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

Good day, and thank you for standing by. Welcome to the Ascendis Pharma COACH Trial Interim Topline Week 26 Data. [Operator Instructions] Please be advised, today's conference is being recorded. I'd now like to hand the conference over to your speaker today, Scott Smith, Executive Vice President and Chief Financial Officer. Please go ahead.

Thank you, operator, and thank you, everyone, for joining us on today's call. Joining me are Jan Moller Mikkelsen, President and Chief Executive Officer; Aimee Shu, Executive Vice President of Endocrine & Rare Disease Medical Sciences and Chief Medical Officer; Sherrie Glass, Chief Business Officer; and Jethro Ekuta, Chief Regulatory & Safety Officer. Before we begin, I would like to remind you that this presentation will contain forward-looking statements that are intended to be covered under the safe harbor provided by the Private Securities Litigation Reform Act. Examples of such statements may include, but are not limited to, statements regarding our continued development of TransCon CNP and TransCon growth hormone combination treatment; our pipeline candidates and expectations with respect to their costs; continued progress; potential commercialization success; our strategic plans; and our goals regarding our clinical pipeline, including timing and results of clinical trials. These statements are based on information that are available to us as of today. Actual results may differ -- could differ materially from those in our forward-looking statements, and you should not place undue reliance on these statements. We assume no obligation to update these statements as circumstances change, except as required by law. For additional information concerning the factors that could cause actual results to differ materially please see our forward-looking statements section in today's press release and the Risk Factors section of our most recent annual report on Form 20-F filed with the SEC on February 12, 2025. On our website is a presentation that we'll go over, and the speakers will refer to the slides as they go through. I'll now turn it over to Jan.

Thank you, Scott. I will start on a high-level summary of the key finding on the COACH trial, 26-week interim analysis that we announced in our press release early this morning here in [California]. After that, Aimee Shu will go more in depth to all the different data. Just to remind you, COACH is a Phase II trial, have 2 elements, our once-weekly TransCon CNP and our once-weekly TransCon growth hormone in children with achondroplasia from 2 to 11 and it's the first ever conducted Phase II trial with the combination of these 2 products. Before I start, I would like to give you a little bit perspective if -- what is my own expectations. Because if I look at untreated achondroplasia children and look at them on the growth chart, seeing them going around talking with their parents, they have typical and annualized growth velocity around [4.0 to 4.5]. And when you compare to ACH height score, obvious reason, there are around 0 if they developed like a normal achondroplasia child. We saw in our trial, our pivotal trial with monotherapy, an increase in annualized growth velocity. We also saw a lot of positive effect beyond linear growth effect, why we have this unique product opportunity that is now under priority review really as a background fundament for further treatment. But we also wanted to explore this situation, can we boost all the positive effect we saw with TransCon CNP? Because we will always need TransCon CNP and I will come back to this. When I not focus on the positive benefit beyond linear growth, but just focus on linear growth, we saw a treatment benefit with monotherapy for moving annualized growth velocity up to 5.5 to 6. This is generally what you see in after 1-year treatment. And when you look for 52-week ACH height score improvement is about 0.3. So when I now report the data to date, where I look on the group coming from the TransCon CNP naive children that basically started immediately on the combination therapy and so and annualized growth velocity of 9.1 centimeter and an improvement in ACH height score about 0.53 over 26 week compared to what is typically seen with any kind of therapy that addresses the hyperactive tyrosine 3 kinase, which are about 0.3 over 1 year or Scott has calculated 52 weeks. I'm really impressed. This is really a boost to growth that we have seen. When we take the other arm that is the CNP treatment naive, and Aimee will tell about how long time they have been on treatment and other things like that. We saw an annualized growth velocity of 8.2 centimeter and improvement in height score about 0.44 over the 26 week. Just remember, always look on the age of the children. They are different, and that is always affecting some kind of growth velocity. I believe this is a result of a new clinical benchmark for achondroplasia and we so clearly, that it was a healthy growth. The linear growth was associated with an improvement in body proportionality, bone age advanced compared to chronological age. And one thing I never thought that will happen, the combination therapy, TransCon CNP, TransCon growth hormone treatment exceed annualized growth velocity 97th percentile of average-stature children. In plain Danish or Scottish English, they are growing much, much, much faster than any of the best growing of a normal child. No patient dropped out and safety and tolerability was really when we look at the data comparable to what we saw from the different monotherapy. Summary, week 26 data demonstrates the potential to boost growth 3x above the observed CNP monotherapy in the same period. So if you have an achondroplasia child, that some may are coming to the situation I need more growth, also needs the effect beyond linear growth that you get with TransCon CNP. But I need more growth, you can get a healthy growth by boosting in 3 to 4-year treatment in 1 year. I think that is a pretty positive proposition. But I think more important, which are summarized in Slide 2. It basically moved to the situation, science is really the key things in Slide 4. People have thought it was interesting. I talk about a car with a brake, a car with a speeder. But I actually believe what we try to do in Slide 4, try to take this simplified manner into the in depth of our biological understanding. This what we did in Slide 4. But the basic principle is the same. When you have a hyperactive tyrosine kinase, as you have in achondroplasia, partly hyper achondroplasia and other things like that, you basically have a break on specific part of the development of the speed of a normal bone. This is the brake. And when you release the brake, you really can see the huge stimulation effect on multiple parts on the bone development with growth hormone. Also going back to the saying, yes, growth hormone has a limit effect when you have brake on, obvious. When you have the car, sitting with a good brake on, you cannot press speed. You still see some positive effect by growth hormone treatment specific, you see durability of the effect. I've seen 40, 50 children up to 4, 5 years now, still positive effect without CNP. But what we do with the combination, we unlock the potential of the positive effect on TransCon growth hormone. I will stop now, and move it over to Aimee that will start to go through all the data.

Thank you, Jan. Hi, this is Aimee. I will start on Slide 5, which depicts the design of the COACH trial. We enrolled a total of 21 subjects, including 12 who had not previously received TransCon CNP therapy that is they were treatment-naive. These patients received a combination of TransCon CNP plus TransCon Growth Hormone together from the outset. That's represented in the purple line. This also includes 9 subjects who had been receiving TransCon CNP monotherapy as part of a prior TransCon CNP clinical trial ACcomplisH or AttaCH. And for these subjects, TransCon Growth Hormone was added on top of their TransCon CNP. Today, we're here to talk about the week 26 interim analysis. The COACH Trial is assessing a variety of endpoints, as you can see at the bottom of the slide. And here, we are reporting on annualized growth velocity achondroplasia specific height Z-Score and body proportionality. I'll now turn to Slide 6. Slides 6 and 7 show the baseline characteristics and demographics of the patient population enrolled in the COACH Trial. The TransCon CNP-treated cohort reflected in green was on average older, almost 8 years old as expected. And overall, the children enrolled were representative of the achondroplasia population and consistent with the demographic we have enrolled in prior studies. So again, the treatment naive cohort average age 4.67 years, just shy of 5 years old and the treatment experience just shy of 8 years old. You see here, we have 2/3 boys, 1/3 girls. I'll now move to Slide 7, where we show additional baseline demographics and characteristics. One important thing to point out that is different between the 2 cohorts here is the growth benefit that is observed in the TransCon CNP experienced group, which is reflected in the higher achondroplasia specific height Z-Score at the COACH Trial baseline. So you see here in the green column, the children who have been on TransCon CNP monotherapy for an average of 2.5 years at the 100-microgram per kilogram per week dose, have now achieved a height Z-score of 1.28. And this is where they are starting the COACH Trial. Slides 8 and 9 contain information about safety. So at the Week 26 time point here, we have seen an excellent safety profile for the combination of the 2 therapies through week 26. In fact, the safety and tolerability profile looks similar to what is observed with each agent individually and the adverse events were generally mild in nature. Importantly, we saw no symptomatic hypotension and no fractures and no bone issues suggestive of overly rapid growth. There was one serious adverse event and this was determined to be unrelated to study drug according to the investigator. Now I'll move to the efficacy results, which start on Slide 10. This is the most exciting thing. What we see in terms of efficacy at week 26 is unprecedented in achondroplasia. We see an inflection in growth consistent across multiple endpoints looking at growth. So here on Slide 10, represented in purple is the treatment naive cohort, who again were on average 4.7 years old, and here, we saw an annualized growth velocity of 9.14 centimeters per year at week 26 representing an increase of 4.2 centimeters per year in growth velocity compared to baseline. This was statistically significant at P of 0.0063. The substantial improvement in growth velocity was commensurate with an improvement in achondroplasia height Z-Score represented here on the right-hand panel, which is a secondary endpoint in the COACH Trial. The achondroplasia specific Z-score in the treatment-naive patients after 26 weeks of therapy was positive 0.99, and this reflects a 0.53 increase compared to their baseline coming into the COACH Trial. Again, highly statistically significant with a p-value of 0.0009. Now on Slide 11. This represents the 9 children who are treatment experienced with TransCon CNP, and they are represented in the green bars. It is very similar to what you just saw in the slide prior. At week 26, these children who are, on average, almost 8 years old, had a AGV of 8.25 centimeters at 26 weeks, representing an increase of 3.1 centimeters compared to baseline. Again, highly statistically significant at P of 0.0006. On the right side of the screen or the right side of the slide, we see the achondroplasia height Z-Score now up to 1.72 after 26 weeks of therapy, reflecting an increase of 0.44 compared to this group's baseline. Again, statistically significant. It is noteworthy that these treatment-experienced children had already reached a mean achondroplasia height Z-Score of plus 1.28 represented in the gold bar there after a mean of 2.5 years on TransCon CNP monotherapy. And yet, they still accumulated a mean increase of 0.44 of the Z-score in just 26 weeks. From these data, we can see that the addition of TransCon Growth Hormone demonstrated a boosted growth in children previously treated with TransCon CNP. Now I'll turn to Slide 12, which is really helpful for contextualizing the efficacy data, here at week 26. The blue line represents the annualized growth velocity at the third 50th and 97th percentile for children of average stature based on the CDC database. While the gray and black lines show the range of annualized growth velocity for children with achondroplasia. So we have the 2 AGV normative reference ranges here represented on the same slide. For both the TransCon CNP treatment naive subjects and the TransCon CNP experienced subjects at baseline, they were within the range observed for growth velocities of children with achondroplasia. You can see here that the gray circle, the treatment-naive children were as expected right at the 50th percentile for children with achondroplasia, whereas the gold circle representing the treatment-experienced children average age almost 8 were already at the top percentile of growth velocity for children with achondroplasia, again, reflecting there were multiple years of TransCon CNP monotherapy. The combination of TransCon Growth Hormone on top of TransCon CNP [halted] these children to a level of annualized growth velocity above that of average stature children in both cases that you can see here in the purple and the green dots, which are both above the 97th percentile line for children of average velocity. This opens up the potential that for children with achondroplasia, that they would be able to achieve new possibilities for healthy bone growth with less comorbidity and fewer complications from their disease over the long run. And this brings us to the slide about body proportionality, which is on Slide 13. Here, we'd like to show you that importantly, the linear growth we are seeing is aligned with significant improvements in body proportionality, here upper to lower body segment ratios in both the treatment-naive and the treatment-experienced subjects. This is a strong indicator for the breadth of the effect of the combination and the fact that we are achieving healthy bone growth. We know that body proportionality, specifically the healthy growth of the appendicular skeleton, that's the limbs is of key interest to those living with achondroplasia. And also the U.S. Food and Drug Administration has also acknowledged that improvements in skeletal proportionality could mitigate complications of the condition. And with this, I will now turn it back to Jan for the wrap-up.

Thanks, Aimee, for this walk through, all this impressive data. For me, when I saw this data, I was really thrilled and I'm feeling we're now in a position that we can expand the treatment option for children with achondroplasia. If there is a desire from the caregiver, the physician, the patients, we have a way we really can boost the effect on what we have seen on linear growth with TransCon CNP, and we hope we can see the same improvement in the other element beyond linear growth. The next step for us, as we said before, is to have the week 52 data as Aimee said will come end of the year, and we plan to begin a Phase III trial here in the end of this year to ensure we can get the fastest way at all to get this important treatment out to the patient. We also see this year as a way to build our franchise as the leading company in the area of growth disorder, musculoskeletal health. We are in a unique position with our once-weekly with our once-weekly SKYTROFA, with our once weekly TransCon CNP that both have 2 distinct synergistic effect, and we will explore that to a lot of different indications. There are more than 20 possible indication that is in this selection of indications. And we believe it that we can really develop the most adapted treatment to each of these single indication, either with SKYTROFA alone or TransCon CNP alone or in combination for this patient group. So thank you a lot for this early morning call. And I will now turn it over to Scott.

Thanks. Operator, we are now ready to take questions.

[Operator Instructions] We will now go ahead with our first question. This is from Jessica Fye from JPMorgan.

Congrats on the update. I guess 2 here. First, curious how you're thinking about the design of the Phase III trial, you're starting in the fourth quarter? Should we expect that to include both CNP naive and experienced children? And then second, just to put a little more context around the combination group here, the children who had been on CNP before adding SKYTROFA. It says that the baseline achondroplasia height Z-Score was 1.28 here. Just to put that in context, can you remind us what TransCon CNP delivered on achondroplasia height Z-score in approach?

Yes, there was a lot of questions. So I hope I got everyone down here. And I think Aimee, will likely help me here in all the different elements. But let me first -- the first thing. When we look on the combination therapy and see how robust that is because what we saw in -- when we look on each single subject, basically everyone benefit from it. So even if you came down with a low annualized height velocity, and you came into the trial, everyone got a benefit for it. So that really shows the robustness in the treatment. So when we think about open up for the inclusion and exclusion criteria, we basically take everyone in. That can be on prior growth hormone treatment before pass we need a washout period, that can be on other short-acting vosoritide product, then could be on other things that really address the hyperactive tyrosine kinase. And we will take them in because we know all of them need it. So we will be open for that, and we think a really single study, we still need to get [through this year] but we still need to have our discussion with regulatory agencies. But we believe it's a simple design with 2 arms, one with TransCon CNP, one with TransCon CNP post SKYTROFA and compare them over 52 weeks. We see that as a very, very standard, simple design, but it will be open basic for everyone. Then you go -- went back and talked about just what I -- as I recall it, we have 2 groups in this trial. We have one that was naive. They come in and started to put -- both on SKYTROFA and TransCon CNP immediately. And then if you go to the slide that Aimee someway -- took up where she looked on the demographic and I can correlate you directly to the slide that is Slide #7, where she came in and looked at the treatment. You can see when you look at the age 1 group, the treatment naive is much younger, 4.7 or the other one is 7.9 and you can also see that the group have been on a mean treatment with TransCon CNP on 100-microgram per kilo per week for about 2.6 years. And during this year, you can see the effect of that, as Aimee explained on the height score that came from basic typical around 0 or a little bit positive to it and then moved up to 1.28. What we generally was seeing on height score in monotherapy is around 0.3 on 52 weeks. And I think what Aimee did, really excellent, which we believe is really a beautiful slide is the Slide 12, where you basically can see the difference on when we compare to ACH Z-score achondroplasia there. You can basically see how we are having the -- our patient group that was naive just in the middle on the achondroplasia 50 line, but we also saw the treatment benefit of the 2 years where the basic are moving up to the high 95% fraction of achondroplasia. That is the benefit on height that you have received with monotherapy for the 2.6 years. Aimee you can take some of the things I forgot.

Thank you. So you had asked about our Phase III trial if we plan to take in both treatment experience and treatment naive and the answer there is yes, that is the plan. And then you also asked for context about the change in height Z-score achondroplasia specific height Z-Score in the APPROACH trial, the pivotal APPROACH trial. And Jan got it exactly on the head there. Indeed, in APPROACH, as you remember, that was a 52-week trial. The children on average, improved their height Z-score by 0.3. So they went up 1/3 of a standard deviation over 1 year and compare that to what we're seeing in half the year here. We're going up 0.4 and 0.5, regardless of if you're experienced or naive. So you can see why we're enthusiastic about this acceleration, this boost in growth.

I think it's going back to Aimee's comments and also what is on the next step. When we look at this from the perspective, just to focus on linear growth, we are making treatment beyond linear growth. That is our attention, but that's looking on linear growth. We look at the same time period, you basically get more than 3x the linear growth in the same time period.

We'll now take the next question. This is from Gavin Clark-Gartner from Evercore ISI.

Congrats on the very strong data. First, and we'll see how the longer-term data evolves. But do you envision that this combo will be a long-term treatment for all patients until they get up to adult height? Or is there the potential that some patients may go on to the combo for a more fixed duration and then continue on TransCon CNP monotherapy after that? That's the first question. And I just wanted to quickly confirm, do you have the ability to co-formulate CNP in growth hormone into a single chamber injection with novel IP and pricing?

Let me take the last one. This is more simple, because that is clear, I guess. We can co-formulate it, we can make it into one single injection for that. We have not seen any kind of, you can say, feedback that was negative to these 2 injections in 1 week. I think 2 injection with this system in 1 week has not given us any kind of concern to anything that really should impact the implementation on such a treatment regime. Co-formulation, yes, I see it more as LCM activity, and it will be part of our continued LCM discussion in this way. So the first question with some way, I believe there the question that some way we cannot come with a definitive answer because I believe there will be parents, there will be patients, there will physician that really will sit together and talk about what do we want to achieve in our treatment. I think they all want to say, I want to have TransCon CNP because TransCon CNP is really providing the benefit beyond linear growth. We have seen so many places for the parents and the patient and physician really have recognized that. So you always see TransCon CNP will be the background. And I think the data we provided was the reason why we got a priority review for this product because it's really unique background. Then there will be parents, there will be patients, there will be physicians when they are discussed, do we want to accelerate some element like the linear growth for a period of time or perhaps for longer duration. And I think there will be a decision for them some way to go in and discuss related to what is really their wanted treatment outcome, what is that thinking related to height, what is the thinking related to the social impact and other things? What we are providing, we are providing a treatment option, then it's them to select if they want to take it.

We'll move to the next question. This is from Paul Choi from Goldman Sachs.

This is Daniel on for Paul. Congrats on the strong efficacy effects. We have 2 questions. For the hGH, human growth hormone, for the move forward dose, are you thinking about fixed dose? Or are you still -- there is flexibility for adjustment there? And how should we think about potential efficacy regressions at week 52? What would you think for the bar on this ?

So what we have seen of data, and that was a really nice study, a Japanese study, where I think the number of patients was more than 40 and they were followed up to was this for 4, 5 years, 5 years. And what we saw in achondroplasia, we saw a boost in the first 2 to 3 years. And then we saw a continued curve that basically continue much higher than the baseline. When we go to growth hormone deficiency children, where they don't have any break on we also see catch-up growth. Catch-up growth is the biological system you some way have that make you to come up to your genetic potential. When you're coming up to the place in the treatment where you can hit your genetic potential, you go over and more develop as a normal child. So what we saw here is that we really can unlock the catch-up growth. That is what we're doing. We're unlocking the catch-up growth. And this is why when you look on the normal development of a child in Slide 11, we are on 97% factored. This is because you're getting catch-up growth. So I actually believe you will see some of the same biology. I don't know yet. The future will see it, but I believe you will likely see the same biology. When the body believe now I have done enough catch-up growth that I can go up to my genetic potential, then you start to develop as a normal child.

We'll take the next question. This is from Derek Archila from Wells Fargo.

Congrats on the data. So just 2 from us. I know it's a small data set, but just curious on how the efficacy compares across the age match patients in the naive and experienced groups in COACH? So that's question number one. And then question number two, just -- I know it's very early, but beyond the body proportionality are there any other improvements that you're seeing on some of the comorbidities in achondroplasia that you can share with us?

Yes. Let me just start with the first question, and Aimee can add in. Yes, everything what we have looked at, we have seen the same development, positive development that we wanted to see. Some of them we wait for the 52 weeks because this is where we basically have the key primary endpoint, and that will be reported at that time. We also would like to see how the development going over 1 year. When we look and analyze high velocity, we actually see it pretty stable between 3% to 6% and other things like that. It's not like we see huge difference between the different elements on that. Aimee, would you describe some of the classical things we also have done in the monotherapy, but we will basically look on some of the same things, Aimee.

Yes. So just as Jan said, we're waiting to see some of these things at week 52, but these do include radiographic endpoints such as, are the legs growing straighter and then additional anthropometric measurements which is measuring leg length, right, the appendicular skeletons leg length arm span, as they compare to the axial skeleton that's the spine. And back to the radiographic endpoint, we will also continue to be looking at the spinal canal dimension.

I think the question that you were asking to was when we look on the 2 age group, do we see the same improvement in age group? And I had to think why I like the slide that you saw in that now I'm referring back to the same slide again. But it's basically illustrated well, when you go to Slide 11, you basically can see, yes, there is an impact on -- sorry, Slide 12. Scott really came with a good comment today. So if we go to Slide 12, you basically can see that when you look on children with achondroplasia, that is a national development in different -- during the different ages. So when I look on the different age group, the 8 and the 4.5 group, I actually think, I see some of the same response in this way. So I'm really feeling confident. And also when we look on each single subject, there was not one single subject that didn't have a boost really, really a type of boost on them, really show that is a robust response.

We'll take our next question. This is from Yaron Werber from TD Cowen.

Great, congrats on a really nice data for me as well. So I have 2 questions. The first one is on body proportionality. The -- was the baseline 1 point? I'm just trying to put the 0.04 and 0.05 in context. It looks to be similar. I mean, this is 26 weeks. It looks to be similar to what CNP does alone, but that's at 52 weeks. So maybe you can kind of address that. And then secondly, I was under the impression perhaps, incorrectly, perhaps, I misunderstood that you did -- you were able to add a control arm at some point later on in the study because you had so much interest in the study. Can you discuss that and whether we can see that data at some point?

We don't have any control arm. We only have the 21 children, and that's 2 arm, it's pretty, pretty clear. So just referring back to you think, if I look on the TransCon C monotherapy arm and then look on 52-week I get it to be now eyeballing, but it's something between 0.03 to 0.04, it's perhaps 0.38. That basically got improved compared to 52 weeks. So this is a benchmark we had in that. If I go back and look on Slide -- now, Scott is helping me. This is the Slide 13 and then I see this is over 26 weeks, meaning half of the time, half of the time, you basically -- when you look on the treatment naive, you have at least 0.04. And for TransCon CNP treated, you have at least 0.05, so whatever I look at that, it's more double up. Perhaps it's triple up the improvement in the element of body proportionality. I would call an acceleration of the positive part of body proportionality. This is how I see on the data.

We'll take the next question. This is from Joe Schwartz from Leerink Partners.

Congratulations. I was wondering if you've done any payer work to test their receptivity to combination treatment? And then what kind of a label would you expect? Would you -- would this be an sNDA for SKYTROFA? And can you get any unique claims on the TransCon CNP label, which you've been used to encourage people to reach for TransCon CNP over legacy CNP? And then just a clarification. Can you provide any color on why patients are receiving 0.3 milligrams per kilogram per week of TransCon hGH versus the FDA label, which -- for growth hormone, which is like 0.24 mgs per kg, I believe.

Yes. Let me take the last one first, Joe, because when you look on achondroplasia child basic we will call it, they have a normal IGF-1 growth hormone access. So this is the same as you saw in our Turner trial. It's the same as you've seen in some of the other growth hormone indication. And when you go into, for example, ISS, SGA or all them, you basically use a higher concentration of growth hormone compared to growth hormone deficiency. So when you look on our Turner trial, it actually also was done on 0.30 milligram per kilo per week. So it's mainly just reflecting on that in achondroplasia, you have a normal IGF-1 growth hormone access. You can still look on the data and if you look at the data, they actually have lower IGF-1 compared to a normal population. So the basic is you can say, low in IGF-1. And it's a potential also why we see this amazing effect in it. So this is why you use 0.30 in it. Related to payer, we see as we -- in some way as a first part to the market, for example, take U.S. We will have SKYTROFA in the market. We will get hopeful as fast as possible TransCon CNP in the U.S. market. This is 2 independent brands. We will conduct this trial as fast as possible. We know we can get the patient immediately like in our pivotal trial we've recruited in 3 months, unbelievable. And we will get the same interest for this trial. And as soon as we get that on our labeling, we can go out and promote this combination. And -- but the product will already be available as soon as the monotherapy will be in the market. Related to labeling is, yes, this is effect you basically only will see with TransCon CNP will have its own brand name and TransCon growth hormone. This is product specific. It's not something you can achieve in other things. It needs to be proven, if it actually can be achieved with other combinations.

We will take the next question. This is from Li Watsek from Cantor.

Congratulations on the data. I wonder if you can maybe just talk about your expectations for the adult height from the combo treatment? And I noticed there's one severe adverse event in the study maybe if you can elaborate on that, that would be great.

Aimee, will you take the last one first?

Yes, sure. Li, that was the respiratory tract infection viral etiology that required an overnight observation in the hospital and deemed to be unrelated to study drug.

And the element of what you asked is some wasy the idea what we're doing with our combination. We unlock the potential for achondroplasia patient to get catch-up growth. When I look on children, for example, in pediatric growth hormone deficiency, when we unlock the children's potential to get catch up growth, and we know that keeping much better of the treatment. We saw basically 50% of them hitting their average or said a different way. The average height was exactly matching and a little bit higher than the expected parental height from the parents. Meaning is that you basically can normalize height. You can never do that if you then or don't under catch-up growth. That is impossible. And this is why it's such a unique advancement in the treatment of achondroplasia because if the parents, the children decide to do it nowadays a treatment option that really unlock to get catch-up growth. And I think that is up to the parents, the patients, to decide what they really want to get out of it. It's not changing my view that you always need TransCon CNP as a backbone to really provide the benefit not only on linear growth, but also on the treatment benefit beyond linear growth.

We'll take the next question. This is from Eliana Merle from UBS.

Curious, your development strategy indications beyond achondroplasia. There's a lot of data emerging from indications where growth hormone is approved such as ISS, [human] shocks of CNP having efficacy from BioMarin. So I'm curious your strategy for development there.

Yes, you're 100% right that there is a unique treatment opportunity for Ascendis now with where we have TransCon Growth Hormone, TransCon CNP. And now we have seen how we really can -- I would not say prove sceince, because we don't prove sceince. We just unlock science. We really have seen the potential of the combination therapy to unlock new treatment option that never existed before. When I look on the different indications, yes, hypochondroplasia, yes, this is someone what we -- Aimee is trying to plan it in. I think we are planning for more than 5, 6, 7 different indications here for the next 18 months to be initiated in late-stage development. And this is our dedication to take each of our single unique opportunities and develop and basic and portfolio of indication that will be supported with them. And you will hear much, much more about that, the label expansion strategy we have for our different product opportunities, not only SKYTROFA, not only TransCon CNP, but also our TransCon PTH, where we also indicate a lot of labor expansion.

And the next question is from David Lebowitz from Citi.

When looking towards the pivotal, what do you expect to have to show the agency to -- is catch-up growth enough? Do you need to have follow-up long enough to determine that it's catch-up growth plus additional kind of increasing the peak perspective, height for a patient? What ultimately do you think they need to see to buy into the combination?

I think to buy in a combination, I think clearly obvious one is safety. And -- but what we saw here in both with the TransCon Growth Hormone, what we have seen with TransCon CNP and the combination, we don't see any kind of unexpected safety reaction compared to what we have seen on the monotherapy from both them, so we feel really, really confident with the safety we have seen. We will need to show that in sites that basic regulatory agencies will someway calculate, and we will justify it for what should be our sample size related to be to safety. Related to efficacy, it's pretty clear, we will have 2 independent trials that both had 12 months data, and we will be part of the filing. This will be true because of the way we have seen our filing. If I go to TransCon CNP, they have never asked anything else than 12 months data. This is what we have. We have long-term open label extension data. But when I look on the efficacy part, it's 12 months where you have a placebo control. And there has never been a discussion about anything else. It was the same thing with SKYTROFA. There was no discussion about anything else. And I think we will see the same and I expect the same thing also be taken up from the regulatory agencies that you will see the same routine, the same standard that we have used on all our other products, will also be the same for the combination therapy.

Next question is from Kelly Shi from Jefferies.

Congrats on the strong data. Maybe from a biology perspective, how does SKYTROFA or growth hormone works synergistically to TransCon CNP? So the combo can actually boost the growth 3x above the CNP monotherapy given that historically, growth hormone therapy in times very limited effectiveness on growth velocity in achondroplasia patients?

Yes, I actually think this is why we developed this really nice slide that Scott will find out now, what slide number it is? It's Slide #4. And it's really what we call the expanding the treatment paradigm because you are right, growth hormone, even we have 40 -- talked about 40, 50 children that have been treated for 5 years where we give some effect. And -- but the problem is, it's pretty logical. It will have limits effect because if you have a break on all the stimulatory effect of growth hormone. Growth hormone stimulants -- make a stimulation of many places inside the growth plate, by different levels. But if you have to break -- that basic break all the stimulatory effect on it, then you don't see the key element of that. So this is why when you take growth hormone and give it to growth hormone deficient children that don't have a break. And this is why you get the catch up growth. So what we're basically doing with TransCon CNP as a base of background treatment is that you unlock this brake. So you remove the brake. So you more have children looking more like growth hormone deficiencies. And then you can get the catch up growth. And I think this is pretty again biology, but it's really simple and it's following everything what we know from biology. So it's not like we're coming with -- I don't think Scott will get a Nobel price for this. But basically, we will get a lot of elements that basically are in a situation that we are proving that what really are following the biology, following the science, it's really always gives the expected results. When we sometimes don't get the right results, it's because we didn't understand the biology good enough. But this year is really, really well understood how when you have a hyperactive tyrosine kinase 3, you basically have a brake in the system, and you cannot do something that really have a brake and this is where the car came in and everything like that. If you have the handbrake on it, you can really turn on the speed a lot, but it's not really moving the car a lot, Scott telling me that. And then -- but you take the handbrake off, you basically can get it really to move forward. But think about in catch up growth, think about the catch up growth, you see with growth hormone deficiencies because they don't have a brake. We're basically unlocking the brake that is and therefore, you see this high, high growth.

And the last question today is from Luca Issi from RBC.

Great. Congrats on the data. Maybe just circling back on the prior question, just to be clear, will the co-formulation be available and ready to go for the Phase III that you're starting in Q4? Or is this more of a life cycle management at some point down the line? And then maybe, Aimee, can you just talk about the powering for the Phase III? How many patients do you think you'll need in order to hit the stat given the signal here? I think the APPROACH trial was 84 patients, should we assume a trial of similar size? Any thoughts there, much appreciated.

As you said, Aimee will answer the last one. I will take the first one. This is a clearly an LCM activity. So for example, if you say in U.S., we have basically already TransCon growth hormone in the market as SKYTROFA. And we will have TransCon CNP in the market on a different brand name, but it will also be in the market before there will be a fixed dose combination. Aimee?

Sure. Luca, and your question to me was about sample size calculation. So we will start having some ideas now at week 26. Ultimately, we will wait until week 52 because that would be also the main end point for the confirmatory pivotal trial. We will take a look at the treatment effect and then the standard deviation, so that is how much variability we have around the effect and using that with the expectation of what mix we have of aged kids and things like that, we will make a sample size determination. But right now, couldn't say more than that until we see the data.

Basically, what Aimee is saying is that when we do the final element of the sample size, we will initiate the trial now. We will have a calculated sample size where we use the parameter we have seen on the 26th week to estimate it and when we basically are getting the 52 weeks, we can confirm that sample size. But it's a typical why we're starting the trial as fast as possible. So we basically can get this out to the patients as fast as possible.

Thank you. And that is all the time we have for questions today. So this does conclude the conference call for today. Thank you for participating, and you may now disconnect.