measure of quality of life and patients with hypoparathyroidism have some specific symptoms that probably are not captured by the SF-36. So another instrument has been developed called the hypoparathyroidism patient experience score or the HPES. And the HPES has symptom score, which looks at 17 areas of physical and cognitive functioning. And then there's the HPES impact score, which looks at four domains, physical functioning, daily life, psychological wellbeing, social life, and relationships. So HPES symptoms looks at the muscle cramping, muscle spasms, muscle twitching, and the things on the left. And the HPES impact looks at the impact on physical functioning. And this has been developed and validated for patients with hypoparathyroidism. So this is to say that in the pathway phase three trial of palopegteroparotide, looking at quality of life with HPES versus calcium and activated vitamin D. When we looked at the HPES symptom, the physical domain score in the transcon group, which is in blue versus the placebo group, which is in purple, was improved. So a lower score here is improvement, whereas in SF36, a lower score is worsening. So it's opposite the SF36. When we looked at the cognitive domain score with the HPES symptom questionnaire, again, those with palopegteroparotide had a statistically significant improvement in the cognitive domain score. We looked at the HPES impact, the physical functioning domain score. Again, there was a statistically significant improvement in individuals treated with the palopegteroparotide. And then when we looked at the HPES impact, daily life domain score, again, statistically significant improvement in that score in the individuals treated with the palopegteroparotide versus those on calcium and activated vitamin D. And this is the SF36 data for the pathway trial. So the area that's in the blue checkered box is the kind of normal general population. You can see the individuals treated with palopegteroparotide started below the general population and rose into the area that is the normal score for the general population, whereas those on placebo or calcium and activated vitamin D did not. So this is a systematic review and meta-analysis of PTH therapy for managing chronic PTH that was performed at the second international summit for hypoparathyroidism. And they looked at three studies that they felt met the criteria for this meta-analysis and looked at quality of life, both the physical health and mental health and depression, and then also looked at the pill burden in those studies. And so for the quality of life, physical health was measured by SF36. And when they pooled the data from these three studies, these three clinical trials, which is PTH1 to 84, the pathway trial, and then another PTH1 to 84 trial, and pooled these data based on data from 263 patients from these three studies, they found that PTH therapy probably results in a small improvement in quality of life in the physical health realm. But I will point out that if you look in the PTH column, that the mean change in the SF36 was 3.3, where the difference, the mean important difference, the minimal important difference in MID was 3.4. So it narrowly missed that. When looked at quality of life for mental health, again, they looked at 179 patients in two studies, and the follow-up was about five months. And here they found that PTH therapy, they have a small improvement in quality of life for mental health. But certainly the physical health was very close to the mean, sorry, the minimal important difference. For depression measured by the WHO5 and well-being, again, they looked at data from 59 patients in one study, which a follow-up of six months, and they found no difference between those treated with conventional therapy and those treated with PTH. So PTH really did not have an effect on depression. But certainly when they looked at a greater than 50% reduction in pill burden for doses of active vitamin D and calcium, there was a statistically significant reduction in the number of pills in those treated with PTH1 to 84 and those treated with palopegteroparatide. So small differences for quality of life in physical health and mental health and large differences in pill burden, but no difference in depression. So with this, I'm gonna introduce Michelle Reyes and have her tell us a little bit about her journey. Thank you, everybody, for sticking by and listening. So I've had quite the long journey with hypopara. I was diagnosed at the age of 23 with thyroid cancer that had already spread to my lymph nodes. So I had quite the extensive thyroidectomy in a radical neck dissection. I don't know if I should say it was fortunate or unfortunate, but I was one of those patients that knew the next day after surgery that I was gonna be permanent. They knew instantly that they had taken all four pills. I was on parathyroids and I had severe symptoms the day after surgery. And that began my journey, but I was 23 and I didn't even know what a parathyroid was. Nobody explained it to me. I do remember the surgeon saying, don't worry, it's not gonna affect your life much. You'll take one calcium pill a day and you'll move on and lead a very normal life. It couldn't have been further from the truth. I then continued on and had a reoccurrence of thyroid cancer at 32 years old, so about nine years later. And after that reoccurrence, for whatever reason, because my PTH was already measuring at zero, it did, however, get worse. And my pelvic burden became quite heavy and I experienced my first incidence of kidney stones in my 30s. At 46, I was lucky enough to start PTH1 to 84. And in the beginning, I thought, wow, this is life changing. Prior to that, I never had achieved, between 2003 and 2017, a calcium level over 8.0 on conventional therapy. I never did. But NAPARA rose my levels enough, not to 8.5, which was the goal, but it rose it enough that I felt better and I was able to manage an eight-hour day but every day around four o'clock, I would start to crash and I would feel low again. And getting through the nights were almost unbearable. So I had to remain, even though I was on NAPARA, I had to remain on some conventional therapies just to make it through the nights until I could take my next shot the next day. Unfortunately, two years later, NAPARA was taken away from me. And then I had the quick withdrawal, made my hypopara even worse. I didn't think it was possible for it to be worse than it was in the years before, but that withdrawal was terrible. I was hospitalized within a few days and my pill burden went from, you know, being on calcium a couple of times a day to I was taking calcium every three hours around the clock. I had to wake up in the middle of the night to take calcium, otherwise the pain was so severe, I couldn't function. So I ended up on 64, between my calcitriol, because I was taking like six calcitriol at a time, I was taking 64 pills a day every three hours around the clock. Imagine what that would be like if you had to do that. On top of that, I continued to have urinary problems. I experienced, prior to that, I had already been told that I was experiencing cataracts at an early onset. I had cataract surgery before the age of 50. Continuing urinary calcium problems, but nobody ever checked my 24-hour urine. They were watching my EGFR slowly decline, but never once did I have a 24-hour urine. I finally was able to get into a PTH therapy trial and when I did that, life-changing. I know what the HPES and the SF-36 scores say about the difference it makes in quality of life, but they have no idea. Besides relieving my pill burden, I became more clear-headed, more happy. I was able to do things that I hadn't done in 20-some years. I'm able to now hike, go out in the sun, exercise. I went with my daughter and figure skated for the first time in 20 years. But it also fixed my kidney disease. I was, four months before I started PTH therapy, I had an EGFR of 39. I'm proud to say, last month, when I had my EGFR tested, it's 105. So PTH therapy does make a difference. I no longer experience kidney stones. It has definitely been a game changer. And what I do encourage people, if you have patients who are on conventional therapy, please do the 24-hour urine, because I had no idea that my urinary calcium was over 400 and I don't know how long it was there for. And I do think it's very, very important Also, like Patty said earlier, this disease, for too long, has been looked at as a calcium disorder, and it is not a calcium disorder. And you'll never fix all the other things that I was experiencing that I didn't even know were a part of my disease until they went away, unless you replace the PTH. This is a PTH disorder. And until you replace that hormone, even on people who are stable, they're never gonna feel normal. They're never gonna be able to do things. I had a job and I pushed myself. And at a point between 2003 and 2009, I was hospitalized over 276 times. Most of those ended up in overnight stays. And you can't fix those things with conventional therapy, no matter how hard you try. Thank you for listening today. Thank you. Great. And I wanna thank all of our speakers here, particularly our patients who have really shared from the heart for us today.

symposium on hypoparathyroidism

current treatment landscape

quality of life impact

body systems affected by hypoparathyroidism

PTH therapy

PTH-1 to 84

palopegteroparatide

personalized treatment

patient testimonials

conventional therapy challenges

PTH replacement therapy