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

Welcome, everyone, to Ascendis Pharma's Virtual R&D Program Update. We are live from sunny Copenhagen here today. I'm Scott Smith, Chief Financial Officer of Ascendis Pharma. Today, as expected, we'll be making some forward-looking statements. Actual results may differ materially from these statements. Please refer to the associated risk factors on our Form 20-F filed with the SEC and our other SEC filings. Today, in our action packed agenda, after I finished my very long part here, I will turn it over to Jan, who will give an overview of Ascendis for new investors as well as some opening comments. We have a great agenda running through 3 clinical stage programs -- 3 out of our 5 clinical stage programs. First, in endocrinology rare disease, we have TransCon PTH and TransCon CNP. And then we'll move over to oncology with our first-ever data from TransCon TLR7/8 Agonist. We'll then conclude with a question-and-answer session. [Operator Instructions] Before I turn it over to Jan, I just wanted to say thanks for all the colleagues that have really got us to where we are today, put in a ton of work on this presentation, some of whom you'll hear from and some of whom you won't hear from. But I really wanted to extend an appreciation of all of our colleagues who made this possible. Thanks also to Art for putting together the presentation and doing the best he could to get an entirely new wardrobe for Jan. And yes, with that, I'll turn it over to Jan.

Thank you, Scott. It's a pleasure to be here in Copenhagen. And why? Because Ascendis Pharma, we got founded here in Copenhagen in 2007. We have progressed to the last year with developing Ascendis Pharma to the next stage. And I'll give you some perspective where we really want to develop Ascendis Pharma to. For some of you that don't know Ascendis Pharma too well, I would like to give a few background on Ascendis. We got public traded on NASDAQ in 2015. This is the only place we are public listed. And all the product opportunities you will hear about today and all product opportunities that has been developed by Ascendis Pharma is built on the TransCon technology. And all of them are fitting our specific algorithm for product innovation. It had been through this combination of the TransCon technology and the Ascendis algorithm for product opportunities that we have developed a late-stage pipeline in endocrinology rare diseases. We have now got the first approval for SKYTROFA in the U.S., and we are progressing with the rest of the pipeline. Today is really a big moment for us as a company because one of the keystones as you will listen to later on in our Vision 3x3 is moving from one [indiscernible] to the next one, and we will present data for first time on the oncology pipeline. So our mission is pretty clear and have been the same as you always have been listened to when we have been talking. We want to address unmet medical need. Our values is really on the patients. And what you will hear today as always how we are deeply involved in the science. The science is how we really build product opportunities, understand and differentiating us to everyone else. And the passion you have seen the passion, even with Scott, how we're moving forward. So I don't believe in brand on process. I believe you need to have a strong vision because people know -- need to know where they need to go to really be successful. You don't climb mountain ever as because you take a wrong mountain. You climb it because you're dedicated. And we want to build a leading globe biopharma company. And that is what we want to execute to our Vision 3x3. This is our strategic vision that we want to fulfill in 2025, and we will get it through to sustainable growth through multiple approaches. That has been our theme. And you can see the first cornerstone in our Vision 3x3 is to get TransCon Growth Hormone approved for pediatric growth hormone deficiency. When we made this vision in end of 2018, disclosed it to you in January 2019 at the JPMorgan conference, we had some prediction, and we achieved exactly what we had hoped for, being in a position that we got our first product approved this year in 2021. And we're also moving forward to the next approval, TransCon PTH for adult hypoparathyroidism, and you will see some updates for -- also for CMP for achondroplasia today. So you can see we have a pipeline approach be below in economy of scale. We believe in synergy. We believe we need to have strong pipelines. But we also have a concept that was built on vast rare diseases, where we believe we also can make high value for everyone. We want to grow our endocrinology rare disease pipeline through global clinical reach. You will hear about that today. We do label expansion, we do life cycle management, and we're also looking on new endocrinology products. We have established our first global commercial presence in the U.S. We have a commercial organization being run out from Princeton that really today are selling SKYTROFA in the U.S. We will have a global commercial reach. For example, in Greater China, we do it through VISEN Pharmaceutical, and we will be a global presence in rest of the world. Today, you will hear about this single line advanced high-value oncology pipeline. And I like this is the step for the new therapeutic area. So when you come later on, you will see our new vision, you will see that oncology at least will fulfill exactly the same amount as the rare disease endocrinology. But we're not stopping there. We are going to win next pipeline, too. This is as a snapshot of our pipeline. And you can see we have 5 independent product opportunities. We have 3 in rare disease endocrinology. And you can see the first one, the most advanced one is TransCon Growth Hormone. And you can see we go for the first FDA approval, and we have a positive opinion in Europe and we're doing global reach and life cycle management through label expansion. TransCon PTH, you will hear about today. TransCon CNP, you will also hear today. And today, you will hear about TransCon TLR 7/8 Agonist. But not at least, we're also starting with TransCon IL-2 beta gamma. We expect it will be best-in-class IL-2 product, and we're looking forward to move this as fast as possible into patients. I will now move over to Aimee Shu that will give a clinical update about TransCon PTH.

Thank you, Jan. Hello everyone out there. As Jan said, I'm going to spend the next 20 minutes talking about the TransCon PTH clinical program. In the next bit of time, I will review hypoparathyroidism, its associated symptoms, conventional therapy and what an ideal hormone therapy would look like. From there, I'll walk into the Phase II trial results, give you a little bit of a glimpse of our Phase III trial and close it out with a discussion with one of our investigators, Dr. Aliya Khan. So let me take you to the next slide. Hypoparathyroidism, as the name implies, is a deficiency of parathyroid hormone and also a second hormone called calcitriol. It's associated with abnormal homeostasis of calcium and phosphate throughout the body, neurocognitive symptoms and the diminished quality of life. To understand it, we should also understand what an intact PTH access does normally. So on the right-hand side of the screen, I show you what an intact PTH access would do. So at the top, you see the parathyroid glands. When they release parathyroid hormone, it reaches bone and kidney for instance, directly. At the level of the kidney, PTH helps catalyze the transition of calcidol over to calcitriol, which is in its own right a downstream hormone also called active vitamin D or 1,25-dihydroxyvitamin D. This hormone has its own direct effects at the bone, kidney and intestine. Together, these 2 hormones work to maintain normal levels of serum calcium and phosphate. We like to say that hypoparathyroidism is the last classical hormone deficiency for which complete hormone replacement has been elusive. Now let me take you through some of the multiple organ systems affected by hypoparathyroidism. There are many here and besides the neurocognitive problems that I alluded to before, as you can see here, many other organ systems are affected, either directly from the disease hypoparathyroidism or as secondary complications from the conventional therapy, calcium and calcitriol that are needed to take it. So you can see here the heart, the nervous system, the kidney and the skeleton are all affected. There are many causes of hypoparathyroidism, among them acquired ones and inherited etiologies. On this figure, I show you what, 146 respondents to the voices of hypoparathyroidism survey told us as their -- or told the Hypoparathyroidism Association reported as their etiologies for hypoparathyroidism. As you can see, characteristics of adults, the vast majority, generally 80% to 80% of patients get to hypoparathyroidism because of a complication after a neck surgery. The other remaining ones are from oftentimes genetic or infiltrative diseases or idiopathic if a cause cannot be found. This is the case for adults. For children, the proportion -- the relative proportion due to genetic causes would be greater in this case. I show this pie chart because these respondents happen to report a very similar proportion to what we've seen epidemiologically across the globe. On the right-hand side of the slide, we show the time to diagnosis. And as you might expect, when the etiology is postsurgical, the diagnosis is relatively -- occurs relatively sooner because there's an index event. On the other hand, when it's nonsurgical, especially if it develops later in life and is from an infiltrative disease or an idiopathic or an autoimmune cause that is not present at birth, it can take a lot longer to diagnose. Hypoparathyroidism does qualify as an orphan disease and we have received orphan designation in many geographies. However, among the rare diseases, it is still relatively common. The estimated prevalence across these 5 global regions is about 400,000. Now I turn to conventional therapy for hypoparathyroidism, which targets the symptoms, but not the underlying disease. On the left-hand side, we show the active vitamin D, or calcitriol, as I discussed on the early parathyroid access slide. The reason that patients have to take this is that endogenous production of calcitriol is diminished in the face of insufficient PTH. On the right-hand side, we show calcium tablets, which are required to keep the serum calcium high enough to prevent symptoms. At the same time, these patients often require a very high pill burden, 9, 10, 20 tablets a day to reach their needs. I will say that this conventional therapy, although it attempts to keep these patients out of trouble and to prevent immediate symptoms and immediate visits to the emergency room or the hospital, it fails to restore normal PTH physiology and in fact, introduce the secondary complications in the long term. So it fails to normalize skeletal dynamics. It fails to improve a diminished quality of life., And then through these conventional therapies that increase the filtered load of calcium through the kidney, these patients are subject to a higher risk for developing kidney stones, nephrocalcinosis which is calcification of the soft tissue of the kidney and chronic kidney disease. We think there's a better way, and so this slide shows goals of an ideal therapy. On the far right column, we show what an ideal therapy, in our minds, would do compared to the middle column called the untreated hypoparathyroidism column, where you see what the derangements are in the metabolic and health markers. So to summarize here, the ideal therapy would be able to keep serum and urine biochemistries in the normal range, help the patients gain independence from those conventional therapies I showed you before, normalize skeletal health and skeletal dynamics and normalize quality of life. That is what we set out to do. This is a rational design of TransCon PTH, which was selected and designed to be a hormone replacement therapy. So everything was selected from the PTH hormone that we're trying to deliver to the half-life in which it is released and the pharmacokinetic profile. So this, as you recognize from before, is a prodrug on the left-hand side. And once injected into the body, the active PTH represented in the orange helix here is released and able to access the receptors around the body. It was designed, as I mentioned, to be a sustained prodrug to give physiologic levels of PTH throughout the day. Here, we took the drug into a Phase II trial. This is called the PaTH Forward Trial and the study schema is shown here at the top. During the first 4 weeks, the patients were randomized to 1 of 4 arms, 3 of them being fixed doses of TransCon PTH and 1 of them being placebo. We did our primary analysis at week 4, and we have previously shared that data. After week 4, everyone was transitioned to open-label TransCon parathyroid hormone and progressively titrated to a dose that was optimal for that individual, meaning achieving normal serum calcium in absence of symptoms. On the bottom, I show you the time line. It goes through weeks -- week 214, so it is still ongoing to this day. And we are -- everybody has passed week 84 at this point. So today, the data presentation will focus on data we have collected a week up through week 58 and week 84. So here's the first slide with the biochemistries. On the left-hand panel, you showed -- we showed the mean serum calciums for this population through week 84. As you can see, the normal range is highlighted there in the blue that therapy with TransCon PTH has allowed these patients to keep their serum calcium in the normal range this entire time. On the right-hand panel, you see what happens with urine. At baseline, as expected, these patients excrete excess calcium in the urine. Oftentimes, it's called dumping calcium into the urine, and it increases their risk for long-term complications. After exposure to TransCon PTH, the average urine calcium normalizes to well below 300 milligrams per 24 hours, and that effect is sustained as you can see, through week 58 and week 84. And this is all the while keeping the serum calcium also in the normal range. What happened to conventional therapy? So for active vitamin D, the patients were able to come off of their active vitamin D relatively early, everybody by week 6 you see here and remain off. The purple and blue lines represent the placebo arm initially and those initially randomized to the TransCon PTH active arm. The green line here represents everybody in the open-label extension period. With calcium a similar image here after everybody was an open label, they were able to keep their doses compared to baseline very low. Most -- the majority actually were able to stop therapeutic doses of calcium. And out here at week 84, you see here that the mean dose among patients is 400 milligrams per day. Stated another way, I can tell you that 93% of subjects in our trial have been able to become independent from conventional therapy, as defined by being off of calcitriol or alfacalcidol completely and requiring no therapeutic doses of calcium, that is no calcium more than 600 milligrams a day. Now we turn to the next few slides to the story about the skeleton in hypoparathyroidism. There are quite abnormal skeletal dynamics, and this figure serves to show that. It is a figure of an iliac crest biopsy, the iliac crest being here at the upper back of the hip under micro CT scanning. On the left-hand side, this shows hypoparathyroid bone. It approximates a chunk of cement. The trabeculate, which are those strands, the plates and rods that you see going downwards in left right are abnormally thickened compared to healthy bone which you see there on the right, which has a spongier look with open spaces. The lack of PTH-driven skeletal remodeling, also called bone turnover, results in this abnormal bone structure and may be associated with poor bone quality and increased risk of fractures. In our Phase II trial, we collected serum markers of bone remodeling. These serum markers on the left-hand side is called procollagen type 1 and pro peptide P1NP. This is an anabolic marker. On the right-hand side is C-telopeptide, which is a catabolic marker. And together, they are oftentimes paired. On the left-hand panel, you see again, purple and blue being during the first 4 weeks when they were in the blinded phase and then green being everybody once they were on open label. You see that upon initial exposure to TransCon PTH, the bone turnover increases initially and with time, the bone turnover falls and trends into the normal range. I don't have the normal ranges here shown to you because they differ by sex and age. But what I can tell you is that, for instance, if we look at the P1NP figure on the left-hand side, that the lower limit is usually 30 to 50. So we start on the lower limit with the hypoparathyroid patients. And the upper limits are around 90 to 100, depending again on age and sex. Bone density was measured by a DEXA scan, which stands for dual x-ray absorptiometry. It's like a low-exposure radiograph. And what happens here, you can see over time is that the bone density at baseline for these patients is markedly increased above what would be expected for age and sex. We're presenting Z scores here. And Z scores typically imply that you -- the normal average person would have a score of 0.0. Somebody below normal, below average would have a negative number, and somebody above average would have a positive number. So for instance, here in the lumbar spine, what you can see is these patients start out with higher than average or just at the top of the average -- top of the high average bone density as reminiscent of that block of cement I showed you earlier -- a few slides earlier. At weeks 26 and week 58 after exposure to TransCon PTH, this bone mineral density starts to come closer to 0. So we see this as a trend for normalization. And now to put it together in this slide, the interesting observations that we have made across the program with having to do with the skeleton and bone turnover. We move from left to right in this slide. And on the left-hand side, we have a cartoon of a woman whose bone here in magnification is quite thick. The trabecular are thick. It's again reminiscent of that block of cement. In hypoparathyroidism, the rates of bone turnover are lower than normal, as we mentioned, and this results in above-average bone mineral density from this accumulated old bone. Upon exposure to PTH in the middle panel here, what we see happening is that the skeleton mobilizes the excess calcium and bone turnover increases. In the blue bars, I'm showing you the same data I just showed you on the slide before, Z scores of the lumbar spine initially higher than 0.0 and making its way down towards 0.0 over time. In the orange line, we show what happens to TransCon PTH doses over time. And you can see there's a slight increase, and this is what we see in our trial as well. So over time, as the rates of bone turnover normalize and the reservoir of bone approach is a more healthy bone, as you can see here in the cartoon woman on the right-hand side of the slide, and we think that this implies that a higher PTH exposure may now be required to enhance the calcium-promoting activities from those 3 important organs: the intestine, kidney and bone. No summary would be complete without a safety slide. And so here is the safety profile so far in this Phase II trial. Treatment-emergent adverse events continue to be mostly mild and mostly unrelated. And importantly, there have been no hospitalizations, urgent care visits or emergency room visits due to treatment-related hyper or hypocalcemia. And no one has stopped the drug or the trial because of an adverse event in this trial. And finally, well, to summarize the Phase II results here, 58 out of 59 subjects remain in the trial beyond week 84, and in fact, up through today. So we have excellent retention. At week 84, 93% of subjects are independent -- were independent from active vitamin D and therapeutic doses of calcium. And as we showed, the mean serum and urine biochemistries continue to be in the normal range. Through week 58, when we last measured them, the markers of skeletal health that is bone density and markers of bone turnover continued to trend toward normalization. Symptoms, impact and health-related quality of life continue to be improved from baseline, and the majority of adverse events have been mild and unrelated. No urgent or emergent visits or hospitalizations related to hypo or hypercalcemia have been reported so far. And now I'll give you a teaser of the Phase III trial. It was designed to be very similar to our Phase II, if slightly bigger, includes more patients and the blinded period is longer. So instead of 4 weeks now, it's 26 weeks. Baseline characteristics here are very similar to what we saw in our Phase II trial and indeed similar to what we understand is the demographics of the disease across the globe. We ultimately recruited 82 subjects into the trial. You see there the mean age is 49. The majority are female, 2/3 from North America, 1/3 from Europe, and the average duration of hypoparathyroidism has been 12 years. 85% of them reported postsurgical etiologies of their hypoparathyroidism. The patients recruited to this trial also reported diverse etiologies beyond post-surgical. So you can see here the pie showing the 15% remaining ones include some genetic ones and also idiopathic forms. So in closing for my section of the TransCon PTH clinical program, I can share with you that we're excited to see TransCon PTH positioning itself as a potential new treatment paradigm for hypoparathyroidism. It has the potential to be the first hormone replacement therapy for hypoparathyroidism, addressing the major unmet medical needs for a large rare disease patient population. I'd also like to share with you some of the exciting things happening in 2022 as we look ahead chronologically and they're shown in this list. We expect to see Phase III pathway trial top line results Q1 2022, and that's from the teaser I just gave you. We plan to submit an NDA Q3 2022. Our PaTHway JAPAN trial will report top line results soon, and we're expecting those Q3 of 2022. We'll plan to submit our MAA submission Q4 2022. And also we'll be initiating a pediatric hypoparathyroidism program to expand the indications for -- in Q4 2022. And now I'd like to introduce one of our treasured colleagues and investigators in the phase -- in our Phase II and III programs, Dr. and Professor Aliya Khan, who's going to share with us 3 patient stories from the Phase II trial. Hi, Dr. Khan.

Hi. How are you doing, Aimee?

Great. Thank you for joining us from the East Coast today.

Thank you. It's really my pleasure. So I was going to go ahead and present the case reports of 3 patients that we chose for differences in gender and age of presentation. And if you can give me my next slide, please. So just a little bit about me. I'm a professor of clinical medicine at McMaster University and the Director of the Calcium Program and the Fellowship in Metabolic Bone Disease. And we have the only fellowship program providing 1- and 2-year fellowships in Canada. And we train future metabolic bone disease experts for Canadian universities and also for international universities. So we really do have a flagship program. I trained at the University of Ottawa. I did my medical school there, and my postgraduate training was in Toronto. And my area of research really has been parathyroid disease. And at our Calcium Disorders Clinic, we see a wide range of complex patients referred for difficulties with diagnosis, difficulties with management, and then we will evaluate them and send them back to the referring physicians. Our work has been recognized both nationally and internationally. And my focus has been on trying to improve the quality of care that we're providing in Canada but also on a global basis that we're working very closely with international leaders in parathyroid disease from around the world. Next, please. These are my disclosures. So I have received research funding from a number of the industry partners, developing new molecules for parathyroid disease. And I've also been involved in leading educational initiatives and guidelines nationally and internationally. Next, please. So our calcium program was actually established at St. Joseph's Healthcare in Hamilton in 2005, and it is a Center of Excellence for the diagnosis and management of complex calcium disorders. So we are a tertiary referral center and we would receive patients who have already seen an endocrinologist. And they are complicated in terms of their diagnosis, what is the underlying cost for their hypoparathyroidism, are they having wide fluctuations in calcium, do they have significant complications and that endocrinologist has kind of reached the end of the options that they can offer to that patient, so they would reach out to us and say, "Can you give us some tips, how can you help us out in this particular patient's care?" We're also involved in clinical research, and we've been involved in developing new molecules for parathyroid disease. And we also have the Canadian National Hypoparathyroidism Registry. So we actually have every single patient who had hypoparathyroidism that has been referred to our center or we've been asked to evaluate and contribute in terms of the management. We have a record of all of these patients. And many of my colleagues are also referring patients so that we can accumulate this data and to get a better understanding, enhance our knowledge of how does this condition present, what are the complications and what are the best treatment approaches so that we can reduce long-term complications of hypoparathyroidism. And we've recently published data describing patients -- these are real-life patients. What's happening to them, what are their complications like. And we've described the presence of, for example, basal ganglia calcification, calcium deposits in the brain that can have an impact on daily function and also on complications such as seizures and decline in cognition or the ability to think clearly as well as the renal complications that you saw eloquently described, chronic kidney disease is a major concern. Our patients can get kidney stones. They can also get calcification of the renal parenchyma, as you mentioned. So we want to avoid these complications. We want to preserve renal function. We want to preserve brain function. We want to improve the quality of life day to day, so that we can improve their ability to participate in society as contributing members of society and lead healthy, happy lives. That's our goal. So we've been involved in evaluating a number of different molecules. And I've also been involved in various new molecules, not just for hypoparathyroidism, but also for hyperparathyroidism. I'm also responsible for educating medical students, residents and fellows. And I'm really pleased to say that our fellows have been recognized by international awards. And recently, this year, one of our fellows was recognized by ASBMR and won the Young Investigator Award as we described as K Series of Barricade syndrome, which is a rare cause for hypoparathyroidism. And next, please. So one of our patients is a 57-year-old man, and he has a history of parathyroid disease. He had a growth in the parathyroid gland resulting in overactive parathyroid function, and he had to have that removed. And at that time, he also had the total thyroid removed as well. And this was in 2015. But unfortunately, due to surgical complications, he was left with absolutely no parathyroid tissue. Now parathyroid hormone is essential to bring that calcium into the normal reference range. And if we don't have parathyroid tissue, then the low calcium will cause death because every cell in our body needs calcium to function. Our heart needs calcium, our brain needs calcium, our muscles need calcium, and our nerves need calcium, every single cell in our body needs calcium. So how do we treat these people? We have to give them calcium supplements. And as you mentioned, not only do they not have parathyroid hormone, but they also don't have active vitamin D because active vitamin D is formed by the action of PTH. So we have to give him active vitamin D and we have to give him calcium. And our patient was taking high doses of calcium and active vitamin D, and he had wide fluctuations in serum calcium. So when he would work and his muscles would use up calcium and his calcium would go down and he would end up and emerge. And then they would give him more calcium and more active vitamin D and they would normalize it, and they would end up giving him more than he really needs. He would go out into the community and his calcium would be too high, and a high blood calcium will cause dehydration, go into shock, end up back and emerge. And it actually took him 1 year to get to see me because every time he had an appointment, he was in hospital, either his calcium was too high or the calcium was too low. And I call this the calcium roller coaster. And it's horrible. It is absolutely most unpleasant and it can be lethal. A person can die if the calcium is too high, and a person can die if the calcium is too low. He used to work as an automobile painter, but he could not work after he developed hypoparathyroidism. And we offered him the option of enrolling into the study, and he was ready to do anything. He said, "Please help me." So next, please. So prior to the trial, as I mentioned, he would have muscle cramping. So when we don't have the calcium, the muscles can go into spasm. There can also be numbness and tingling in the face and hand and tetany where the hands and the muscles can go into a very significant spasm and rigidity. And he also had laryngospasm, and he wasn't able to breathe. They can also be bronchospasm. They can be cardiac arrhythmias. Many of our young patients actually present with a catastrophic event because nobody takes their symptom seriously, and they end up in emerge and may even die. So he had several admissions with hypocalcemia and hypercalcemia. And after starting PTH, his symptoms all resolved. We were able to give back the missing hormone. And because TransCon PTH has a long half-life of 60 hours, we were able to give him a stable level of PTH. So that his calcium was not fluctuating up and down, up and down. And he was able to actually go back to work. He was really a contractor at heart. And he told me, "I always wanted to build a house." And he actually went back into construction. He was never really in construction, used to just paint cars, but then he said, "No, I really can do physically demanding stuff. I want to do what my heart wanted to do all along." And he began to build houses. And he was actually able to participate in sports again, and he recently qualified for the golf tournament finals. So this is a life-changing treatment for this man. And we were really pleased to see him go from being an inpatient for the most of the year to being a really happy guy able to pursue his dreams. And we can see this, if you look at the HPES scale. So the HPES scale, the higher it is, that means that you have more symptoms. And prior to starting treatment, he had a lot of symptoms. He described these on the scale. And then after starting a TransCon PTH, you can see his symptoms dropped. And the HF 36 score tells us how well you're doing. And you can see that previously, he wasn't doing well on the mental component or the physical component. But after starting TransCon PTH, this scale was able to show a dramatic improvement in his overall wellbeing. And we saw that. I mean, the scales are numbers, but we saw this in his life. And it was really, really nice to see that it was very rewarding to be able to offer him such a significant improvement in his quality of life and his ability to function. Next, please. So here's his lab profile. And one of the problems, as you mentioned, Amy, was that if you have patients with hypoparathyroidism and they don't have PTH, there will be a leak in calcium through the kidney. And this leak in the calcium through the kidney causes calcium deposition in the kidney. And we want to drop that urine calcium. And we can see over here, if you -- I can't really point to the slides. But if you look on the right-hand side, the right upper graph, you can see that his urine calcium was high because he was leaking calcium through the kidney, and we were able to drop that urine calcium by giving him back PTH. So PTH reabsorbs calcium through the kidney, and we were able to drop his urine calcium. And if we look at the -- wonderful, thank you so much. Pointer from Denmark. If you look at the serum calcium, we can see that his serum calcium was really stable. And it was -- we were able to demonstrate that implementation of drug therapy. Giving him back PTH, we were able to achieve a stable serum calcium. The ups and downs were gone. The fluctuations in his serum calcium were gone. The loss of calcium through the kidney was gone. We're now able to reabsorb calcium through the kidney and maintain normal serum calcium. Every day, we filter 10 grams of calcium through our kidney. And we reabsorb 9.8 grams every day. But people with hypoparathyroidism, they can't reabsorb that calcium. So they lose a lot of calcium through that kidney and that's one of the reasons why we have to keep giving calcium and active vitamin D. Now if you look at the graph on the bottom left-hand side, you will see over here the phosphate, and his phosphate levels did decline with therapy. And if you look on the right-hand lower side, we will see the drop in active vitamin D and calcium supplements. And so we can see that he was taking large doses of calcium and active vitamin D. And when we started him on TransCon PTH, we were able to stop all his supplements. And that means a lot. If patients have to take pills several grams of calcium every day for breakfast, lunch and dinner, there's not much appetite left for your food. So his requirements dropped and he was able to just take his one dose every day and he was set. Next, please. Thank you. So here's another patient. As I said, it was a really rewarding study to participate in. And we've been involved in many, many trials. And I would say this was a really nice study because every patient did so well and came back with gifts. We'd get gifts from our patients, not just at Christmas, but pretty well at every visit. So this is patient #2. And this was a 62-year-old lady, and she was quite involved with the church choir, and she was an organist. She would also play the piano. And she had a goiter, and she had a total thyroidectomy done in 2012. And unfortunately, she also lost all parathyroid function and develop hypoparathyroidism and she was postsurgical. And as you described, Aimee, 75% to 80% of patients are postsurgical, but then we can also have hypoparathyroidism due to genetic causes or autoimmune causes. Next, please. Now she had daily cramps and numbness and tingling in the face and hands. And when the muscles cramp up, it affects your ability to function. So she was afraid to hold her grandchild because of muscle cramping. And after introducing TransCon PTH, it improved her energy, it improved her sleep. And to her, the most important thing was that it improved their ability to use her fingers. And the muscle cramping resolved because prior to entering the study, she had to stop the choir. She could no longer play the piano because of the muscle cramping. And so then she was able to go back to the choir. So that was a very important part of her life and also her ability to play with her grandchildren. That was a safety issue that she was concerned about. And that was, again, a very important part of her life. So a different person, a different family situation, different social situation, but again, life-changing. Can I have the next slide, please. So again, this shows us her serum calcium, the blue line against stability. We've lost the up and down. So we've taken away the fluctuations because TransCon PTH has a 60-hour half-life. It's like an infusion. It's like replacing the work of the parathyroid glands. You can see that urine calcium dropped and that's important to preserve renal function. It's critical to be able to do that. And we can see stability in phosphorus. Phosphorus levels also declined to some degree. And we can see -- again, she was able to stop active vitamin D and calcium. And that was very important for her as well. Because oftentimes, yes, you could take a pill in the morning, take it with your -- well, you're brushing your teeth, after you brush your teeth, take your medicine. But what about at lunch time? You have to remember to do this and you could be in a very busy part of your day and you might not be able to remember to do that. And if you don't remember to do it, you're going to pay a very heavy price because you could have a seizure or your muscles could go into spas them or you might have laryngospasm. So these are serious, serious consequences if you miss your medication. And it's important for individuals to not feel so dependent on medication to be able to function normally. Next, please. Here's another patient in a different social situation. This was a young lady, relatively young lady, 44-year-old female who was an operating room nurse. And she developed papillary thyroid cancer. She had thyroid surgery in 2016. Unfortunately, she also became hypoparathyroid. And what this meant for her is that she could no longer work as an operating room nurse. And we have to remember that when the blood calcium is low, we can't think clearly. And I tell my patients, if I had hypoparathyroidism, I would not be able to do my job. I need to have optimal functioning brain cells. And our patient could no longer be an operating room nurse. She was no longer able to meet the requirements of her job. Her calcium would be high. Her calcium would be low. She could never predict where her calcium would be. So conventional therapy has a lot to be designed, replace the missing hormone. It's like a band-aid treatment. So unfortunately, our patient had to leave her role as an operating room nurse. Next, please. Prior to the trial, she had brain fog. Brain fog is the way that patients will describe how they feel and they don't have clarity of thought. They can't think clearly. She had overwhelming fatigue. Our muscles need calcium. Without calcium, they don't work. She had headaches, the PTH has an important effect on the central nervous system, irritability, depression. And she really had to leave her position as an operating room nurse. And we offered her TransCon PTH. She would actually fly in from Eastern Canada to our center to participate in the trial. She's still in the trial. And her last, she was actually crying and she told me, "Dr. Han, you gave me my life back." And it really -- you feel so -- it's so rewarding to be able to see that and to be able to the impact on our patients. She noticed a dramatic improvement in her energy, her sleep, her ability to think clearly. And she actually was able to return to her work in a very demanding position as an operating room nurse. Let's see what she marked on her HPES score. So the HPES, again, as a reminder, is what are her symptoms. Her symptoms were significant. But after starting therapy, her symptoms declined. And her well-being, how well was she feeling, the SF-36, well, she wasn't feeling well. She had scores, which were lower than average. And then after starting TransCon PTH, her values improved. She's feeling better, both mentally and physically. Again, another life-changing situation. She's able to go back to work as an operating room nurse. Next slide, please. So what I have seen is that hypoparathyroidism has a dramatic effect on patients' life. They may not be aware of this prior to consenting to thyroid or parathyroid surgery. But it is really a major impact on their physical well-being, on their psychosocial well-being. Patients have to take 9 grams -- some of our patients are taking 9 or 10 grams of calcium. And it's very easy for the doctor to say, "here you go. Here you have to take 3 grams with breakfast, lunch and dinner." Well, do you know what that means? 3 grams means 6 calcium pills. So you take 1, 2, 3, 4, 5, 6 with water. By the time you've taken that, you don't have any appetite for your breakfast. And you have to do that at lunch as well and at dinner. And any time you have numbness or tingling because we don't have real-time calcium measurements available for our patients like diabetes patients can measure their glucose at any time at all times, but our calcium disorder patients don't have that luxury, so they have to rely on their symptoms. And if they don't take action, then they don't even have the assurance that they'll be able to think clearly to make it to the hospital. So they're living in constant anxiety and it's got a major impact on family. One of my young patients, 25 years old. He came home, and he saw his all his clothes and furniture and his belongings on the lawn. His girlfriend had thrown him out of the house because she didn't want to live with someone who had such a significantly impacting disease. So it affects families. And unfortunately, it can lead to divorce. It can affect a person's ability to be a good parent. It can affect the person's ability to function in society. And the pill burden is very, very dramatic and significant. I mean people can't even remember to take antibiotic pills. That's like a one pill a day. You can't expect people to take that many pills and to be able to function well. And these are real-life concerns for patients with hypoparathyroidism. And we really welcome molecules that can make a dramatic improvement on quality of life, on well-being, mortality and morbidity. And this is what modern medicine is all about. So thank you for your attention.

Thank you so much, Dr. Khan. I think you did such a nice job sharing with us, not only these individual stories and their patient journeys, but also the impact that reverberates, right, to those loved ones around them, including their family. So thank you. I think that really helped us see this condition in a very much more deep way. So at this point, thank you. I would like to turn the microphone over to my colleague, Kennett Sprogoe, who will discuss the science and biology of C-type natural peptide, CNP, as a treatment for achondroplasia.

Thank you, Aimee, and thank you, Dr. Khan. I think this is very clear to everybody what fuels the passion here at Ascendis hearing what kind of impact our medicines are doing. So I would like to shift gears here and shift our attention to one of our other rare endocrine programs, C-Natriuretic Peptide for the treatment of achondroplasia. Those of you who have followed us in this for a while, you are very familiar with our growth hormone deficiency program, TransCon Growth Hormone. So I would like to just pause quickly here and explain a little bit the difference between growth hormone deficiency and achondropasia because both are growth disorders. However, they differ significantly and particularly at the level of the growth plate. So if you think about growth hormone deficiency, this is a pituitary disorder where insufficient amounts of growth hormone are being secreted into systemic circulation. If we zoom in on the growth plate, we will see that this is actually normally organized. It is intact but it's missing the catalyst for producing longitudinal growth. The way you treat it as you have seen for our transient growth hormone asset is you replace the insufficient growth hormone at the correct level in the blood stream. And the effect that you see immediately is catch-up growth, and the patient start growing. For achondroplasia, it's a different situation because it's not a hormone deficiency disease. It's a mutation of a gene also found in the growth plate called FGFR3, leading to a constitutive active signaling pathway, which really puts the brakes on the growth. And again, zooming in on the growth plate, you will see it looks very different from a conventional growth plate and that, it's dysfunctional and it's disorganized. So what we want to achieve is to inhibit the hyperactive signaling by providing continuous exposure to C-Natriuretic Peptide. And what we want to get out of it and what the biology is telling us is that we can reorganize the growth plate, which is permissive for having longitudinal growth. Zooming in on the target cells affected by this condition, these are the chondrocytes. And in fact, achondroplasia means lacking the chondrocytes. And they are located in the growth plate. So if we look on this side, we can see a cell and we can see the different receptor confirmations that you have as a result of this heterozygous mutation in the FDFR3 gene. The key takeaway message here is that you will have signaling irrespective if the ligand is binding or not binding to the receptor. So -- and this is on all the time. So it is important that when we come and modulate with CNP, that you also continuously are exposing the growth plate to the effects of CNP so we can counterbalance this overactivation of the FGFR3 pathway. And if we look here in the red circle, this is highlighted where the disease is, so your drug needs to be able to access the growth plate here in order to drive the desired therapeutic effects. Looking at the derangement of the signaling pathway, here we have depicted the FDFR3 receptor and the red star in the transmembrane domain is where the mutation is located. This leads to a confirmational change on the intracellular level of the receptor that causes this pathway to be chronically on. It is well established and described in the literature that if you stimulate the NPRB receptor with C-Natriuretic Peptide, you will induce another signaling cascade that will inhibit the overactivation at this level. So in essence, you're taking the brake off the brake and allowing growth to resume. This has been studied and explained well in the literature by a series of elegant experiments that involved both wild-type mice, but also mice with achondroplasia mutation. And this is what is highlighted here on the figure on the right of the screen. So if you look for the wild-type animal, you will immediately see that it looks different from the achondroplasia mouse. You have the normal organization of the chondrocytes arranged in a columnar fashion, and you have nice width of the growth plate. In the animals with the achondroplasia mutation, you will see much more disorganization of the growth plate and it's also more narrow. However, when you then expose these animals with the achondroplasia mutation to continuous exposure to CNP, you will see that the phenotype is reverting towards the wild-type phenotype again with proper orientation of the growth plate and the aligning in the typical columns and the growth rate is widening up again. So CNP definitely at the level of the growth plate is able to counteract the block that the overactive FGFR3 mutation is causing. So we took the knowledge from the literature and incorporated it into how we wanted to design our TransCon CNP molecule. So here, we're using the soluble carriers that you already know from our other rare endocrine programs. And then we took the CNP wild-type sequence and conjugated into our TransCon linker carrier system. What we wanted to achieve was to be able to provide efficacious levels of CNP over the course of a week, but importantly, engineer the linker such that our Cmax levels never came into the area where you are starting to see the typical hypotensive effects that are well described for natriuretic peptides. Once released from the linker and carrier, CNP is in free to diffuse into the growth plate and act on the NPR-B receptor in the growth plate. The carrier and linker are then cleared by renal clearance. We wanted to achieve a few things by conjugating the CNP molecule to a soluble carrier, not only extend half-life, but in order to do that, we also needed to make the peptide too large for degradation by a protease called endopeptidase, but also to prevent renal clearance. Importantly, also, while bound in the prodrug, the CNP is not able to bind to the receptor itself. So also a week's worth of CNP is not causing hypertension, as you will see when Marie-Louise Hartoft-Nielsen presents the initial clinical data. So now having seen and learned a little bit about our consideration for deciding the drug, let's talk about the stages that are required in order to promote growth in achondroplasia. We think of it as 3 sequential stages. First, we administer the drug on a weekly basis in order to have a continuous release of CNP into the bloodstream. As we have CNP circulating in the blood, it will all be able to diffuse into the growth plate and reach the deep compartments of the growth plate where CNP, in reality, is supposed to be acting. And finally, we have continuous exposure within the growth plate in order to inhibit the FGFR signaling 24/7. And digging deeper into each of these 3 stages, let's start first with the pharmacokinetic parameters. Per design, we ensured that we have continuous exposure to the free CNP peptide. Also from a pharmacokinetic standpoint, this molecule is very well behaved. We have continuous exposure. We have dose proportionality. So it's behaving as designed. And as mentioned, importantly, our Cmax is low, and well below levels that has been described in the literature to be associated with hypotension. And then as we are well experienced from our efforts in growth hormone, we know that once-weekly dosing is a dosing frequency that the children like. Zooming in on the growth plate, starting to think about the biology of the growth plate. The growth plate is unique in that it is avascular. So there's no blood vessels entering this portion of the growth plate. It's also very hydrophilic and it's negatively charged. So if you have a large molecule like an antibody, this will have penetration restrictions due to size and charge. CNP by natural evolution is designed to act and work and be retained in the growth plate. For example, it has a small size that is permissive of crossing the endothelial walls and diffuse into the growth plate. It's hydrophilic so it likes to be within the hydrophilic matrix of the growth plate. And then it's positively charged. So once it's there, it's attracted to the negatively charged matrix and will be retained. So this is what we are showing here with the blue arrows, you have the ability for CNP to leave the bloodstream and penetrate deep into the growth plate to the area of disease. Similarly, we want to have continuous free CNP exposure to constantly inhibit the constitutive hyperactivity of FGFR3 signaling. In fact, the biology of CNP was discovered and investigated using continuous exposure of animals to CNP, either by genetic modulation or by continuous infusion. And this is also retained in the human setting. So in individuals over-secreting CNP, this is associated with tall stature and overgrowth of the skeleton. So definitely, continuous exposure to CNP is associated with growth. So we designed TransCon CNP to really address the key manifestations of achondroplasia. We wanted to achieve continuous exposure, and you'll see interesting data on this. We have dose proportionality with a Cmax that is well below levels that is known to induce hypertension. And we were able to get to a once-weekly dosing using our TransCon linker and carriers. We also were able to retain the wild-type sequence of CNP. This has ideal characteristics for growth plate retention and penetration. And also, we have seen in our preclinical studies, a nice growth promoting effect and Marie-Louise will also present initial considerations from our ongoing Phase II study. So with this, I would like to turn the stage over to Dr. Hartoft-Nielsen for the clinical update.

Thank you so much, Kennett. Welcome everybody out there. I'm very happy now to spend the next 20 minutes taking you through the clinical aspects of achondroplasia and our clinical development program. Achondroplasia is a rare disorder. It's also the most frequent skeletal dysplasia and the most common cause of short-limbed, short stature. It's caused by a gain of function mutation in the FGFR3 gene, and the estimated prevalence is around 4 per 100,000 birth. 20% of the children with achondroplasia are born in families where either 1 or both of the parents have achondroplasia and the remaining 80% is born in families with parents of normal height. Globally, approximately 250,000 people are living with achondroplasia. Due to the characteristic manifestations of achondroplasia, most of the children are diagnosed either pre-birth at birth or at least within the first year of life. Achondroplasia is affecting the growth of the long bones, the bones at the base of the skull and the bones in the spine, resulting in characteristic manifestations. The manifestations are short stature, short limbs with apparently -- primarily affecting the proximal part of the limbs, narrowing of the foramen magnum which is a hole in the base of the spine, where the spinal cord is entering into the spinal canal and midfacial hypoplasia. These characteristics are present at birth and seem to progress over time. Achondroplasia is also associated with a lot of complications. Most important ones are foramen magnum and spinal stenosis, leading to neurologic symptoms. Others are other spine deformities, sleep apnea, otitis media and so on. As both the manifestations and the complications are progressing throughout life, many people with achondroplasia needs several interventions to alleviate the symptoms. The interventions could be cervicomedullary compression, where you actually pin out a bit of the base of the skull to allow sufficient space around the foramen magnum. Other interventions are other spinal surgeries, CPAP, XXXXXXXXXXXXXXX et cetera. Also life expectancy is impacted in -- throughout most age groups. In infancy, it's due to foramen magnum stenosis, through most age groups due to accidents, and in adulthood, it's due to an improved -- an increased prevalence of cardiovascular diseases. All this cause a huge burden on the people living with achondroplasia and their families, and many people with achondroplasia experience reduced health-related quality of life. Most treatments and multidisciplinary care for the people with achondroplasia have been symptomatic. And the first medical treatment for achondroplasia has just been approved in EU and U.S., but there remains a huge unmet need for additional medical treatments that will relevantly affect the pathophysiology in the growth plates to alleviate the manifestations and avoid the complications. So TransCon CNP was designed to continuously inhibit the hyperactive signaling FGFR3 and at the same time with a low risk of cardiovascular side effects and low immunogenicity. So TransCon CNP shows dose proportional increases in exposure and a continuous exposure over a dosing interval, which is a weak and a low Cmax. The prodrug TransCon CNP utilizes and releases a wild-type CNP peptide sequence. And by these properties, TransCon CNP is designed to relevantly provide meaningful impacts in clinical manifestations and the burden of achondroplasia. So before we brought TransCon CNP into clinical development, we did nonclinical studies to support safety and efficacy. And this slide shows a nice summary of key findings on our nonclinical development program. To the left, you see data from a study in young monkeys, where we found that TransCon CNP provided a dose-dependent increased linear growth here illustrated by the tibial growth in these young monkeys shown as placebo-corrected percentage changes from baseline. In studies in a mice model of achondroplasia, we found that TransCon CNP also had the potential to prevent premature fusion of the synchondroses of foramen magnum as shown on the images to the right. If you look at the images to the far right, you see the foramen magnum from vehicle-treated mice. And what you can see is that the foramen magnum is fully closed, all the synchondroses are fused. On the contrary, if you look at the images from the TransCon CNP mice, you can see that some of the synchondroses are still open illustrated by the arrows. From these studies, we also did safety evaluations. These are not shown on this slide, but they all showed that TransCon CNP was well tolerated without adverse hypertension issues. So encouraged by these data, we brought TransCon CNP into clinical development. And this slide nicely illustrates the integrated clinical development program that we are pursuing. A patient-centric clinical program is essential to us. And in addition to doing clinical trials, we are also engaged in patient outcome research because we strive to be able to identify important outcomes and experiences for children and families living with achondroplasia. So let's start having a look at the clinical development program, and let's start with the Phase I trial, the first in-human trial. In this trial, we evaluated 5 different single doses -- 5 different dose levels of TransCon CNP administered at single doses. And the key objective in this trial was to establish the pharmacokinetics in humans. And what you see on this graph is the free CNP levels in plasma after the 4 highest doses. And what you can appreciate is that there was a nice dose-dependent increase in free CNP exposure. There was a continuous exposure throughout 168 hours corresponding to a week, and we also saw that this would be supporting weekly dosing. Of course, we also had a huge focus on safety. And in particular, we had focus on vital signs due to the potential risk of hypertension caused by natriuretic peptides when given in high doses. So it was reassuring to see that the mean resting blood pressures and heart rate were unchanged from pre-dose. We also looked carefully at orthostatic changes throughout the trial. And what you can see on the figure to the right, is the green line, which is a plasma concentrations of free CNP throughout 3 days. And you see red and blue dots which are orthostatic changes from baseline in systolic and diastolic blood pressure. And what we can see is that the orthostatic changes in vital signs were unrelated to CNP exposure and they were consistent with the findings we found in placebo subjects. There were no serious adverse events reported in this trial. And importantly, the injections were really well tolerated, and we did not detect any anti-CNP antibodies. So based on this first-in-human trial, we concluded that TransCon CNP is well tolerated in humans with mean -- and orthostatic vital signs unchanged. So let's move away from healthy volunteers, and let's have a look at the clinical development program in children with achondroplasia. On the top, you can see the ACHieve trial. ACHieve is our natural history study. It's a noninterventional study in children with achondroplasia, and this study will inform us on the natural history in terms of growth, manifestations, complications and interventions in this population. It's a global trial. It involves 14 countries, and we have enrolled 230 subjects in the trial. Below, you see our ACcomplisH studies. We have 3, ACcomplisH and ACcomplisH China are evaluating safety and efficacy in children aged 2 to 10 years, and we are soon about to undertake new trial ACcomplisH Infants, which will demonstrate the impact of the early interventions in children below the age of 2. Let's now have a look at ACcomplisH trial. ACcomplisH is a dose escalation trial. It's a multidose trial evaluating 4 different dose levels of TransCon CNP. Within each of these dose level cohorts, children are randomized 3:1 to either placebo or to either TransCon CNP or placebo. The children to be included in this trial are children with achondroplasia aged 2 to 10 years old. We have now completed enrollment in the trial, have enrolled 57 subjects. The treatment or the randomized treatment duration is 52 weeks, after which the children can roll over to the extension period where we will evaluate long-term safety and efficacy of TransCon CNP. The primary endpoint in the trial is related to growth, annual height velocity, which is a well-established primary endpoint in growth trials, also recognized by regulatory bodies. Due to the disproportionate short stature in achondroplasia, body proportionality or the upper to lower body ratio is an obvious secondary end point. As we want to keep our trials patient-centric, we have involved a panel, a battery of patient-reported outcome measures, and we are also happy to explore a full panel of relevant biomarkers. Based on the preliminary still blinded data in this trial, we have decided that we will pursue with dose levels of 50 and 100 micrograms in future clinical activities, and there's no need to go above 100. This is the baseline characteristics of the trial -- of the patients in the trial. As I said, we have completed enrollment and included 57 subjects. The mean age in the trial is 6 years, with little higher mean age in Cohort 1, a little lower in Cohort 4. And as growth is not linear in this population, it's relevant to look at different age groups. And this is what you see here, where we divided the populations into age groups of 2 to 5, 5 to 8 and above 8 years of age. And what we can appreciate is that there's a fairly equal distribution across the cohorts among these different sub-age groups. What we can also appreciate is that we have a fairly high number of children in the youngest age groups across the cohorts, which means that we are actually with this trial generating safety and efficacy data in this young population. When we look at the distribution between males and females, this a fairly equal distribution and it's aligned across the cohorts. What about the age at diagnosis? What we can appreciate from these data is that we can confirm that children with achondroplasia will have the diagnosis within -- at least within the first year. The majority of the patients have the diagnosis before the age of 6 months. The last parameter we have shown here is height SDS which is a measure of the deviation of the height from a normal population. And you can say it's a proxy for the disease severity. The height SDS is around minus 5 in this trial, which is very much aligned with what we will expect from a population like the one included in the trial. An important objective in this trial was to confirm pharmacokinetics in children with achondroplasia. So what you see on this picture is the free CNP for the 4 different cohorts. The red line represents predicted values based on model data from our Phase I trial, and the black dots represent actual values measured in the trial. What we can see is that there is a continuous exposure over the weekly dosing interval the half-life was confirmed to 110 hours. We do see that there's dose proportionality across the cohorts, and we can also see that the Cmax level even for the highest dose evaluated is still below the levels where we would normally see hypertension in humans. What I show you here is the preliminary safety profile based on the 57 subjects enrolled in the trial with up to 65 weeks of exposure. And these data are based on a data cutoff from the 8th of December this year. So far, there has been no withdrawals or discontinuations for any reasons, illustrating or maybe indicating that TransCon CNP is well tolerated, but also that there is a huge wish for treatment. We have had no serious adverse events related to trial drug reported. The adverse events reported in the trial are generally mild, a few are moderate, and most of the events are related to upper tract infections and which is very much aligned with what we would normally expect from the population of children with achondroplasia. 13 adverse events have been reported to be related to trial drug procedures. Of these, 8 were mild and transient injection site reactions, and this is after 1,900 injections in the trial in general. Otherwise, injections were well tolerated for all doses and all cohorts. Importantly, we did not see any -- we have not seen any adverse events reported to be related to orthostatic blood pressure changes. And importantly, we have not seen any treatment-emergent anti-CNP antibodies. So really reencouraging, we find that TransCon CNP is well tolerated in children with achondroplasia with up to 65 weeks of exposure. As part of our global development program, we are also doing a trial in China ACcomplisH China. The trial design is very similar to the ACcomplisH trial. And based on the preliminary blinded data from the ACcomplisH trial, we have identified that the doses we will investigate in this trial will be 50 and 100 micrograms per kilo per week. We plan to include 60 subjects, and the trial is now enrolling. We believe that early intervention is essential to be able to relevantly address the pathophysiology in the growth plate. And we're happy to initiate the ACcomplisH Infant trial, where we plan to demonstrate that early intervention will be important to demonstrate treatment effects beyond growth. The Infant trial will include around 30 subjects, and we plan to submit the IND in Q2 next year. A cornerstone in our development program is to be patient-centric and relevantly address what is found to be important by the patients. Currently, little is known about the impact of achondroplasia in children. And disease-specific measures are important tools to assess the experiences that children, parents and caregivers are having with a disease and potential impacts of treatment. We wanted to develop some disease-specific measures to relevantly address these issues. So we engaged in research to do so. So we have conducted interviews with patients, caregivers and clinical experts. And based on these interviews, we have confirmed that achondroplasia has a huge impact on children's lives and well-being. All these impacts can be divided into 5 different concepts, physical function and symptoms, functioning and daily life, school participation and emotional and social well-being. When we look more carefully into each of these, we can also see that there is a huge variability in the reporting for different age groups within each of these concepts. So there's still a lot to learn and still a lot to address when developing new drugs for achondroplasia. These interviews has also now led to that we have developed 3 different achondroplasia experience measures. 2 of them are addressing symptoms and impact of life for children. And this last 1 is addressing the impact for patients and for parents and caregivers when having a child with achondroplasia. These measures are now being validated in observational studies and in our clinical trials, and we will, of course, apply them in future clinical activities. So summing up, we are very pleased with the progression of exciting TransCon CNP clinical program. We have completed enrollment in the ACcomplisH trial and included 57 subjects. Based on interim blinded data, we have decided to pursue 50 and 100-microgram in the ACcomplisH China trial. And based on the preliminary PK data, we see that TransCon CNP results in continued CNP exposure, and we see that the preliminary safety data indicates that TransCon CNP is well tolerated in achondroplasia across all doses. ACcomplisH Infant will be a trial where we aim to demonstrate the impact of early intervention to prevent disease progression. And we are very excited and looking forward to next year where we will submit the IND for the infant trial and are looking forward to getting the top line data from ACcomplisH. So thank you very much for your attention. I'll now hand it back to Kennett, who will bring us into new exciting adventures.

Thank you, Marie-Louise. And as you heard in Jan's opening statements, an important portion of our Vision 3x3 is expanding beyond our endocrinology franchise and also developing pipelines in additional therapeutic areas. So I'm very happy to shift gears here and give you an introduction to some of our efforts within the oncology space. and in particular, focus on our TransCon technology for intratumoral administration. So we believe that TransCon is uniquely positioned to transform cancer care. We can use both our systemic TransCon technology that you know from our endocrinology franchise, but also the topic of today, our intratumoral hydrogel technology that utilizes the same linkers, but an insoluble carrier in order to deliver the drug directly to the tumor. We think these technologies, both as stand-alone but also in combination, may give us the opportunity to greatly enhance antitumor effects by a couple of different mechanisms. One is to provide sustained modulation of the tumor microenvironment, which in turn also may help to activate cytotoxic immune cells, prime T cells in the draining lymph nodes and drive systemic abscopal effect. So in reality, we want to take cold tumors that are infiltrated with immune suppressive cells, activate them and turn them hot so that we also can educate our adaptive immunity so we can come to a situation where both treated tumor and untreated tumor is eradicated. Where are we today? We already have 2 clinical candidates that address different steps in the immunity cycle. If we start with TransCon TLR7/8 agonist, this is a molecule using the hydrogel technology designed to be injected into the tumor and enhance your innate immunity, so really activating your antigen presenting cells in order to promote also activation of cytotoxic immune cells and thereby drive systemic immune activation. We also have TransCon IL-2 beta gamma, which is a IL-2 molecule, where we're utilizing our soluble carrier. And this molecule is designed to help expand your T cells and NK cells to really infiltrate tumors and also drive robust antitumor effects. We're also using our algorithm for product innovation to identify additional TransCon candidates that may address other areas of the immunity cycle. Just mentioning briefly on this slide, our TransCon IL-2 beta gamma asset. Here, we're actually using the exact same linker and carrier that we're using in our TransCon Growth Hormone program. The only difference is that instead of releasing growth hormone, we're releasing our bias IL-2 beta-gamma molecule. And through this 2-step approach we have actually been able to optimize the IL-2 molecule with a small bias in pack so that it's biased away from binding the alpha subunit of the IL-2 receptor and towards the beta-gamma confirmations. Because we're not using the bias in pack for half-life extension, we have been able to optimize for potency and bias without having to worry about half-life because this is taken care of by the TransCon linker and carrier. By using the TransCon linker and carrier, we're also able to have a low Cmax and a sustained exposure, which we believe is key to expanding the therapeutic window of the IL-2 pathway, having low systemic exposure, but sustained release of fully active IL-2 molecule. But for the topic of the remainder of this talk, Dr. Stina Singel talk after mine, this is TransCon TLR7/8 agonist. So this is a little bit of new technology that we haven't discussed so much in the past. So we are using the same linkers that you know from our soluble platforms but rather than conjugating to a soluble carrier, we are conjugating to an insoluble hydrogel carrier. This allow us to take the drug-loaded hydrogel and injected directly into the tumor where you want the effect of the drug. And slowly and controlled release the fully active drug at the site of intended activation. Once the drug has been released from the hydrogel after approximately 3 months, the hydrogel itself will disintegrate into small polymer-based fragments that are cleared out of the tumor and cleared by the kidneys. So conceptually, what does this look like? And why do we believe that this is a potential paradigm shift in how we treat cancer. So if we start in the schematic on the top and look at a normal injection of a drug -- a soluble drug into a tumor without using TransCon technology. The result is because there's nothing to keep the drug in the tumor, you will have a rapid absorption out of the tumor into systemic circulation. What this means is that in the orange schematic -- orange curve, you'll see short tumor exposure. The drug is being lost out of the tumor. But consequently, because it's going rapidly out of the tumor you will have a rapid increase in the systemic exposure, leading to a high Cmax, which may be driving significant systemic toxicity. In contrast, using TransCon technology and the hydrogel in particular, we can inject the drug into the tumor, slowly release it in the tumor where you want it, so you get a long tumor exposure also highlighted in orange in the lower figure. But because we are tuning the linkers to only slowly releasing it within the tumor, what the systemic exposure sees from a concentration standpoint is very low because it's only slowly coming out of the depot and into systemic circulation. So this is another way that we believe that we can expand the therapeutic window for these potent immune stimulators. But we are not just interested in treating the injected tumor. When we do and use our algorithm for product innovative, we study the literature and try to figure out how can we optimally select compounds that will drive not only a local immune response but also drive systemic immunity and abscopal effects. So when we select compounds, we want compounds that locally prime the immune system, but then also home to the tumor draining lymph nodes to help educate your adaptive immunity and drive, for example, cytotoxic T cell expansion so that we can also have surveillance of the organism and clear abscopal and metastatic lesions. So how does this look like then in vivo. This is a PK study that we conducted with a hydrogel-loaded -- TransCon hydrogel-loaded compound injecting into mice bearing tumors. So the top light blue curve represents the intratumoral concentration of the release drug. Contrast that to the dark blue curve below it, and note that despite the Y-axis missing on this figure, this is a logarithmic scale. So what it should have shown was that we have a thousand-fold difference in the concentration between what is in the tumor and what is in systemic circulation. So this clearly shows that we are able to drive very high local concentrations with minimal systemic exposure. One important aspect to keep in mind when we're using our hydrogel technology is that -- I mentioned that the hydrogel itself remains intact for approximately 3 months. But when we dose it as we're doing in our clinical study every 3 weeks, that means that at any given time, you will have multiple hydrogel depots within the tumor. So what we are showing here is a model showing with the arrows, the repeat every 3 weeks injections and then the amount of hydrogel within the tumor. And you can see that you reach a steady state after approximately 5 administrations, where will have 4 to 5 depots of hydrogel sitting inside the tumor. And once you stop injecting hereafter the 9th dose, the hydrogel will start disintegrating one at a time and slowly return back to baseline after which no more hydrogel material is present within the tumor. The reason this is important, as long as the patients stay on therapy, you will -- when you do your tumor size measurement, you will be able to measure both the actual tumor tissue, but you may also measure the resultant hydrogel material that is inside the tumor. So rounding off, we're using our algorithm for product innovation not only to build our pipeline in endocrinology. We are also using it in oncology, and we are committed to also applying it and enter a third therapeutic area. So we used that algorithm for selecting our TransCon TLR7/8 agonist. We used it to figure out how do we find a compound that has the efficacy we want that also will -- when combined with the TransCon technology, will have the safety that we are hoping for. And then definitely, we want to use the combination of known biology together with our TransCon technology to a broad applicability. The physicians that we talk to, they mentioned that if you can biopsy a tumor they -- then you can also consider it for an injection. So I mentioned a few times that we believe that TransCon represents a potential paradigm shift in how we treat cancer. We have 2 clinical stage candidates with potential best-in-class properties, and we use both our systemic as well as our localized technology. We haven't talked much about TransCon IL-2 beta/gamma today, but we hope to do so at future meetings. But I'm very excited to hand the stage over to Dr. Stina Singel to explain to you and go through the initial clinical data of our TransCon TLR 7/8 Agonist and share some of those interesting findings.

Thank you, Kennett. Hello, everyone. In oncology, unmet medical need remains high despite recent advancements. Next slide, please. Immunotherapy, particularly checkpoint inhibitors, has given hope for dramatic improvement in cancer treatment. However, only a small proportion of patients are actually benefiting from immunotherapy. You can see in the box on the right, that in the U.S., although up to about 50% of patients are eligible to receive checkpoint inhibitors, fewer than 20% of patients actually benefit from checkpoint inhibitors. So although immunotherapy has so-called raised the tail for multiple tumor types in survival, more effective therapies are clearly still needed. Toll-like receptors or TLRs, are well-validated targets for activating the immune system. They can activate antigen-presenting cells, not only activating the innate immune system, but also the adaptive immune system. They can also inhibit immunosuppressive cells. Resiquimod has been a well-described TLR7/8 Agonist. It has been clinically evaluated as a potent TLR7/8 Agonist to kick start the immune system. Clinical limitations of TLR agonist has largely been due to systemic toxicity such as cytokine release syndrome that is associated with high drug concentrations peripherally. Previous IT approaches has not been able to deliver the prolonged exposure of active drug levels that is needed for antitumor activity. Consistent with short exposure, pharmacodynamic effects of previous intratumoral TLR agents in the clinic have been reported at about 24 hours post dose. We believe that sustained IT exposure of TLR agonist is likely necessary for therapeutic benefit while we minimize systemic toxicity. Taking advantage of clinically validated TransCon platform, the clinical development strategy in oncology is to quickly build a safety and tolerability profile while we find a dose across different indications as monotherapy and in combination with different treatments. Then we would like to establish proof-of-concept efficacy in various indications of high unmet need. Then we intend to expand to multiple indications. Today, we're going to talk about first update of clinical data from the first-in-human trial of TransCon TLR7/8 Agonist. Here is the overall study schema. We have dose escalation 3 plus 3 design, with dose escalating as a monotherapy and also in combination with pembro. Once we identify recommended Phase II dose, we'll move on to dose expansion in multiple indications, initially starting out in HPV-associated tumor types. Our key objectives of this first study is to evaluate safety and tolerability, define maximum tolerated dose and recommended Phase II dose, to evaluate pharmacokinetics, pharmacodynamics and also get a sense of preliminary antitumor effects. Our initial interest in HPV or human papillomavirus associated tumor types is from strong scientific rationale. HPV is able to have persistent infections because it alters TLR expression. This leads to decrease in Th1 response, decrease in inflammatory cytokines, and decrease in activation of antigen-presenting cells. HPV can also decrease HLA expression, which then ultimately decreases adaptive immunity. HPV-associated tumor types include head and neck squamous cell cancer, cervical cancer and other tumor types around the anogenital region. We do intend to expand to other indications of unmet need with emerging data and the rapidly changing treatment landscape. For today, we're going to present data largely from patients who have been placed in dose level 1 in monotherapy and also in combination with pembro. Dose escalation is ongoing with dose level 2, with dose expansion expected to start enrollment in quarter 2 of 2022 after we declare recommended Phase II dose. To start out looking at PK. We feel we are assured that we are hitting the 2 aims with the TransCon technology. You can see here that there is sustained release of resiquimod with half-life of 7 days. And secondly, the average drug level that can be detected peripherally is about 50 picogram per ml. This is well below the level that we expect to be associated with significant systemic side effects such as cytokine release syndrome. You can see the dash line at the top around 4,000 picogram per ml that is associated with cytokine release syndrome. So we feel that we do have a differentiated drug here where the peripheral PK indicates we have sustained release of resiquimod with a relatively long half-life of 7 days and a wide safety margin. As of the November 16 data cut, we have enrolled 8 patients: 5 in monotherapy and 3 in combination. You see here the different tumor types listed. We have enrolled patients with melanoma, triple-negative breast cancer, pancreatic cancer and basal cell carcinoma. Median prior number lines of treatment these patients had before coming into the study was 3 and 2. Majority of the patients have progressed on prior anti-PD-1 or PD-L1. In the table below is overview of safety. We have not seen any patient with a related serious adverse events or grade 3 or higher adverse events. And you can also see that we had no patient that discontinued the study drug due to an AE, and we had no deaths related to AE on the study. So far, we see that intratumoral TransCon TLR7/8 Agonist is well-tolerated as a monotherapy or in combination with pembrolizumab, consistent with what we saw in the PK data that we have low systemic exposure. So far, no dose-limiting toxicities have been observed. Even though we have dosed only 8 patients so far, we have not seen any systemic side effects related to TransCon TLR7/8 Agonist. The only related adverse events we have seen are transient and mild injection site-related reactions. 2 out of 5 patients treated with monotherapy have reported injection site reactions that are mild and transient, and no injection site reactions have been reported so far for the 3 patients treated with combination treatment. Moving on to clinical activity. Out of the 8 patients, we have 3 efficacy evaluable patients who have at least 1 post-baseline tumor assessment. Two patients have discontinued due to progressive disease before first tumor assessment at week 9. One discontinued to go on to hospice. And we have 2 patients recently dosed ongoing on study but have not reached their first efficacy assessment at week 9. In the table, you see our 3 efficacy-evaluable patients. One, treated with monotherapy; and 2, combination treatment with pembro. The tumor types elicited melanoma, pancreatic and basal cell carcinoma, and all 3 patients have progressed on 2 prior lines of treatment before coming on to the study, 2 out of the 3 had prior PD-1 -- anti-PD-1. We'd like to provide some more detail on these 3 efficacy evaluable patients. So starting out with the melanoma patient who had 2 prior lines of treatment, including pembro. He was in the monotherapy dose level 1 cohort. His best overall response per RECIST version 1.1 is an unconfirmed partial response at week 27. You can see the detailed tumor measurements listed in the table. He had 2 measurable lesions, 1 was chosen for injection and 1 remained non-injected and was followed for response. What is very interesting to us is to observe the tumor biopsies that were taken at week 27 in the injected lesion and the non-injected lesion. In the injected lesion, 3 core biopsies after 9 doses show tumor cells found in up to 50% of the total tissue. The rest of it was hydrogel, and this is something that Kennett alluded to before, something we expected to see. And this hydrogel was surrounded by granulomatous inflammation. In the non-injected lesion, now by week 27, radiographically, it has disappeared. But this site, this was a subcutaneous nodule. The lesion site was previously marked. A punch biopsy at week 27 showed mild chronic inflammation, reactive changes, no evidence of malignancy. So to us, this was pathological confirmation of complete response in the non-injected lesion that indicates abscopal effects of monotherapy TransCon TLR7/8 Agonist in a patient who previously treated with pembro. Moving on to our second patient. Second patient had pancreatic cancer. Two prior lines of multi-agent chemotherapy. This patient had no prior immunotherapy. He was put in the dose level 1 TransCon TLR7/8 Agonist to combine with pembro. This patient's best overall response was stable disease at week 9. What is interesting about this patient is that the initial lesion selected for injection to 22-millimeter lesion; by cycle 2, it became very flat and was very difficult to inject into. So the investigators started injecting another measurable lesion, that's the 90-millimeter lesion. At 7 weeks after that single dose of injection into that 22-millimeter lesion, 3 core biopsies were done. It showed no tumor present with minimal lymphohistiocytic reaction. So this pathological evaluation after a single dose actually gave us the information that there may be an early and potentially deep response in an injected tumor. Moving on to our last efficacy-evaluable patients. This patient had basal cell carcinoma, also had 2 prior lines of treatment. What is interesting is this patient immediate therapy with cemiplimab, which is an anti-PD-1. He was -- entered the study, treated with TransCon TLR7/8 Agonist at dose level 1 combination with pembro. His best overall response was stable disease recently at week 9. You can see here, again, his tumor measurements in the injected and non-injected lesion. At the time of first tumor assessment, investigator decided to do a punch biopsy. This was after 3 doses at the injected lesion. It showed atypical basaloid proliferation at the base of the biopsy, but no evidence of malignancy. So this again was a pathological evaluation that suggests that there can be an early and potentially deep response in an injected tumor in a patient who progressed on anti-PD-1. Moving on to look at pharmacodynamic effects from paired biopsies. These are biopsies taken at baseline and also biopsies taken 7 days after a dose. You're looking at a heat map of gene expression of 14 predefined interferon-related genes or TLR signaling related genes. Each column represents a patient, different tumor types. And also, we have collected paired biopsies from injected lesions and non-injected lesions. Red represents upregulation of those genes, and you can easily see there is consistent and robust immune activation in different tumor types, and that's observed in both injected lesions and also non-injected lesions. The target activation of these key immunological pathways seems to have been maintained through at least 7 days post dose in both an injected and non-injected lesion. Looking specifically at the top 3 genes, IRF7, STAT1, CXCL10. And we have information cycle 2, day 8 biopsy on some of these patients. What we observed here is that there is sustained upregulation of interferon-related genes in tumor tissue with repeat dosing, and there is no attenuation of effect. To sum up, TransCon represents a potential paradigm shift in cancer treatment. We have shown today early data from the ongoing TransCon TLR7/8 Agonist, the first in-human trial that indicated early signs of activity in 3 out of 3 evaluable patients, including patients previously treated with a checkpoint inhibitor. We have seen monotherapy activity, and consistent and robust target engagement. We have seen well-tolerated safety profile and expected low systemic exposure based on early PK data. So we believe TransCon TLR7/8 Agonist has the potential for sustained immune activation and systemic antitumor response with infrequent dosing. At Ascendis, we are creating a pipeline using TransCon technologies that may enable a new treatment paradigm, building upon well-known biology. Our second oncology program, TransCon IL-2 beta/gamma, our first-in-human trial, which we call [ Our Belief ] is now open for enrollment, and we are expecting clinical data in 2022. So thank you for your attention. With that, I will turn you over back to Jan.

Thank you, Stina, for this presentation. I would like to make a small summary of what you have heard today. You have been -- or many of you have been listening to us for years and years, how we have progressed our rare disease endocrinology pipeline for 3 preclinical candidates now to the first approval for SKYTROFA in the U.S. for TransCon Growth Hormone. We have a positive opinion now also in Europe. We have advanced PTH from the preclinical candidate into now where we expect to get Phase III data in Q1 next year. We have advanced TransCon CNP from the preclinical candidate and really expect in Q4 next year to get real outcome data in patients with achondroplasia. You heard from Stina that we're building up an oncology pipeline, built on the same TransCon technology, built on the same algorithm for product innovation that Kennett talked about. I believe we have been extremely successful, and we have been successful in developing highly differentiated product opportunities no one else can make. Highly differentiated product opportunities that really are addressing major medical needs. And this is really what makes me passionate about my job, to be in a position to listen to a physician, describing our product, TransCon P&T (sic) [ TransCon PTH ] as life-changing, giving my life back again. That gets me to work. That is why we have that passion on Ascendis Pharma. And also, I believe we, as a company, has grown and are ready would like to thank all the employees, everyone that had part in creating this kind of success helping so many patients continue to do it. And we believe it this is the passion we have to see how we really can benefit the society, how we really can benefit the patient and we're really happy to continue to do it. So I would like to turn it over to Scott, and he will come in and some way arrange the QA section.

Thanks, Jan. So now we will turn over for a Q&A session. And operator, if you can read the instructions as well as the e-mail address for people to e-mail questions to. Thanks.

[Operator Instructions] And your first question comes from the line of Michelle Gilson.

I guess I'll just do one on kind of each of the 3 programs that you gave clinical updates for. The first on TransCon PTH. You associate this need for -- the increased need for PTH and kind of increased doses over time being related to the bone normalizing and stabilizing. And it seems like in the Phase II extension, it starts around week 26, the bone turnover markers start to come down. And I'm just curious, when you move from Phase II to Phase III, there was a change in the dose titration algorithm and also patients aren't continually titrated. How do you expect those -- do you expect that, that increased or that need for an increased dose of TransCon PTH will be -- I guess will affect the results of the Phase III study at all? And kind of how do you translate that from Phase II to Phase III with the changes you made in those studies?

Thanks, Michelle. The question, well, what we really are seeing today? We are coming with a complete new treatment paradigm shift. The data we are generating no one else has generated before. And what we saw and Aimee explained about how we see the long-term change happening under the continuous treatment with physiological PTH. And we saw it in different stages. And I actually believe what we saw now after 84 weeks, is basically the new way we can see how we stabilize the body to a new treatment with physiological PTH. But Michelle, we only have a 6 months' data in our Phase III. So therefore, from our perspective is the data we will generate in the Phase III trial only reflect the first 6 months' data. But we will continue to observe this patient. But Aimee, you are near the patient, you can add in?

Sure. Thanks, Jan. Michelle, so as you pointed out, the titration algorithm is different in the 2 trials. In Phase II, it was just a 4-week blinded period, so we fixed the doses. In Phase III, the patients are allowed to whether they've been randomized to active drug or to placebo with conventional therapy, both are co-administered with conventional therapy, but they are both titrated to whatever might be optimal for the patient. So we will see at week 26 patients ending up on different doses that are correct for them. And that is how we designed this program, understanding that many hormones require a broad distribution of doses, we think that the patients here will also show that.

Okay. And do you think that this higher requirement of PTH does the Phase II open-label extension kind of satisfy what the FDA might need to see around it? And has it come up in your discussions with the agencies?

I think, Dana, will you address that?

Yes. We've had discussions with FDA about what the full program should look like, the entire safety database, and they've been comfortable with our plans to continue these patients for long-term therapy to gain continuous information about how they're doing from an efficacy and safety point of view. And of course, with our Phase III program taken together, we will have a fairly robust package that will allow the agency to assess both the shorter term and the longer term therapies.

Okay. Also for TLR7/8 Agonist program, will you see additional updates -- since it seems like week 9 may not be a long enough time here. And then you saw some very good responses in these early data. And does that suggest that maybe your trial plans are too narrow with only HPV-associated tumors? And then I was wondering if you could comment, you saw some of the scope effects but not affect the original -- at the injected tumor? And can you kind of explain what you're seeing and how you think that this -- do you expect a more robust response over time?

Stina, will you take that?

Sure. Great questions. So as you pointed out, this is really our very first time taking a look at dose level 1 and very short follow-up time. So therefore, we -- for 2 of the patients, we only have 9 weeks' worth of efficacy follow-up for those patients. So certainly, we'll need to follow for longer. I think what is interesting for us is to really get a first sense of our PK and PD profile, get a sense of clinical safety in that first dose level. In terms of indications, while our initial focus is on HPV-associated tumor types, we do fully intend to expand to other indications of high unmet need or indications where we see particularly interesting responses out of our dose escalation portion.

Thanks.

And if I can sneak one in on TransCon also. You mentioned that you don't think you need to go above 100 micrograms. How did you determine this because your Phase II dose escalation study, I don't think evaluated doses higher than 100? And then maybe you can touch on the end point in the ACcomplisH infant study?

Yes. There was multiple questions, Michelle. So let us try to see if we can get through them. The first question is that, yes, you are correct. We are not dose escalation on the 100-microgram per kilo per week. We are stopping on 100. And second question is that we have taken 50 to 100-microgram and using that in our cohort expansion. We did it by the look on blinded data because we cannot anyway touch it on an unblinding. So we have been in a situation where we have analyzed and looked at that and came to the conclusion that we believe that the 50 and 100 micrograms per kilo per week is suitable dose to advance in a cohort expansion. Ma-Lou has done an extensive work on trying to look on how we really can help and really change this kind of disease when we can initiate a treatment from the newborn state. And perhaps, Ma-Lou, you can say some of the element you are thinking and consider how we want to move the treatment behind height because height is 1 element, but we really want to address some of the comorbidities from the early stage.

Yes. Thank you, Jan. Very nice questions. So it is true that height is of course, key manifestation in achondroplasia, but what is also really crucial for the patients is what is actually impacting the quality of life And we do see several aspects impacting the quality of life of these patients. For the very young ones, we have the opportunity to actually early on go in and impact the pathophysiology in the growth phase. And that's where we think we have an opportunity to address the major other manifestations like the narrowing of the foramen magnum, which is also leading to devastating foramen magnum stenosis and similarly to stenosis throughout the spine. So there will be multiple other aspects of achondroplasia that we will be addressing in our infant trial.

And your question comes from the line of Jessica Fye from JPMorgan.

First, and maybe this is following up on the last question, but I just want to make sure I understood. Can you just elaborate on what specifically in the blinded data for TransCon CNP helped inform the dose selection for the ACcomplisH China trial? Is the decision to select 1,500 based on biomarkers or blinded height data or both? And if biomarkers, can you tell us which biomarkers informed the dose selection?

Let me just add here. So let me come out and give you some kind -- how we see the situation with biomarkers. Currently today, there is no validated biomarkers for achondroplasia. [indiscernible] CNP some people have measured have nothing to do with target engagement in the growth plate, just illustrate an effect of measuring something in the cardiovascular where you have CNP exposure or target engagement. If you go to specific biomarker reflecting the different development of growth you have 4, 5 different biomarkers. None of them are validated. None of them are established as a way to correlate to growth. So when we look on biomarkers and why we are not really super [indiscernible] about it is because if I see some changes, I really do not know is that a validated change for really giving a meaningful impact on really the disease, the thing we want to see the target engagement. So from that perspective, it's really, really hard to discuss biomarker inside this kind of condition as achondroplasia. The selection is done on blinded data. And the most important thing is sure to look on how our primary outcome, which are analyzed height is developing on a blinded basis. And this is how we came to this decision.

Great. And can you talk about when we could expect data from ACcomplisH China to get some larger sample size at those higher doses? And I guess related to that, when could we expect Phase III to start for TransCon CNP?

Yes. Let me just go back 1 step because what we really are finalizing now is what we call the ACcomplisH trials. The ACcomplisH trial is the 57 patients that have been treated for 1 year, double-binded, placebo control, and we will have this data available for you and everyone in the end of next year. We are enrolling now in the ACcomplisH China with the dose expansion, and I believe it will be in 2023 before we will give you the top line data from that perspective. When we look on these 2 trials, we will basically look on the efficacy, safety on double blinded, and then it's really up to Dana and her team to find out how do we really progress to the next data. Are we going into discuss this with the regulatory agencies in Europe and in U.S. and see what is their feedback. What do we potentially need more. Dana?

No. I think, Jess, it's always dependent on the data, right? And so once we get the unblinded data, we have the full package, we have the China data, then we'll put it all together and talk to the agency about how we feel that, that sort of demonstrates efficacy and safety for the product. And then that's when the discussions about any further clinical trials would take place.

And your next question comes from the line of Alethia Young from Cantor Fitzgerald.

One, just can you talk a little bit about with the European and the U.S. kind of PTH market? I mean, I know obviously not any therapies there, but kind of any nuances that we should be thinking about? And then how much does the ped hypoparathyroidism opportunity add to the number that you kind of talked about as well?

Thanks a lot for this question. And I could asked about how do you really describe your pipeline in rare disease endocrinology. And one person and investor come back to me. When I look on your rare disease endocrinology pipeline, I see the appetizer, TransCon Growth Hormone. I see TransCon PTH, the main meal. And then I see TransCon CNP, the dessert. And I really like it because when I see the different kind of patient we really are addressing, yes, we are addressing a huge patient population with TransCon PTH. When I just look on the numbers and that is patient that already has been confirmed chronic hypoparathyroidism, is about 200,000 in just what we are addressing in U.S., in Europe and Japan in where we have a Phase III trial going today. When I listen to the patient, when I listen to the physician, looking on the data and then looking on the background demographic and everything like that, do you see any kind of sub-population that is benefit more than anyone else? No. All the patients benefit exactly in the same manner. So out from my perspective, all as we heard today should have the benefit to get a normalized life again. All of them should have the benefit to get a TransCon PTH treatment. I really believe this is our vision to get out to all this patient. Would that happen? No. But at least, we can have the vision and when I look of the patient that need the treatment, it's all of them. Aimee, do you have any comments to the patient perspective?

Not in addition. I think, Alethia, you asked about different between U.S. and EU. And as far as we understand, hypopara looks the same, although conventional therapy may be different from country to country and geography to geography, the experience is very similar.

And your next question comes from the line of Joseph Schwartz from SVB Leerink.

I'm Joori dialing in for Joe. I wanted to follow up on the TransCon PTH question asked earlier, but maybe ask it a little bit differently. Could you talk about the higher PTH exposure needed to treat hypoparathyroid patients? Does the bone turnover marker seems to cool off and trend towards baseline at week 58. But did you see a reversal and an increase after higher doses of TransCon PTH? Can patients achieve steady state and bone turnover? Are you expecting bone turnover to continuously increase with higher doses?

Aimee?

Sure. So what we see overall in the program are that patients really need a broad diversity of therapies. And you could think of it like insulin, you could think of it like levothyroxine therapy for hypothyroidism. Different people have different needs depending on what potentially the duration of disease and what they're asking their body to do. You heard very eloquently that calcium and phosphate are important from nerve and muscle function, brain and heart, right? So on the background, you're always going to have folks who need different doses. And sometimes life situation changes, right, weights change, exercise, stress. So there's going to be a background fluctuation, not often, but at times when you're asking the bodies to do different things. On top of that, we think there is -- what we're seeing with our data is this initial burst -- release of calcium from the skeleton that is not going to continue to release after a certain amount of time. We're still going through that amount of time, so we'll figure it out. But eventually, we do expect that the skeleton would reach a steady state, and that's what we're already seeing, for instance, with the CRM markers getting there. And then we wouldn't expect that the dose would keep changing up or down by a whole lot, except for life changes. You asked what we're seeing in the trials? We're seeing people going up, but we are seeing at times some people going down. And I think this is very much the heart of hormone therapy in general.

Okay. Great. That's helpful. And then my second question is on TransCon CNP. A competitor needed to submit 2-year data to the FDA. And the agency appears to be focused on about heights. And I understand that your 2 Phase II programs combined has the potential to be robust in volume, but many patients may not have reached the 2-year mark. So we have a 3-part question. First is, how are you thinking about the possibility of needing to show 2-year data? The second is how many patients worth of data -- how many patients worth of 2-year data do you have? And three, how long until some of your patients will reach adult height?

Yes. Let us just recap where we are in the program. We are in the program now where you can already see from the data we presented, we already transferred patient over to open-label extension study, meaning is that they already have 1 year. Basically, when we come end of year, there will be patients that will have 2 years of data. So we continue to accumulate the patient data, and we will also have long-term data that will go over 2 years. But what I think is important was Dana's comments reflecting to let us look at the data, let us see how powerful they are. But what we have done, which I think is the fundament from our program to have 2 double-blinded trials going in a position where we will generate more than 120 to 130 patient data. And we will have them for 2 independent trials, both double-blinded placebo-controlled. We believe this is a very strong target. We believe that Dana and her teams will go back and discuss it with the regulatory agencies, and we will come back and inform you when we have got that feedback. But until we have seen the data, until we have got the feedback from regulatory agent, it's speculation from our side.

And your next question comes from the line of Anita Dushyanth from Berenberg.

Just as a follow-up to the PTH candidate. And at some point you said that the patients would need to have a higher dosing to promote the bone turnover activity. And when that happened, would they still be needing that 600-milligram per day calcium supplement?

Yes. I think, first of all, when we think about 600-milligram calcium per day, this is what you typically take in a multivitamin tablet. So having 600-milligram today and not like me as eating cheat and cappuccinos and all things are led with a lot of, lot of dietary calcium in it. Potentially, you should take a multi-tablet with 600-milligram a day. So when we talk about multivitamins, 600-milligram, I think that the majority or many people should take that just to be quite sure if they not have a dietary intake has high enough. This is why we have a limit on 600-milligram because that reflects what you typical will take in a multivitamin tablet.

I absolutely concur. So Anita, the recommended daily allowance for general population, just not even hypopara is to get dietary calcium of about 800 to 1,200 milligrams per day. So 800 to 1,200 milligrams. For some, just like Jan said, that's pretty straightforward. For others, it can be really difficult. And that's whoever you are, hypoparathyroid or not. And that's the reason you want to take enough dietary calcium every day is so that you don't ask your skeleton to subsidize. That's a dangerous position to be in. So initially, the skeleton subsidizes in this disease population of hypoparathyroid. But once they reach a steady state, we don't want their skeleton to continue subsidizing, right? The kidney and the intestines should do their job, and the intestines can only do their job if we're eating enough dietary calcium.

Yes. And what is really important for me, what is important for us, what is important for the TransCon PTH program that we basically can do the normalization of what we want to achieve. So what we are looking for, what we're seeing now, we're just seeing the normal people. Some normal people need to take calcium supplement because the dietary intake is not high enough. And this is the important part of we're normalizing the PTH level to the physiological level, making them independent on it. But if you are a normal person, potential some of them will take a 600-milligram just to be sure that you are in a position, that you have sufficient calcium intake.

I can share with you based on NHANES data in the United States, the average adults is estimated to take about 400 to 500 milligrams a day by diet, right? So that's the average American adults. So one could say on the flip side that the average American adults should be taking a supplement if they expect to get adequate dietary intake.

That is also reflected in our discussion with regulatory agencies, both in Europe and U.S., we're saying is hormone replacement is defined to 600-milligram or less that is really what we call normal. And therefore, it's basically successful if you just take less than. The treatment goal is not 0. The treatment goal is to be normalization.

Okay. That was very helpful. And then my second question is on CNP. Now the candidate is for -- is aching a different place and different joints. So can you maybe just talk about how you sort of plan to check on that in the different joints, the effect of CNP?

It's really difficult for us to check in each single joints, but what we can look in our outcomes, basic to measuring that reflecting that we do an expected normalization of a normal yin and yang related to different bone growth. And that is we can do different places like, for example, this proportionality in my view, is the simplest form of anything to look for you had an uneven growth between different bones. And Ma-Lou, I looked on different ways to look on bone growth, for example, related to [indiscernible] and face and trying to see can we really find way to do measuring for that. Ma-Lou, if you have any comments to that?

No, Jan, I fully agree. We are, of course, doing different measures when looking at the bone and bone growth. We're measuring total height of the children, but we're also measuring individual bone parts of our arm, lower arm, whole arm, arm span and so on to evaluate where the growth actually takes place. And then, of course, we are, for safety reasons, also thoroughly doing physical evaluations at all visits to ensure that there are no potential complications. But so far, it seems really reassuring.

Thanks, Ma-Lou.

And your next question comes from the line of Vikram Purohit from Morgan Stanley.

So I wanted to go back to your comments at the start of the presentation regarding your efforts with broadening the pipeline. So first, you noted that you would like to file one oncology IND every year going forward. So my first question is, how are you thinking about which targets might make sense for future INDs? And what's guiding your prioritization process there? And then secondly, you also mentioned efforts around standing up a third pillar beyond endocrinology and oncology. So just wanted to see when we might hear some more updates on that effort?

Let me start on your last question. We have seen how successful we have been with utilizing the TransCon technology and our specific product algorithm for innovation together. This is the combination of 2 elements, both the TransCon technology, but the way where we use validated target, validated parent drugs. Combine them in highly differentiated product opportunities, really addressing some major unmet medical need. That is the combination we have seen extremely successful. What we have done with the first 2 oncology product. One, using 1 part of our technology platform, the 1 you know for growth hormone, 1 you know for PTH and CNP, but we took it on to what I believe is potentially one of the most interesting product opportunities, our best-in-class or expected best-in-class IL-2. Really, I think it's an interesting compound. We have seen data now from Stina related to the other technology platform, a paradigm shift, how you inject in the tumor and having a compound being liberated for weeks, months inside a tumor really changing the microenvironment of the tumor to be immological reactive. What we are looking for? Can we find some kind of limitation now with these 2 product opportunities? Where we need to add a third, fourth, fifth candidate into it? That is what we're looking for in oncology. And I think we see limitation, we see things we can do. But -- and that is where we see synergy in what we do. We are in hemological treatment paradigm shift, and we will continue to look at that. We are not going in and developing me-too products, never. When we go to the third topic, Kennett and his people had been working to find out where can we really develop a new where we can use the same TransCon technology that you have seen already now, for example, in oncology or what I call the localized delivery. And Kennett has promised me that all his effort now has been really been successful. So we expect sometime next year, we can come out with a new therapeutic area that will be built on the same technology platform, the same algorithm of product innovation that we have seen successful in other therapeutic area. Kennett?

So definitely, what we are looking for is to make sure that we have a pipeline approach every time we go into a new therapeutic area. You have seen it for you have seen it in oncology. And for the next therapeutic area, we want to ensure also that we have a deep pipeline as we go in. So this is what we are doing now. I think we have a good idea of the direction we want to go in. And now we're ensuring that we have those additional product opportunities so we can build a deep pipeline in the new therapeutic area as well.

Your next question comes from the line of René Wouters from Kempen.

Two questions on TLR7/8. Did you expect dose level 1 to be an active dose level? Or did you start to sub-therapeutic this? Secondly, regarding larger and or more dispersed tumor types. I'm curious if you have a sense of how far the drug or hydrogel travels inside the tumor? Are you planning to inject in multiple places when redosing in subsequent injections?

Yes. I think Stina will address both questions. But what the way I describe our TransCon TLR is not really the penetration then mean something. What it really means, can you kickstart the hemological system to be reactive into the tumor? And can we kickstart the hemological system also to provide an [indiscernible] effect in the rest of the body and eliminate it. This is the element not so much what we penetrate just in the tumor. But more specific question for you, Stina.

Great questions. To follow up on what Jan was mentioning, as a kick starter, this is the resiquimod mechanism of action is really to be that kick-starter of the immune system. So it's not really depending on direct cytotoxic effect, meaning it's not dependent on the fact that you can distribute resiquimod all throughout the tumor. So from that perspective, we expect that the antitumor effect is really from the immune system being trained to recognize the tumor-specific antigens, being able to give you that not just local but also potentially abscopal antitumor effects. Your other question is on how we picked the dose. So I think there are 2 key criteria we use. One is on safety, we understand from nonhuman primates. And the other one is to look at a dose that we expect not only good amount of pharmacodynamic effects, but also a likelihood of antitumor efficacy from our preclinical models. So we fully intended to start at dose level 1 at a potentially efficacious dose for the patients who are on the study.

Thanks, Stina.

And no question. Back to you, Scott Smith.

So thanks, everyone, for joining the call today. We really appreciate taking the time to hear more about Ascendis in our programs, and we look forward to delivering on some great catalysts in the coming year and chatting with you further. Thanks, everyone. See you.