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

Ladies and gentlemen, thank you for standing by, and welcome to the Ascendis Pharma TransCon PTH Clinical Development Update Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your speaker for today, Mr. Scott Smith, Chief Financial Officer of Ascendis. You may begin, sir.

Thank you, operator. Thank you, everyone, for joining our TransCon PTH Update Conference Call today. I'm Scott Smith, Chief Financial Officer of Ascendis. Joining me on today's call is Jan Mikkelsen, President and Chief Executive Officer; Dr. Dana Pizzuti, Head of Development Operations; and Dr. Aimee Shu, Clinical Development Lead for TransCon PTH. Before we begin, I would 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, statements regarding the market potential of our pipeline candidates and statements regarding planned 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. Please note that our TransCon product candidates are investigational product candidates and are not approved for commercial use. As investigational products, the safety and effectiveness of the TransCon product candidates has not been reviewed or approved by any regulatory agency. None of the statements made on the conference call regarding our TransCon product candidates shall be viewed as promotional. On today's call, we will discuss preliminary 6-month results from the open-label extension of our Phase II PaTH Forward trial and provide an update on the TransCon PTH clinical development program. An updated slide deck for today's presentation is posted this morning on our website under the Events and Presentations section, and the link can also be found in our press release. We will be using these slides for today's discussion. Following the presentation, we will then open up the call to questions. I will now turn the call over to Jan Mikkelsen, our President and Chief Executive Officer. Jan?

First, thank you, Scott, for having this opportunity to have this very early call. And before I go to the data, I would like to step back and take it, why did we really start to work on TransCon PTH? We got extremely inspired when we saw in the [indiscernible] heard from different clinician physician that they really could help the patient provide them in meaningful treatment by taking a short-acting PTH, take them to an insulin pump, provide them continuous exposure 24 hours, 7 days a week. By doing that, we were in a position that really could address both short-term symptoms and long-term complication. That inspired us to see, could we really make a TransCon PTH? And we defined our target product profile for TransCon PTH to provide the same continuous exposure of PTH 1-34 in the physiological level 24 hours, 7 days a week. That was our target profile. We know from the literature, we know from other data that it will provide the optimal treatment regime. We made an extensive Phase I trial with more than 100 healthy volunteers, and so we could mimic this PTH profile with having continuous exposure 24 hours a day. We also saw the associated PD effect on all different parameter in our Phase I trial that were related to increased serum calcium effect of the kidney system, effect of bone structure and others. Out from this extremely promising Phase I results, we went into our Phase II study. We showed already in our first 4-week data double-blinded that we could have a replacement therapy because we can take the patients and really let them start with standard of care in this very, very short period for the basic majority of the patient. We also, later on, showed that we could increase the quality of life of these patients. We saw that with the very common use SF-36 instrument. Now we are in the position that we basically are providing to you the 6-months data. The other thing that inspired us is the burden of this disease. The number of patient with HP is one of the largest rare disease, endocrinology diseases where there is no treatment option today. In the Europe, in the U.S. alone we have at least 150,000 to 200,000 patients. And if you see their burden of having this disease, where you have both short-term symptoms and you have long-term complication, and the patient burden is extremely high. We have 76% of the patients saying they're unable to work or have really significant interference with working, where about 35% completely stopped working. And then on top of that, you have long-term complication. This was why we started to work on TransCon PTH, really to be in a position that we can provide a meaningful treatment for this patient group. As we always do at Ascendis when we release data, we try to in very, very, very short time combine all the data we can get available for all perspective of the machinery we have. We have done the same thing here in our Phase II 6-months open-label data. So it will be impossible on this call to go through all the data, and therefore, I will select a few slide and take them up and discuss it, but we still will be in a position that we will be open for question related to the entire slide deck. So let me start on Slide 3, which are the TransCon PTH overview. And if you go to the first line, it's basically summing up all the integrated learning we now are accumulating, not only from our preclinical data but also for our Phase I and now Phase II data. That TransCon PTH all the data we see is supporting that we have a replacement therapy for adult HP. And we see that because we can eliminate standard of care with a well-tolerated once-daily injection. We see the improved quality of life, not only on the summary domains but all -- on all domains. And also, when we talked about long-term complications, one indicator of risk is 24-hour urinary calcium, and what we saw a major improvement on that with our 6-months data. We realized that we will not expect to see that in the very, very short 4 weeks double-blinded period because we need to restore the normal hemostasis of calcium in the body, net loss for sub tissue, net loss from skeletal before we will see values on 24-hour urinary calcium that basically are reflecting the improvement we expect to see. We have discussed the 4 weeks data, the 4-weeks data double-blinded peer with regulatory agencies in the U.S. and Europe. We got feedback, which basically are indicating that they understand this is a replacement therapy and not an adjunct. We have from this discussion related to the 4-weeks double-blinded data made it clear that a Phase III trial, this which, I believe, is a very, very, very small Phase III trial. We have basically discussed 68 patients, we have improved it to a little bit more than 76 adult patient, randomized to 3 to 1, with an open-label extension trial. And the treatment period is only 6 months. Meaning that I think this is a where -- a Phase III trial that is really providing all the benefit of what we will see with TransCon PTH in the 6-months period. We are in a position now that we believe we are well powered to this trial with that samples when we look on the data we have from our Phase II trial. And this is how we like to operate, really make intensive Phase II trial that basically are derisking in the best possible way before we move into a Phase III trial. Reflecting the Phase III clinical endpoint, we had a great discussion with the regulatory agencies. And we agreed about, you can say, a simpler Phase III endpoint that we actually used in our Phase II trial because it's now composite only about 3 element. But I believe the discussion with regulatory agencies was really rational because these 3 composite endpoint really reflecting that you have a replacement therapy because it's defined by normalizing serum calcium independent of activating vitamin D and calcium supplement to a dose less than 600 milligram. And then you can say, why -- how do we look on this 600 milligram? Typically, if you take a healthy meal every day, you will get about 1,000 milligram in calcium every day. But a large part of the population don't get this kind in their food, therefore, they take calcium supplement. So basically, the calcium supplement that we're discussing, the 600-milligram, is basically to compensate for the lack of calcium that you typically are missing because you not have the optimal daily intake of calcium. So from our interaction and the plan forward in the summary is that everything what we have seen until now is really safe, well tolerated treatment. We have seen the data that continue to show elimination of standard of care with a positive effect on 24-hour urinary calcium, which are accessing is the biomarker that had the best possible correlation to comorbidity at -- like kidney stones and other things that indicate renal complications. I will now go to the next slide where we're going into more detail on our Slide 4 where you can see we could eliminate standard of care in 91% of the subjects. Meaning is they are not taking active vitamin D and taking less than 500-milligram per day of calcium supplement. That really indicate that you have a compound that basically are replacing standard of care. We also saw this significant reduction in urinary calcium, and we will show you more data about that, where we have 86% of the subjects had 24-hour urinary calcium in the normal range or 50% reduction from baseline. Going to the quality of life, we saw really what we had hoped for. And one of the element that you also need to look at, how is baseline really for this patient group? That baseline of this patient group is in a situation when you compare to perhaps more broadly well-known disease like chronic heart disease, that basic are in the level where you see the quality of life at that level. And what we saw, a really major improvement on that. When we go to the composite endpoint, and you can actually say, is that really highly relevant now? No. It's not highly relevant now as much as before because we are in position that the composite endpoint we are utilizing in our Phase III will not have the 24-hour urinary calcium. We're taking that out as an independent as regulatory agencies told us multiple time plus we see urinary calcium more as a safety element of really the treatment effect you see. And this is why it's going as an independent key secondary element. And -- but if we use the same composite endpoint for independent element, we see still 71% of the subject response. Safety, as we have said, actually well tolerated. And the other part, what really are unique for at least for me is this is the first time I've ever been part of an open-label extension trial, where we still have 58 patients. And that is independent on the pill burden which we some ways started in the beginning, described as disease. And what we see, all patients benefit of having, even if you use pill burden to describe them as mild, moderate or severe. Going to Slide 4 -- 5 is just a recall of our design, and I will move fast to an update related to our safety summary. And I'd like to thank Aimee Shu, will take the slide related to the safety summary, and this is Slide 12.

Thank you, Jan. So on Slide 12, what we see, and this goes right behind Slide 11, that's the table for you, but here's the top line summary. That TransCon PTH was, in general, very well tolerated. And as Jan mentioned before, 58 subjects continue with the open-label extension now. You may recall, we started with 59 subjects. One of them after the 6-week visit decided to withdraw for personal reasons, not related to study drug, not related to AEs, adverse events. There were no serious drug-related adverse events reported so far. No one has stopped the drug because of an adverse event. And the adverse events that we have seen have reflected known PTH pharmacologies. And those things include nausea, cramps, headaches, things like that. In general, the injections were also well-tolerated, using a pen injector that we planned to use for commercial presentation, and there were no new safety signals here at 6 months compared to what we saw and reported at 4 weeks. Finally, no one went to the emergency room or sought emergency care or urgent care for anything related to hyper- or hypocalcemia.

Thanks a lot, Aimee. Going to the next slide, 13. What you see now is that you see how each single subject now is starting to be individualized to the optimal dose. One other thing that we had as restriction in our Phase II trial that we only have allowed for the patient to take between 6 and 30. And what we're now seeing here in the open-label extension trial where they have got synchronized to the optimal dose that some patient are more difficult to treat, and therefore, potential would benefit of having a higher dose than the 30. And that is what we now implementing later on in the continuation of the open-label extension trial. There was an extremely important learning for us, it's a few percentage, but it is very, very clear that a few percentage are difficult to treat and remain a higher level of PTH than the 30 microgram. Going to the next slide, I would like to take-up is Slide 15, where you're basically going into more detail of the elimination of standard care. And what we can see, 100% got eliminated activated vitamin D, 95% took less than 1,000 calcium, less than 91% calcium, 0 calcium, 76%, activated vitamin D and 0 calcium, basic, nothing at all, 76%, and activated vitamin D and calcium less than 500 milligram, 91%. This data, I believe, is a very, very strong platform to show that we are basically eliminating standard of care. Going to the next slide, 16, you can see the time. And you can see active vitamin D dose is basic getting eliminated extremely fast in the first 2 weeks. Going to calcium. And there, you really see that it takes longer time. But you also need to remember, this patient group, some of them after 20 [ years ] being used to have a lifeline of calcium supplement, meaning is that is the difference for them to end in emergency room or not. And it takes long time for them basic to be in a position to accept that I am possible can live a normal life without taking calcium supplements. And this is why we see a continuation on it. The other part is that we also know in this open-label extension, there was not a high level of awareness from the physician to continue to basic down titrate or up titrate PTH doses and the continued removal of calcium supplement. This is also something we're implementing now because we saw when you come further in the deck that some of the patients that still are taking calcium supplement are basically on a low dose of PTH and therefore, basically if they got up titrated in PTH, we also could eliminate that. But when you look at the data, we just see what we have hoped for, a continue decrease. And we believe when we have all our integrated learning for Phase II, this is what you -- why you run this kind of Phase II, we have the optimal protocol and design from our Phase III. Going to Slide 18. When I looked at that data, I saw that was impressive. Why did I get so impressed by it? Because when we also did sub-analysis for it. So even when you look on our demographic, which we actually show first, we have patient, but we have an impairment. And what we basically saw independent on any kind of baseline element or got an improvement, meaning is that we still are in a position we can improve on such a key important long-term complication risk. And what we saw we can keep our serum calcium stable basically in always in the normal level, meaning around 9, and then at the same time, we saw a dramatical improvement in the 24-hour urinary calcium, independent of any kind of demographic precondition. That was what we had hoped for. Going to Slide #19. We're going into more detail about the 24-hour urinary calcium and 6 months. And you can see we had the expected improvement in urinary calcium and change from baseline. Going to Slide #21. We are coming to an acceleration where we saw we had 10 subjects without complete composite endpoint around month 6. And we believe that we want to be extremely transparent, show why this patients were in this position, why we were missing data. And I do not know, Aimee, will you go to the different patients?

Sure. Happy to do so, Jan. So what you see at the top of the slide here is, ultimately, we were missing 10 data points or 10 subjects from this preliminary analysis. So that is 10 subjects did not have all components of the primary -- the complete composite endpoint at month 6. Of those 10, one subject who, as I've mentioned before, initially randomized to placebo, withdrew for reasons unrelated to safety or efficacy of the study drug, and she did so soon after entering the open-label extension. Then on top of that, 4 subjects were excluded due to having 24-hour urine samples collected out of window. It turns out that all 4 of these subjects had achieved what we consider to be very important endpoints. That is they were independent from vitamin D -- active vitamin D and independent from therapeutic doses of calcium supplement. And 3 of the 4 actually had normal 24-hour urine calcium and normal serum calcium at this out of window time slot. So it's really too bad, bad luck for us that they didn't get into the analysis. But this is what we set out a priority, and so we followed our own rules there. On top of this, 3 of the 24-hour urine sample were not collected properly. So redo samples were done, but they did not make it in time for this data analysis. Finally, 2 urine samples were not received by the laboratory. And this rounds up the 10 samples that were missing here. We've learned from these lessons, you could say, and we intend to do better for Phase III.

So when we come over to the next slide, Slide 22, and we have the 49 in the sample, and then we go back to an analysis related to the primary composite endpoint that we have -- where we have the 4 different element. Recall again, the study is potentially not so relevant now because the composite endpoint we have in Phase III is basically only the first 3 element and not the urinary because the 24-hour urinary is basically going to be an independent key secondary endpoint. And you can see that even when we do this analysis, we basically have 71% of the 35 subject meeting all the criteria for the response. And basically, also 14 subject have a partial response. I think that is pretty impressive because what we can see when you go over to the next slide is that all the subject benefit on the treatment. It's not like that. Basically I'm saying is that they are non-responder. No, they are not non-responder. They basically just have 1 of the element where they didn't hit the right value. And some of them you can see is basically extreme. There's 2 that have serum calcium of 8.2. And you can also see the 2 patients that are on 30 microgram, subject 4 and 5, this is, for example, the 2 subjects that will extremely benefit for having a higher PTH dose. They're just difficult to treat patient. You can also see some of the subject that still could benefit it, like subject 9, that is taking still 18, could still be in a position you can increase the dose. You can see that for some of the subject, which should continue to get an increased PTH dose, and you will see a benefit of that. First of all, one of the thing that is not being happening here, none of them was optimized to any other parameter than basic serum calcium. That was the key titration for increased PTH doses. We do not know still, and we're still learning a lot from all this data. With an increased PTH dose-independent arm serum calcium actually will have a more positive take on 24-hour urinary calcium. We don't know that either. But we're learning still a lot of data. Going to the next slide is basic our quality of life. And I think when I look on Slide 26, you can see all the different domains. And in the [ 2n ] growth, you can see the summary score. And what we see then from the baseline that all of them are lower than normal. Remember that 50 is the norm to a normal population. I don't want to go through all the data, but I think it's really showing a continued improvement from 4 week to 6 months. We see better and better quality of life and improvement over time. Just illustrate the benefit of the TransCon PTH treatment. Slide 27 and 28 are basically showing us our bone markers. We took that snapshot on our bone markers even if we know that this is a process that continue over long time. We look forward to see the bone markers after 12 months, 18 months, where we basically believe we will have a much more stable system. But from the initial look on of our bone marker, we see -- specific, if you look on Slide 28, we see what we expected to see, an increase in the CTx, which are reflecting an increased bone turnover related to the non-anabolic effect. And what we see with P1NP which are basic anabolic bone marker, we actually see much less increase. That is what we will expect to see out from at-patient that's getting over and start an increased bone turnover. Remember, HP patients have at their low level of both P1NP and CTx in their disease. Meaning is that when we increase them to a higher level, we still will be operating into what we call the normal landscape of bone markers. But what is important to see out of our data that we're not getting a shoe's boost in the anabolic bone marker because that is not what we want to see. That is typical what you will see in an osteoporosis treatment, where you want really to address the anabolic bone marker and increases much, much more than the catabolic bone marker like CTx. More to come. The Phase III design, Aimee will go through how we're working on our Phase III design.

So our Phase III design is -- this trial is going to be called PaTHway. You can see here it's going to be a double-blind, placebo-controlled trial with an open-label extension period similar to our Phase II. The main difference here is that the placebo-controlled blinded period is now 6 months rather than 4 weeks. And hence, we've spent a lot of time discussing our 6-month data from Phase II as we intend to look at something similar in Phase III. I will emphasize that Phase III represents a different data set of subjects, so it's the distinct recruitment process for a distinct group of subjects in this trial. We plan to enroll approximately 76 adults with chronic hypoparathyroidism, randomized in a 3 to 1 fashion to TransCon Parathyroid Hormone versus placebo. You may notice that the 76 subjects represents a slight increase from what we may have said before, and this is to ensure evaluable data for 68 subjects. The design here, you see, 2 arms, as mentioned before, 3 out of 4 will be randomized to active TransCon PTH at a starting dose of 18 microgram, and they will be able to titrate right away. They will not be fixed. And they will follow an algorithm that we have designed, learned from our experiences in Phase II. And they will be blinded until week 26 when the primary endpoint is being evaluated. 1/4 of subjects will be randomized to the placebo arm and similarly follow a sham titration scheme. The primary objective, as before, is the confirmed treatment effect of TransCon Parathyroid Hormone in adults with parathyroidism. You see here the key eligibility criteria and the countries planned, which are North America -- in North America and Europe. The primary triple composite endpoint at week 26 will be the proportion of subjects with a normal serum calcium, as defined by our central lab, that is 8.3 to 10.6 milligrams per deciliter, and also have independence from vitamin -- active vitamin D, that's calcitriol or alfacalcidol, and demonstrate independence from therapeutic doses of calcium supplements. Our selective secondary endpoints at week 26 that will -- that we're showing here on this slide will be the proportion of subjects meeting all those 3 endpoints I just mentioned, the triple plus the fourth one, and that is with the urine calcium, the 24-hour urine calcium excretion being normal or at least a 50% reduction from baseline. We'll also look at CRM phosphate levels. And 2 measures of patient-reported outcomes, including a disease-specific one called the Hypoparathyroidism Patient Experience Scale, we call it HPES here, and also a well-validated general patient measures that is the SF-36. The long name is 36-Item Short-Form Survey.

Thanks, Aimee. So last slide, I would like to, first of all, thanks a lot all the people that have been part of this trials, the physician, the patient and everyone that had contributed to it. Has been a major achievement in the circumstances that we are living on now. But we really have seen the benefit to the patient. And when we look on the hard-core data, which some way are part of it, but also the patient stories are such an important part of why we're doing what we're doing. 86% of the subject had a normal serum calcium, off activated vitamin D and taking less than 600 milligram per day of calcium. Yes, that is really unique when we look at that data. 71% of the subject achieved our composite endpoint, as we talked about, which consist of the 4 independent elements. We see the improvement on all summary and subdomain of the SF-36. This is all our preliminary Phase II data, but all of them are supporting the continued flow of data that is providing -- that we really are providing TransCon PTH and our hormone replacement. What is the step forward? Just to remind you, what we have discussed with regulatory agencies is not all this data target that we have given you today. This has now been discussed with regulatory agencies. Dana and her team are working dedicated with rest of clinical development and many other people to ensure that this pack as fast as possible will come out to regulatory agencies. But all our 6-months data, our SF-36 data from the double-blinded 4 weeks have not been discussed with regulatory agencies. The design and the PaTH Forward we have now is all built on the 4-week double-blinded period. And we are a global-thinking company. We're thinking about reaching the patients everywhere under the globe. We have a overall global clinical strategy for TransCon PTH and that is building on a Phase III trial in Europe and U.S. because we know that is the way we can do it extremely fast. We will have an independent trial for Japan and independent trial for Greater China. And the PaTH Forward trial that's built with regulatory interaction after the 4-week double-blinded period is a 76 patient adult trial where the primary endpoint will be as Aimee described. And we already have filed the IND for this, so we already are initiating the trial now. And we expect very soon to also imitate it and file the application in a few European countries to ensuring we also get the sites in Europe activated. I thank you a lot for your continued support and discussion. And now we open for question.

[Operator Instructions] And our first question comes from Jessica Fye with JPMorgan.

I have 2. The first one is, can you help me think about, on an ITT basis, with the patients who started the extension, how many of those would have met the primary endpoint planned for Phase III? Exclusive from Slide 15, you had 53 patients of vitamin D and calcium on -- on vitamin D and on calcium doses up to 500 milligrams. And then later in the slides, you say 86% of subjects meeting the Phase III criteria. If we just look at the -- maybe a simple [indiscernible], what's the numerator and the denominator in that 86%? And if it's not ITT, can you just tell us how many patients which the number of patients who would have hit the Phase III endpoint here?

So [ exiting ], yes, this is some of the question that we -- when we have now all the data now, we basically give it out to the [ biosynthetic ] people. They're looking on all the data we have generated in our Phase II trial. And then if we need to make a lot of assumption, the assumption will be is, if we basically have the same patient group and other things like that, and this is where we're coming out from this assumption that having this patient population that we have in our trial, we are extremely well powered for success. And if we -- some way -- and there's a lot of assumptions we are using there. And I actually believe that if we take the 60 -- 600 milligram, we will actually have something like 45 of the patients of the 49 being actually hitting this primary endpoint. But I have to say, that is a calculation where we use -- basically there are a lot of assumption for this kind of calculation. And I actually believe that this is -- meaning is that we will some way from that thing, we believe that we have the same, you can say, patient population that we basically will have in the Phase III trial.

Okay. And then the second question relates to the -- against the endpoint you're using in Phase III that doesn't have urinary calcium as one of the components of the primary endpoint. It seems pretty clear that you're well positioned on the primary endpoint that is written. But given the feedback from physicians that urinary calcium is important to them, I'm curious if you think that your urinary calcium data can get on the label if it's in the secondary endpoint?

I believe that is exactly what we are thinking about. We believe that is a key endpoint, but we believe that it's potentially much better bet with as an independent key secondary endpoint. And Dana, perhaps you can also reflect about the regulatory feedback we have got from U.S. and Europe about the difference between, is that a really efficacy endpoint or a safety endpoint.

Right. Yes. We had some interesting discussions with the agency about the use of the urinary calcium. And it was somewhat surprising to us when they told us, the head of the division at FDA, that they don't consider urinary calcium as an evidence of efficacy. And that it's really considered a safety endpoint related to potential consequences of high levels of calcium and phosphate in the urine, right, causing deposits and stones, et cetera. I think from our perspective, we looked at it as a scientific situation too, though that reducing calcium in 24-hour urine is a reflection of PTH's ability to recover calcium, in other words, get that exchange going back in the kidney. But from their perspective, they said they really only consider it as a safety endpoint. So that's what finally led us to eliminate it as part of the primary endpoint, but we still kept it as a key secondary with the primary, right? And then we also have it as a safety endpoint on its own. So we felt that, that was more what the regulators were looking for. And the other important aspect too was that we were approaching them about replacing standard of care, right? And since standard of care includes the supplements with vitamin D and calcium and having normal levels, we felt that, that composite is the one that proves the replacement aspect of it.

I think just from an overall view, we see removing standard of care with a normal serum calcium prove the component of replacement therapy. What you then see, what is the benefit of a replacement therapy? And there, you see a lot of benefit. One of them in urinary calcium, where you measure 24-hour urinary calcium. The other one is phosphate complex, which are also one indicator of long-term complication. Then you have the quality of life also as a major effect on having a constant PTH. So out from that point, we basically are some way analyzing and taking together our primary and key secondary endpoint in such a manner that we basically are reflecting the key element replacement therapy and then moving it out to the different element where you see the benefit of really having a key replacement therapy.

And our next question comes from Michelle Gilson with Canaccord Genuity.

Congratulations. So I guess to start out, could you help us understand how many patients had normal urinary calcium at baseline and how many were coming into normal range? And also, you mentioned previously, Jan, that a lot of these patients could have become responders had they been titrated perhaps a little bit more. And have you seen additional titration of dose in -- following the 6-month period and having patients maybe coming into the biochemical endpoint or the deposit endpoint that you're evaluating?

Thanks, Michelle. Really great question. This is something we really had looked a lot because we really believe that the 24-hour urinary is really one of the key differentiator we have seen. And Aimee will just summarize our analysis what we have achieved here.

Sure. So, Michelle, at baseline, to your question, 41 of the 59 data points reflected a high urine calcium at baseline. 9 were normal at baseline, 9 of the 59, and then 9 of the 59 were missing for those reasons that I had explained before during the presentation. So depending on how you -- what denominator you want to use, it's the numerator for the folks who had a normal urine calcium at baseline which is 9 and the denominator is either 50 or 59. It's 18% to 15% have a normal urine calcium at baseline. And then you had a question regarding Slide 23, correct? About what we might expect to see when some of these subjects are able to titrate up higher on their parathyroid hormone. So this is a good example of harnessing what we learned from Phase II and taking it forward to Phase III as we would want to do with trials such as this. So we previously thought 30 micrograms might be the ceiling dose. We are now realizing, as you can see from subjects 4 and 5, is that right? 4 and 5, yes, that they would likely benefit from a notch or 2 higher. So we have made a protocol amendment for this trial. And once that amendment goes through and it's approved by the ethics committees, these subjects will be able to go one notch higher and continue as needed. Similarly for subjects 10 and 11 that you see there on Slide 23, they have -- well, at least subject 10, that subject is hanging out there because of urine calcium her -- urine calcium -- sorry, her serum calcium is normal, right? And the titration algorithm, as read by the investigator, did not guide her to further titrate downwards on the calcium and upwards on the TransCon PTH. The new protocol amendment will make that more clear so that there's clear encouragement to keep titrating up on the TransCon PTH, with the goal to demonstrate that you can eliminate all oral tablets. It's just we needed to make that a little bit more clear.

Okay. And just to follow-up, in the Phase III design, could you maybe more specifically talk a little bit about how some of these learnings made its way into perhaps that 10-week titration algorithm? How some of the -- maybe some of these challenges have helped you to, I guess, be more specific about these things? And then also on the design was -- I noticed that in the endpoint, you had -- you're using 600 milligrams of calcium. Could you maybe describe why that changed a little bit? And also, on the powering in the 4-week analysis, previously, there were some placebo responders. What would you expect or what would you expect for that placebo arm as far as those response rates to this endpoint as well?

So Michelle, there was a lot of questions. Let us try to take one by one. But I'll start with the funny one, about the 600 instead of 500. Aimee can talk about the tablet side.

Sure. So this was mostly driven -- absolutely driven by the recognition that the most common calcium tablet available in the United States and also Germany, where we also have a site, is a 600-milligram tablet rather than a 500-milligram tablet. For instance, what you get at Costco, the Kirkland brand calcium carbonate is a 600-milligram tablet. So we didn't want people who are falling in between 500 and 600 just because they were taking 600 milligrams to miss the endpoint. When we actually looked at our Phase II data, we only -- a sensitivity analysis where you take 500 versus the 600, we only lost 1 person, but we thought this was a safer bet to -- recognizing that this is the common calcium tablet available in some countries at least.

Related to the placebo response, Michelle, I actually think that we -- someway, when we look on the larger data set, we have different ways to assess that. We can, for example, go out and look on the REPLACE Phase III trial, where they had a complete different composite endpoint. They had a serum calcium that was down to, as I recall, 7.6, for activated vitamin D, where should only be in a position where they should get 50% reduction. For calcium supplement, they should only get 50% reduction from that perspective. And as I remember is there was only a few presenters in that trial with a -- even on this very, very, you can say, different compositive endpoint, which are much, much, much more easier to hit that basically were being positive in the placebo arm.

And our next question comes from Joseph Schwartz with SVB Leerink.

I'm Joori dialing in for Joe. The first one has to do with Slide #21, can you provide [indiscernible] will not prepared properly in the 2 subjects whose urine samples are not [indiscernible] did they meet 3 other endpoints?

So I only heard the last part of the question where you asked about the 2 urine samples that were not received by the laboratory. So I don't know -- we don't know what their urine endpoint was, but were you asking how their calcium, serum calcium, for instance, and how they did on the oral supplement?

Correct. That's correct. Yes. So like on Slide 23, for the second bullet, for example, you kind of list out how they've gone on like vitamin D and calcium supplement and serum calcium, but you haven't done that for the 3 patients and the 2 patients. So I was just wondering if you could just characterize a little bit more.

We're looking. I think -- we are looking at some of our data.

In the meantime, I could ask you another question. Would that be okay?

So what we can tell you is that everybody on that list on Slide 21, did meet the endpoint of independence from active vitamin D and taking less than 1,000 milligrams of calcium. We'd have to do a little bit of digging to find what their calcium dose was below 1,000 mil.

Okay. Great. And then my next question has to do with the bone turnover data on Slide #28. So it appears in the beneficial efforts for patients who typically have high bone density to undergo more catabolic bone turnover than less and less anabolic bone turnover, as you've shown with TransCon PTH. However, is there a point at which you need to kind of kick off the brake with chronic use with TransCon PTH? Or do you think that the physiologic levels of PTH that you provide with TransCon PTH could kind of stop auto-correcting and the bone tends to normalize with longer use?

Yes. That was exactly the point is that we now currently have 6-months data. What we expect to see with the 12 months data, 18 months, that you basic will see that in an HP patient, the skeletal has been basically been sleeping with a very low bone turnover. So what do you expect to see that the skeletal will go to a much faster remodeling. And this remodeling, you will basically see that bone turnover potential plateau up. We expect that potential. We already have seen that for the CTx. And then we expect potential, it will go downwards for the 6 to 12-month point, but we still need to see that data point, and this is what we have seen. But what we basically have seen now from the bone turnover, we have seen the exactly the expected effect we have very low amount of P1NP, the anabolic bone marker compared to the catabolic bone marker from the perspective is that we just see the expected normalization of bone turnover. And this is one of the benefit you get of this treatment here. One of the huge benefit of you're getting of this treatment, that you're normalizing the bone structure and not have the, what we call the old bone density, which are higher, but it's not in a positive high manner in this way.

We did manage to ...

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