Ascendis Pharma A/S (ASND) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen, and welcome to the Phase III PaTHway Trial Results Conference Call. [Operator Instructions]. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Tim Lee, Senior Director of Investor Relations. Please go ahead.

Yes. Thank you, operator, and thanks, everyone, for joining our Phase III PaTHway Trial Results Conference Call today. I'm Tim Lee, Senior Director, Investor Relations, of Ascendis Pharma. As part of today's webcast, we have an accompanying slide deck available for download that you can follow on our Investor Relations website. Joining me on today's call is Jan Mikkelsen, President and Chief Executive Officer; Dr. Aimee Shu, Vice President, Clinical Development Endocrine Medical Science; Dr. Dana Pizzuti, Head of Development, Operations and Chief Medical -- Head of Development, Operations and Chief Medical Officer; and Scott Smith, Senior Vice President and Chief Financial Officer. Before we begin, I'd like to remind you that this conference call will contain forward-looking statements that are intended to be covered under the safe harbor provided by the Private Securities Litigation Reform Act. Examples of such statements may include, but are not limited to, our progress on our pipeline candidates and our expectations with respect to their continued progress, statements regarding our strategic plans, our goals regarding our clinical pipeline and statements regarding our regulatory filings. These statements are based on information that is available to us today. Actual results or events could differ materially from those in the forward-looking statements, and we may not achieve our goals, carry out our plans or intentions or meet the expectations or projections disclosed in our forward-looking statements, and you should not place undue reliance on these statements. Our forward-looking statements do not reflect the potential impact of any licensing agreements, acquisitions, mergers, dispositions, joint ventures or investments that we may enter into or terminate. We assume no obligation to update these statements as circumstances change, except as required by law. For additional information concerning the factors that could cause actual results to differ materially, please see the forward-looking statements section in today's press release and the Risk Factors section of our most recent annual report on Form 20-F. On today's call, we will discuss the results from our Phase III PaTHway Trial. Following some prepared remarks, we will open up the call to questions. I will now turn the call over to Jan Mikkelsen, our President and Chief Executive Officer.

Thanks, Tim. Morning, everyone, and thank you for joining us today as we today are celebrating the positive results from our Phase III PaTHway trial of TransCon PTH in adults with hypoparathyroidism. Hypoparathyroidism represents an area of major unmet medical need, with an estimated 200,000 patients in the United States, Europe and Japan. The great news is that our trial met its primary and all key secondary endpoints with high statistic significance. Let me share a few points with you before I turn it over to Aimee, who will review all the data with you in detail. Why is this area of such an unmet medical need? Conventional therapy, the calcium supplement and activated vitamin D, is aiming to maintain serum calcium in the normal range to reduce short-term symptoms and is simply not able to address the underlying disease. In addition, conventional therapy can lead to long-term complications, including severe diseases such as chronic kidney diseases, liver and basal ganglia calcifications, cardiovascular complications and bone damage. All this leads to more emergency room visits and hospitalizations. This is why the patient see this unmet medical need and really are trying finding an effective new treatment option. And why I believe we all study patients continue in the open-label portion of our Phase II and Phase III studies. At week 26 in our Phase III trial, 95% of TransCon PTH-treated patients achieved control of the disease independent on conventional therapy. We believe these results are a great outcome for patients. This is the first Phase III trial, where more than 3/4 of patients achieved control of their disease, that is, normalization of serum calcium and independency from conventional therapy. This is also the first Phase III study to demonstrate statically significant improvement in patient-reported symptoms and quality-of-life domains. I believe this is also one of the main reasons why, after 2 years, we still have the vast majority of all patients still in our open-label extension trial. We are thrilled to see this improvement across different domains and through independent separate measuring tools. With these positive results, we are ready to advance TransCon PTH and are on track to submit our NDA during the third quarter and our M&A during the fourth quarter of 2022. The vision we had in Vision 3x3 to build a leading biopharma company was built on the fundamentals of achieving approval of 3 independent rare disease product opportunities. With the approval of TransCon Growth Hormone in both U.S. and Europe, with the Phase III data now for TransCon PTH, we feel we're really on track to fulfill our vision to build Ascendis Pharma to a leading biopharma company. We're using it through our TransCon technology and our proven algorithm for product development. And we have seen this combination being extremely successful through our first product opportunity. We continue to develop our rare disease endocrinology pipeline. We will continue to develop our oncology pipeline, and we will continue to develop the [indiscernible], all building on the same fundamentals, the same technology, the same algorithm. But let me now go over to what we are interested to hear today. So Aimee, can you give us more detail on our Phase III data?

Sure. Thank you, Jan. I will start from Slide 5 of the accompanying slide deck. A few words in advance. It's really an honor and very exciting to be one of the voices describing Ascendis' good news today. To share my personal perspective, I had been taking care of patients in the parathyroid and metabolic bone fields for many years by the time I heard about Ascendis' parathyroid hormone program 5 years ago. And although the program was in its preclinical stages at the time, it was easy to recognize, based on the thoughtful design of TransCon PTH, the potential for the compound to fill a health void, to go where no therapies had gone before for patients living with hypoparathyroidism. As many of you know -- I'm going to start with Slide 5 here -- hypoparathyroidism is a 2-hormone deficiency, that's parathyroid hormone and calcitriol, resulting in abnormal calcium and phosphate homeostasis, neuromuscular symptoms and impaired quality of life. Besides the neuromuscular symptoms, many of the other organs and tissues are also affected. One can appreciate from the symptoms and comorbidities in this slide that they are numerous. Some are day-to-day symptoms, some are long-term complications of the disease and some, such as kidney disease and ectopic tissue calcifications, are complications from conventional therapy itself. On Slide 6, I turn to design of the trial. This pivotal Phase III PaTHway Trial was designed to assess the efficacy and safety of TransCon PTH as a potential physiologic therapy for patients with hypoparathyroidism. Specifically, the main period was a double-blind, placebo-controlled trial, where participants were randomized in a 3:1 fashion to TransCon PTH, starting at 18 micrograms a day, or placebo co-administered with conventional therapy. Over the course of the trial, patients underwent titrations of study drug and conventional therapy according to a dosing algorithm. The primary analysis occurred at week 26, marked in the orange triangle there, and that is the data we are sharing today. After week 26, patients were eligible to continue in the open-label extension. Eligible patients had a diagnosis of hypoparathyroidism, were at least 18 years old, and required conventional therapy, here defined as calcium, calcitriol or alfacalcidol, above minimum threshold levels. On the right-hand side of this slide, you can see the primary endpoint was the proportion of patients who achieved all the components listed here at week 26, that is, a serum calcium in the normal range, independence from active vitamin D and independence from therapeutic doses of calcium. The 5 prespecified key secondary endpoints at the bottom right were measures of patient-reported symptoms and impacts. Four of the key secondary endpoints are part of the disease-specific Hypoparathyroidism Patient Experience Scale, or HPES. The fifth key secondary end point is the Physical Functioning subscale of the general and well-known Short Form 36, SF-36 Survey. According to our statistical plan, the primary and key secondary endpoints were tested in a sequential manner to handle the testing of multiple hypotheses, that is, statistical significance had to have been met from one to the next endpoint to advance to the next endpoint in the hierarchy. Slide 7 illustrates patient disposition in the PaTHway Trial. Ultimately, 84 were randomized, 82 were dosed and thus formed the intention to treat population, they're in orange. During the blinded period of the trial, 3 patients discontinued or dropped out, in each case unrelated to study drug. Details of these dropout subjects are noted on Slide 8. Two dropped out from the control arm. One control subject withdrew consent for reasons unrelated to study drug on day 30. Another controlled subject withdrew on day 62, after receiving a new diagnosis of breast cancer, considered unrelated to study drug. One patient randomized to TransCon PTH died on day 111, having sustained a sudden death. This event was assessed by the investigator to be unrelated to study drug or study procedures. The patient was a 74-year-old man with multiple cardiovascular risk factors, such as hypertension, hyperlipidemia and obesity. His serum calcium had been consistently within the normal range during this trial and his course in the trial unremarkable, with no other symptomatic adverse events prior to this terminal event. And now, we will turn to the demographics and baseline characteristics, on Slide 10 for those following along. Here, we have separated the columns by treatment allocation, with 61 in the TransCon PTH-treated group and 21 in the placebo control arm. As you can see, in general, the groups are well balanced. There's a slight higher age in the TransCon PTH arm, which therefore translates into a slight difference in the age breakdown above and below 50 years old and menopause status. On Slide 11, we show that 2/3 of the patients were from North America, 1/3 from Europe. And together, these 2 slides represent a very similar population to what we recruited in the Phase II trial, what's been recruited in other parathyroid trials. And overall, these age and sex distribution also match the epidemiology of hypoparathyroidism across the globe to date. Similarly, on Slide 12, we show the etiologies, again similar to who is treated today. About 85% have hypothyroidism in the postsurgical setting, whereas approximately 15% have it from other reasons, including genetic and idiopathic reasons. Mean duration of hypoparathyroidism was about 11 or 12 years. And you can see here, some of the associated disease comorbidities at the bottom of this table. On Slide 13, we show the baseline doses of conventional therapy. On average, the subjects were taking almost 2 grams of calcium a day, that often translates into 4 tablets. If they were taking the active vitamin D form of calcitriol, which is in fact an endogenous hormone produced by those with intact PTH axes, their typical dose was [ 0.75 ] micrograms. If they were taking alfacalcidol, an analog of calcitriol, they were taking 2 -- 2.5 micrograms per day. On Slide 14, we show the baseline serum calciums coming into the trial prior to treatment. They were in the mid-8 milligrams per deciliter range. As you can see here, 8.8 milligrams and 8.6 milligrams in the 2 different arms. And baseline 24-hour urine calcium, a measure of calcium handling in the kidney and excretion into the urine over the course of the day, was high and abnormal in both arms, 392 in the TransCon arm and 329 in the control arm. And now the most exciting slide of today's presentation, which are the endpoints. So I'm on Slide 16 now. So at week 26, 78% of the subjects treated with TransCon PTH achieved the primary composite endpoint, versus 4.8% or 1 patient in the control arm. This was a highly statistically significant difference, with a p-value less than 0.0001. As mentioned before, there were components that are included in this composite endpoint. They are listed in the bottom of the table. The most important pieces being that 95% or 57 out of 60 of the subjects were able to gain independence from therapeutic doses of active vitamin D and calcium while feeling well, as you'll see, and generally maintaining a normal serum calcium. In addition, during the last 28 days leading up to this week 26 visit, 57 out of 60 were able to remain on stable doses of study drug, as shown here. The next few slides go over some of the components of this primary composite endpoint. On Slide 17, you see here TransCon PTH is represented in the blue line, those who are in the control arm are represented in the purple line. This shows the doses of active vitamin D over the course of the trial. As you can see, the patients were able to discontinue their active vitamin D early, within the first 4 weeks; if they were treated with TransCon PTH, and remained completely off through week 26. I'll pause to point out exactly why this is so important in our view. As mentioned before, calcitriol is the downstream hormone of parathyroid hormone. So when parathyroid hormone is available, one can generate their own calcitriol. In the absence of parathyroid hormone, one cannot generate it and must take it as a capsule. The fact that the treated patients were uniformly able to gain independence from their calcitriol or alfacalcidol tablets and capsules, really implies to us that the PTH axis and its physiologic processes have now been restored. On Slide 18, we show the calcium supplement doses over the course of the trial. Again, the 2 colored lines diverge, with those who are treated with TransCon PTH being able to reduce their calcium supplementation early on in the trial and continue that way for the rest of the trial. On Slide 19, we have the serum adjusted -- excuse me, the albumin-adjusted serum calcium levels. Again, both groups started in the mid-8 milligram per deciliter range. And over time, the TransCon PTH arm ended up a little bit higher at week 26. And during the entire -- at every study visit, the treated patients, the TransCon PTH-treated patients, were able to maintain serum calcium levels within the normal range. And now we move to the key secondary endpoints, which were all prespecified according to the statistical analysis plan. There are 5 panels here, each one representing one of the key secondary endpoints. Each one is a patient-reported outcome. The 4 on the left, the HPES ones, show improvement if the scores reduce, the lines go down. On the far right, the Short Form 36 shows improvement if the scores go up, towards 50. So you can see here visually that the purple lines are all going in the directions of improvement, and the p-values shown at the very bottom are all highly statistically significant. So that is, with the symptoms and the impact scales here, physical domain scores, cognitive domain score, physical functioning score, daily life domain score and the HPES scale, we have improvement across all of those. And in the SF-36, the Physical Functioning subscale score, the TransCon PTH also shows improvement with a difference from placebo. To our knowledge, this is the first time a placebo-controlled trial in hypoparathyroidism has shown such differences in patient-reported outcomes. Now, on Slide 21, we turn to the skeletal health in hypoparathyroidism. As a reminder, in the absence of PTH, so in hypoparathyroidism, there's abnormal communication with the skeleton, an abnormal release -- an inability to release calcium and phosphate from the skeleton. Bone turnover is low and the skeleton may be more likely to fracture. Here, we show that TransCon PTH, as expected, increases skeletal remodeling. The left-hand panel, procollagen type 1 and propeptide, or P1NP, is a marker -- serum marker of bone formation. On the right-hand panel, the collagen telopeptide, CTx, is a bone resorption marker. In both cases, the TransCon PTH-treated group increased their bone remodeling. And this is a similar pattern that we saw in our Phase II trial, which, as you know now, has gone beyond the week 84 or 1.5-year mark. What we saw in the Phase II trial was an initial increase in bone remodeling as expected, reaching a peak by week 26, with a downturn towards the normal bone turnover marker reference ranges by week 58 and week 84, such that the bone turnover markers were no longer as abnormally low as they were in the beginning and lower than they were at peak, close to week 26. We think this represents another meaningful change, another meaningful demonstration that PTH is restoring activity at all the important tissues in the body. Now, we'll turn to the safety results, starting on Slide 23. TransCon PTH was generally well-tolerated, with no discontinuations related to study drug. 3 patients discontinued during the treatment period, we discussed them before, 2 from the control arm and 1 from the TransCon PTH arm. Overall, as you can see in the top row, 82% of TransCon PTH-treated patients and 100% of patients in the control group reported treatment-emergent events -- relatedness is not specified here -- and the majority of these were Grade I or II, mild or moderate in severity. 49% and 38% of treatment-emergent adverse events were considered by investigators to be related to study drug. The most common of these related adverse events were injection site reactions, headache, nausea, hypercalcemia and hypocalcemia, which are consistent with expectations in the double-blind, placebo-controlled trial design. One serious related adverse event of hypercalcemia in the TransCon PTH arm was recorded due to a dosing error. One death in the TransCon PTH arm was assessed as unrelated to study drug. On the next slide, we provide additional detail on the most commonly reported adverse event terms in the trial. And as you can see here, this lists any adverse event where more than 5 patients across the trial reported this type of adverse event. So the most commonly reported ones regardless of relationship to study drug in the TransCon PTH group were injection site reactions, headaches, paresthesia and fatigue; and in the placebo group were hypocalcemia, fatigue, paresthesia and muscle cramps, many of these very characteristic of this hypoparathyroid population. The injection site reactions seen in the TransCon parathyroid hormone group were typically mild localized redness or erythema, smaller than 2 centimeters, and located at the injection site. The majority were self-limited, without associated pain or itching and spontaneously resolved within 1 week. It was generally seen more in the beginning of treatment and resolved again within weeks of starting. No patients interrupted or discontinued treatment due to these reactions, and none required specific therapy for these reactions, and I think that's really important to point out. These were nuisances and not much more than that. I'll turn to the Slide 25 now, which is one of my favorite slides here, one of my favorite pieces of results in this trial, showing the 24-hour urine calcium, measured as milligrams per day. We'll focus on the left-hand panel, which is the figure, bar chart, showing how the 2 groups did. As you can see here, the TransCon-treated group and the placebo group both had high urine calciums at baseline. Yes, there is a difference, but both are abnormally high. Over time, the TransCon PTH-treated group, represented in blue, were able to reduce their urine calcium excretion into the normal range, which is defined as lower than 250 milligrams over 24 hours for women and lower than 300 milligrams per day for men, such that by week 26 all the subjects in the TransCon PTH-treated group gave a mean urine calcium right there at 219 milligrams for 24 hours, well within the normal range. By t-testing, this was also statistically significantly different from baseline, whereas you see there in the purple bars, although there is a slight decrease, probably related to the reduction in conventional therapy in the placebo arm, according to the titration algorithm, that p-value shows that there is no difference, numerical -- no difference between the arms, the purple bars. In the table on the right-hand side, we show change from baseline in urine calcium. So the TransCon treated group was able to drop 154 milligrams over 24 hours, whereas the placebo arm did drop 64 milligrams over 24 hours, for a difference of 90 milligrams between the 2 groups. Again, this finding was statistically significant between the 2 groups, showing that the TransCon PTH arm was able to statistically significantly reduce their urine calcium compared to the control arm, and this p-value was 0.0085. So now, back to Slide 26, which is a summary slide that was also shown at the beginning of the presentation, the key points being that 78% of the TransCon PTH patients were able to achieve the primary endpoint compared to 4.8% in the control group. All 5 key secondary endpoints were met at highly statistical significant levels. These were all patient-reported outcomes, some from a disease-specific measure and some from a general measure of quality of life. TransCon PTH was generally well tolerated, with no discontinuations related to study drug. Most of the adverse events were mild and moderate. And importantly, TransCon PTH-treated patients showed a mean decrease in 24-hour urine calcium into the normal range, going from 390 milligrams over 24 hours down to 220 milligrams over 24 hours. Finally, on Slide 27, we look ahead to the next steps and update you on the program status. So at this point, in our late phase PTH program, we have 2 trials ongoing. They're both now in the open-label extension phase. In our Phase II PaTH Forward Trial, 57 of 59 patients remain in the trial after 2 years. In the Phase III trial, which we've been discussing today, all 79 subjects who completed the blinded period, continuing the trial. This is extremely meaningful, acknowledging that this is a hard trial to be in, requiring many visits and blood tests, and yet these patients have found it meaningful to continue in the trial. Ascendis looks forward to engaging with regulatory authorities regarding registration plans in the United States and Europe later this year. We continue our TransCon PTH trial in China through our strategic partnership with VISEN. We also have a Japanese trial, with top line data expected later this year. And we plan to initiate our pediatric program with a trial also later this year. And with that, I'll thank you for your attention and turn it back to the team.

Okay, operator, we'll open up the call for questions.

[Operator Instructions]. Your first question comes from the line of Jessica Fye with JPMorgan.

I guess I have two. First, just bigger picture, when we think about how physicians may interpret this result, it seems like it shows that standard of care carries a liability in higher urinary calcium relative to treatment with TransCon PTH. I'm curious kind of how you think physicians will interpret that safety finding as they kind of think about how to take care of their patients. Second is, what explains the gap -- I think there's maybe a 16 percentage point gap between the 79% who met the primary endpoint and 95% of TransCon patients coming off of conventional therapy. Did those patients tend to be above or below the normal serum calcium range? And -- just trying to figure out kind of why -- what explains that delta.

Thanks, Jess. First of all, what we actually observed with the 24-hour urinary calcium was actually reflecting the same biology that we saw in our open-label extension trial. So when we go into the concrete numbers, we can discuss this in different means. I think the data clearly indicates there is a statistic positive effect on 24-hour urinary calcium. What we see is a basic lowering of the placebo arm. But I've always -- some may want you to go back and look on serum calcium, because these 2 elements are related. If you come to the kidney with a much higher load of calcium, if you actually need to resolve more, if you -- for example, if you can see in our data, we lower serum calcium, we're basically coming to the kidney with lower load of calcium, and therefore you actually will get a lower 24-hour urinary calcium. So when I look at the result from what I observe with our TransCon PTH-treated group, we are increasing the serum calcium. We are increasing the load that's coming to the kidney, but at the same time we're dramatically taking the 24-hour urinary calcium down to the normal level. But Aimee, you're a physician, you're still treating HP patients. How would you look at the trial [indiscernible]?

Thanks, Jan. So Jess, I agree. I think you asked about the liability of the placebo arm, right, or the conventionally treated patients, would physicians view this as positive news. And absolutely, I think this is what many have been waiting for, was a way of therapy to not only boost serum calcium into the normal range, but to make sure that the kidney issues were also handled. So the fact that we went from 390 milligrams at baseline to 220 milligrams on therapy at week 26, it's amazing. I think it's really amazing that we've been able to see this. And this hasn't been seen with any other treatment for hypoparathyroidism before, other than off-label thiazide use, which doesn't even do it consistently.

And your next question comes from the line of David Lebowitz with Citi.

Would you be able to elaborate on the reimbursement situation in this market? NATPARA did not have an easy time of it out there. How do you think this data could shift that question relating to TransCon PTH?

When you look at the product -- I will take it from the perspective of the algorithm I'm looking on when I see the opportunity of the product. First, you look on the unmet medical need. Are there huge unmet medical needs, where you really can address with the product you're developing? That is number one. I believe there is no doubt hypoparathyroidism is a severe disease with both short-term symptoms, long-term complications, without doubt of that. The second part comes in if you develop a product, the target product profile, what do you want to achieve, this is really addressing the unmet medical need in a holistic manner. And if I look at HP, what do you need to address in a holistic manner, you need to basically be in a position that you're normalizing serum calcium. Take them away from all the conventional therapy. Meaning is that you normalize serum calcium, take them away. That was what we proved in our primary endpoint. That is exactly what we can do. And when we talk about serum calcium, you're not talking about 7.5 mg/dl, which actually was the starting point for being successful with NATPARA. We are talking about 8.3 mg/dl. If we, for example, have lowered it down to 7.5 mg/dl, we basically will have much, much more patients being positive on the primary endpoint. That is one part of it. This is the tree, but you need to see the forest. You need to have the positive impact of all the other elements. To our knowledge, this other product never show a statistic significant effect on either urinary calcium, either on quality of life, never return the normal metabolism, such as [indiscernible]. So when you think about a product and really [indiscernible] how do you address the unmet medical need, you need to do it in a holistic manner. And not only one single parameter, but sure you address all the unmet medical need that is in this specific disease. And that is what we see TransCon PTH. We do normalization of all the parameters we have measured. And this is where we see the huge differentiation to it. Then you go over and watch the U.S., the reimbursement system, what I see what we're doing in the subpopulation analysis, there's about 80,000 to 100,000 patients in the U.S. How many of them will have benefit on the TransCon PTH product. When we look at the data, everyone will have a benefit of the TransCon PTH. We cannot still find any subpopulation that don't get the benefit of it. It's not like that it's only 5% or something, 10%, all of them getting the benefit of getting a TransCon PTH treatment. Then you take the second part, will it be reimbursed? I believe a product which really are going through acceleration, where they restore the normal physiological hormone, this patient group [ I mention ], I cannot see any kind of reason it should not be reimbursed, out from the perspective you're really addressing a major unmet medical need. And for the other point, trying to think about, you have a type 1 diabetes. Would you deny a type 1 diabetes to get insulin? Would you deny an HP patient, hypoparathyroidism patient not to get PTH? I really cannot see that. So when I see the -- what product opportunity be developing, I believe we are having a product opportunity with a completely different target product profile that's really addressing really the holistic view of the treatment of a patient with hypoparathyroidism. But going back, I got cut off a little bit earlier because we never came to get the second question. And if I understood it right, in our Phase III trial, we have 13 nonresponder in our TransCon PTH team. And when I look on the data, we can go out and analyze and see what was the reason not to be a responder? And the main, main thing for being nonresponder was serum calcium. Meaning is that we took it up to 8.3 mg/dl. If we had lowered down to 8.0 mg/dl, we basically have about 5 to 6 patients more being positive. If we went down to 7.5 mg/dl, we basically have the majority of the patient being positive. But I believe normal serum calcium is not starting at 7.5 mg/dl, and I think Aimee will agree with that. It's why we took it up on 8.3 mg/dl. But basically, the key element that was not hitting the primary endpoint was the serum calcium. And if we had lowered down to what other trials are doing, to 7.5 mg/dl, we basically will have about the majority of the patients also fulfill the [ criteria ]..

And Dave, did you have a follow-up question?

Had the dosing -- the high dose leading to the adverse event? Could you just elaborate on what happened with that specific patient?

Aimee?

Sure, Dave. So this patient was sort of miscommunication and labs coming in at the wrong time. So let me -- not the wrong time, but not following the most recent labs. So what happened was this patient was early in the trial. They had blood drawn for serum calcium, both at central and local labs at every visit, the local labs coming back sooner, the central labs often kind of taking a few days. So although one of the labs did show, the most recent one showed, that the patient actually had a high serum calcium by this time and thus should have been reducing study drug, the investigative site thought the patient's serum calcium was in the normal range and continued to increase study drug doses. So went from a high serum calcium situation to an even higher one. The patient had to -- ended up going to the hospital for care and observation when the serum calcium came back high. So with fluids and observation and holding up the drug for just a few days, recovered completely, remains in the trial on a lower dose nowadays -- now we know, now we have the hindsight -- at a lower dose than they had been on at the time of the event.

Your next question comes from the line of Michelle Gilson with Canaccord.

Congratulations on the results here this morning. Maybe one on the safety. Can you elaborate a bit more on the 4 patients that experienced adverse events related to hyper- or hypocalcemia that led to hospitalization or urgent care visits? I know there was the one that was misdosed, but could you give us a sense of, I guess, when in the course of the 26 weeks did these events occur, and was hyper or hypocalcemia more common on the treatment arm? And then maybe just one follow-up there too. Can you confirm that the patient that died wasn't one of the patients that was hospitalized? I know you mentioned the patient had normal serum calcium at the time of the event. And then a second question on urinary calcium. You talked about the importance of that urinary calcium signal. At baseline, 25% of patients had a history of kidney stones and 5 patients had a history of renal insufficiency. Is there anything trending or improving, I guess, in terms of those underlying kidney disease for those patients? Or is this too short of a period of the trial?

Before I give Aimee the word, I actually think I would like to clarify a key element. In the design of our Phase III trial, we had placebo treatment and we had active treatment with PTH. And the algorithm we have implemented in the Phase III trial was a compromise between the 2 elements. It was not optimized for an optimal treatment for the patient. It was a compromise, being ensuring that when you had a placebo patient that it didn't crash the calcium level down. And that was why when we saw the algorithm being implemented, it's not exactly how we will do it for a patient if we didn't have placebo. And I think this is the key element that actually we need to take into account when we talk about the hypocalcemia episodes, because all the hypocalcemic episodes came only in the early start of the program, the first 3 months. After 3 months, no more hypocalcemic episodes because we were through the titration period and the titration period was not optimal for the patient because there was a compromise between the 2 elements, and I think that is a key element which has mainly been forced on us, because there was a requirement to include a placebo arm in our clinical trial. And I'll give you a background why we actually see the first period of time not the optimal regime for the patient, but more compromised in our clinical trial. Aimee, you can go more in the detail for each single patient.

Sure. Hi, Michelle. So I think your question, if I remember correctly, was specifically about the patients who required medical attention, that row about hyper or hypocalcemia leading to ER, urgent care or hospitalization. So the additional context is, yes, this tended to be more in the beginning of the trial, exactly for the reasons you heard from Jan, as an artifact of the necessary placebo -- titration algorithm. The other times that this can happen for patients is sometimes when they -- something else happens. There's a fracture, they fall, they fracture, they get a hemorrhage, and that this can send them into a tailspin that time. So much like type 1 diabetics, if an intercurrent illness occurs, it may be harder to control their glucose for a while. This is similar to what we see with our hypopara patients is that, in general, when bad things happen, the parathyroid hormone helps a lot. But sometimes, when it's quite a big event, it may be a little bit harder to control. So in terms of which ones were -- in the beginning, those who were treated with TransCon PTH were more likely to have hypercalcemia than hypo if they were going to have an excursion. The placebo arm was more likely to have hypocalcemia, as you can imagine, since they took a placebo and having their conventional therapy titrated, and they did not experience hypercalcemia during this time. The death you asked about, you wanted to confirm that this was not one of the ones who's reflected here as a hospitalization, and I can confirm that, yes, that patient, the one who died in the TransCon PTH arm, is not reflected in the row of hyper or hypocalcemia leading to medical attention. And finally, you asked if we had seen yet any trends with kidney stones or renal insufficiency in the trial. And yes, we're really excited to start digging into this. I can share with you that we don't have that data available yet, but we are interested to see it and we'll certainly be following over time. I can only share an anecdotal story with you about the kidney stone, is that there was -- there are a few patients in the trial who literally would have a kidney stone every 2 to 4 weeks, such that it was so painful and requiring so much medical attention that they were unable to hold down jobs. Once exposed to study drug, and we didn't even know what it was at the time, there was one in particular who was able to be stone-free for almost 4 months and actually secure a job. So this one subject, I've heard, was very happy. In terms of the renal insufficiency, we are watching that through both serum and urine markers, and we will be able to, over the long term, take a look to see if things stabilize or in fact improve from the kidney health standpoint. But I just don't have that yet.

And your next question comes from the line of Derek Archila with Wells Fargo.

Congrats on the data. Just a couple of quick ones from us. Maybe, just first off, maybe provide your updated thinking on potential labeling scenarios given the data today? I know you talked about potential terms of replacement therapy versus what NATPARA had. So I would love just to get your updated thoughts there. And then also, just in terms of the filing, I know you gave some timing, but just thoughts on priority review. Thanks.

Dana, would you take over?

Yes, sure. Now, in terms of the sort of proposed indication statement, right, our intention would be that the drug should be indicated for the treatment of hypoparathyroidism, right, and full stop. Of course, this is going to have to be negotiated with FDA, but the big distinction for us is that it won't be as an adjunct therapy in addition to standard of care, because as Aimee mentioned, 95% of people were able to eliminate the therapeutic calcium and vitamin D. So as I say, this is a sort of a process in terms of our interactions with FDA. And in terms of the potential for priority review, obviously that would be very important for us. I think that the compelling results that we have here certainly would make a strong case for that. And so we intend to have a call with FDA fairly soon, and this will be one of the items we will discuss with them in terms of the possibility for priority review.

Thanks, Derek.

Then your next question comes from the line of Joseph Schwartz with SVB Securities.

Great. Congrats as well. I was wondering, what do you make of the decrease in mean serum calcium over time? And I noticed it's accompanied by a slight increase in calcium supplementation. So I'm just wondering, do you have any ideas on why that might be occurring? And how do you think patients will be titrating TransCon PTH over time?

That is a really, really an interesting comment from the scientific in nature of how we really love to understand everything of our product. And I think this is the integrated hemostasis view about how we see the treatment with TransCon PTH developing through times. And we know from the demographic, we look on bone density, looking on it, they have an unnatural bone structure that is characteristic with a high bone density because of lack of normal bone remodeling. It has been shown this bone structure is not beneficial as [indiscernible] statistics showing higher rate of bone destruction and fracture. And what is happening in the building when you kickstart the basic remodeling -- because you start to have a normal PTH level again, we start the remodeling. Therefore, you don't see the bone marker start to come up. And when we go to our open-label extension, we saw that picked up about 6 months. And then after 6 months, that basically went down to the [indiscernible] level of the normal level. What do that tell us? It tell us that basic, when you are in the first 6 months you liberate and net result from the skeletal, the biggest reservoir of calcium in the body, will release net free calcium through this restoring of the normal remodeling. So therefore it's a very, very critical time when you come to 6 months, because at that time you basically have peaked the remodeling. And this is also why we see in our Phase III trial, why we, for example, when the majority of the patient partly missed the primary endpoint at 8.3 mg/dl, because in our protocol, the last 4 weeks before the basic ending the trial, we kept the dose constant of TransCon PTH. But at the same time, the net liberation of calcium from the skeleton is also decreasing. And that was why we basically saw so many patients, 5 patients or 6 patients, that just went down from a normal over 8.3 mg/dl down to between 8.3 mg/dl and 0, because we kept the PTH dose constant at that time. And this is when we come back and expect to go back and having the interaction with the physician. Yes, at this critical time, you need to increase PTH dose, because you will start to have a less net release from the skeletal, meaning is that you need to increase PTH, you go down and increase PTH, you go in and increase activated vitamin D, you get a higher uptake of calcium from the food, from the dietary component, and therefore you basically will be in the position that you will absorb more calcium. That is what we call the established or normal calcium hemostasis. And we know now from our 2 independent trials, 6 months is a critical phase. We know that. This is where we should guide the patient to look very much on the serum calcium and start to increase it, because you all come over to a new calcium hemostasis, where we basically had stopping the release of net calcium from the skeleton. Aimee, you [indiscernible]?

Yes. I think, Jan, you said it well. All I can add is that we can tell from our patient-reported outcomes data that these patients felt extremely well. So despite the fact that their serum calcium may have been on the lower side at week 26, they felt really well compared to how they did at baseline. And what we heard from the investigators was they seem to tolerate their lab values wherever they are a lot better. They just seem to be happier, more productive people at this time. So again, it's a holistic [indiscernible] integrated picture that we see here is one of great benefit.

I have to say, Aimee is addressing one of my biggest learning from this here, is that we always have believe that this kind of improvement in quality of life, was that driven by serum calcium or it was driven by downward effect on PTH of physiological PTH on the brain. And what we're believing more and more -- this is just our belief, but I think it's built on the scientific data -- to have a constant physiological PTH really functions through the PTH2 receptor in the brain, is basically providing the well-being of the patients, independent on the actual serum calcium. And hard to believe that is what we see more and more. Surely it's a contribution of both of them. But we also believe that keeping the physiological PTH level is the main driver of the improvement in quality of life we see in the TransCon PTH.

Your next question comes from the line of Vikram Purohit with Morgan Stanley.

Great. So 2 from my side. First, could you provide any context you might have on what you think might have led to the significant drop in active vitamin D use in the placebo arm in the early part of the study? And then secondly, when we think about the study underway in Japan and then the pediatric study you're planning to start in the fourth quarter, how should we think about the translatability of the pathway data to these studies? And what are some of the key similarities and differences we should keep in mind when thinking about odds of success for these expansion opportunities?

Okay. That was a lot of questions, but I think we will digest them and take one by one. Aimee, will you take the first one?

Sure. So the first question was about do we have any thoughts on why there were some subjects in the placebo group who are able to decrease their active vitamin D doses, their alfacalcidol or calcitriol. Yes. So absolutely, we have thoughts there. For many hypopara patients who have arrived at the diagnosis through postsurgical hypoparathyroidism, it is possible they have recovered and recovered quite a bit of function without knowing it. So when the -- in the acute postoperative setting, the symptoms are so, so scary, so compelling, that patients are prescribed high doses of conventional therapy, and they're very worried to ever come off of that or ever reduce them. And also, they typically wouldn't have the opportunity to do an iterative process where you'd decreased a dose of conventional therapy, get a blood test, decrease another type, get a blood test. And that's exactly the opportunity we had in this trial. So what was interesting is, when we looked at these patients who are able to eliminate their calcitriol, some replaced it with calcium instead, and this was just how their physicians were following the titration algorithm. Others really didn't seem to need it that long. So they could come off of their active vitamin D and still maybe maintain a normal serum calcium, maybe some of them did have a lower serum calcium. But this was a function of the titration algorithm and also a function of potentially some of the subjects uncovering for themselves that they are -- they did not need as much drug as they had been taking before. As is true with all hormone therapies, if you take the hormone, then your body will reduce what it could make. So the fact that one could take so much conventional therapy, calcitriol, calcium, doesn't necessarily mean they always needed it. And now, I think you had a question about the Japanese pediatric trials will be translatable. I'll pass it over to Jan.

I think the Japanese trial is really one of the most simple trials I ever have been part of. This is 12 patients, single arm. Adult patients with hypoparathyroidism, single arm, 12 patients. And we are enrolling them really, really well. So -- but it's a very, very, very small trial. The pediatric, if I see the unmet medical need in the pediatric, it's huge. It's some of the stories we're really feeling that we need to really live up to our vision, live up to the mission about doing something for patients. And we are dedicated to get TransCon PTH out to the pediatric as fast as possible. The pediatric are typically not coming from post-surgical, but more from both genetic, [ immunological ] group. But we believe, and I think what we're believing on is built on the scientific data, where you take this group of patients, pediatric patients, take them into infusion pump, use either [indiscernible] or [ NATPARA ], and take them for years and years on infusion pumps. It's highly demanding for the children. It's very, very complicated for them. And what, when we see the clinical result from that, we really see the benefit of having the physiological PTH, 24 hours, 7 days. And we believe we can mimic this physiological PTH dosing exactly with TransCon PTH as a single, small subcutaneous injection every day. So from that perspective, we expect to see the same benefit that we saw in adult hypopara patients and also in the pediatric. And I know Aimee, she cannot wait to get this started, because we know the need. We hear the stories from them and everyone is waiting to get it.

And your next question comes from the line of Tazeen Ahmad with Bank of America.

Can you just clarify what needs to still be done in order for your application to be submitted in 3Q of this year? And also, what is the latest market data research that you have on patients in the U.S.? So I know that numbers-wise, it could be quite large, but how many patients would you say are actually diagnosed with hypoparathyroid in the U.S. today? And what kind of work do you think your team needs to do between now and when you launch in order to potentially increase that number?

The positive part, when we talk about adult chronic hypoparathyroidism, this is the patient we have in our time. All of them have already been diagnosed because it takes 6 months to make this diagnosis. So when we talk about the patient population of 80,000 to 100,000 patients in the U.S., all of them are diagnosed with chronic hypoparathyroidism. We don't need to go out and find them. We don't need to go out and make a new diagnostic kit. We don't need to discuss if this new genetic testing really giving the right patient. All of them have the physical, established diagnosis of chronic HP. That makes it very, very simple for you in your calculations. The other point, what do we need for the filing? And I think Dana can go through that. But we have the data now, and we have the rest. Dana, please?

Yes. Well, this is obviously a very important component of the filing. And so our next step is to schedule a meeting with FDA and walk through the planned structure of the filing, and then we can discuss the content of the filing. The other important component is the completion of all the requirements for the device, right, so -- because this is a combination product. So we need to have both things ready at the same time. So those are really the 2 key components of the filing at the moment. Many of the other outstanding issues in terms of the manufacturing and all that are really already sort of squared away. So again, those are the things that are sort of key elements right now.

I think one of the elements which we have done, which we also did with TransCon Growth Hormone SKYTROFA from the U.S., we're not running a Phase III and then changing manufacturing side [indiscernible]. What we're doing is that we do it in such a manner that in the Phase III trial, we had exactly the presentation we're going to be launching with. I don't believe I would take the risk ever to change manufacturing, the team, Phase III and launch, because this is where I see the main CMC issue come up, because it's really, really hard to bridge biological in this way. So we already have to risk it by being in a position that both scale, size is exactly what we're going to launch from, which give me big comfort that we can get this important compound out to the patient next year as a commercial product.

And your next question comes from the line of Josh Schimmer with Evercore ISI.

Just a question about the types of patients who were enrolled in the trial. Could you help characterize their baseline severity, whether they were generally mild, moderate or severe? And maybe even help define what mild, moderate or severe hypoparathyroidism might look like.

I think, Josh, this is where I was really, really, very confused when I started to move into this disease, because I read a lot of publications, as you do, and what we saw was that people describe the disease, mild, moderate, severe, out from the pill burden. And I believe we have not seen any kind of correlation between the pill burden and basic the severity of the disease. Nothing is really related to that. So old publications where it was described for that, we think the same time, we try to look on our Phase II. We are looking in our Phase III trial. If we take the pill burden and then define them in different ways on mild, moderate or severe, we actually see the same huge benefit in quality of life and other things like that. No difference with that, meaning is that independent on the severity of disease defined by what we call pill burden, all of them have the same huge benefit of it. Then you go back and then we do the opposite. Can we make subpopulation analysis, where you basically look in our entire demographic and see are there some things that actually had less positive effect compared to huge positive effect? We cannot find one single way where you basically not see the same positive effect on all the different subgroups. So when we looking on the severity of the disease, if you have been to the right diagnosis, meaning is that you have been through the 6-month period it takes really to define you as chronic HP patient, we believe everyone will have a huge benefit. And that is what the data shows of taking TransCon PTH.

Very helpful. You preempted my follow-up question about whether there is any predictor of response based on baseline severity in terms of patient-reported outcomes. It's a great result.

Thanks, Josh.

All right, thank you. Ladies and gentlemen, this concludes today's conference. Thank you for your participation, and have a wonderful day. You may all disconnect.

Thanks a lot.