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

Thank you for standing by, and welcome to Ascendis Pharma's Phase II COACH trial top line week 52 data Call. [Operator Instructions] I would now like to hand the call over to Scott Smith, Ascendis Pharma's CFO. Please go ahead.

Thank you so much, operator, and thank you, everyone, for joining us on today's call. Joining me are Jan Moller Mikkelsen, President and Chief Executive Officer; and Aimee Shu, Executive Vice President of Endocrine and Rare Disease Medical Sciences and Chief Medical 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 and 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 is available to us as of today. Actual results 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 the 12th of February 2025. Today, we are pleased to review top line week 52 data from the COACH trial, our first trial to investigate how the addition of TransCon hGH, our established once-weekly growth hormone, may increase the clinical benefit of TransCon CNP monotherapy in children with achondroplasia. On our website is a presentation that we will go over, and the speakers will refer to these slides as they go through them. With that, I'll turn it over to Jan.

Thank you, Scott. It's a pleasure to be here today. As I said before, and Ascendis has said multiple times, we always have been confident in TransCon CNP's ability to be a leading treatment for children with achondroplasia. As a monotherapy with full degree of linear growth outcome, where we are addressing the overactive FGFR3 receptor. Beyond linear growth, we also have seen a statistic improvement in leg bowing, body proportionality compared to placebo. And when I look at the safety profile, the tolerability profile, we see all the benefit of the TransCon product technology, which are exactly compared to placebo. We see this very low rate of injection site reaction and no cases of symptomatic hypotension because we have a continued long-acting exposure of a constant level of CNP. We believe TransCon CNP monotherapy can really be transformative by itself. But we also want to really work on how we can give choices, how we can improve treatment outcome, making a new benchmark for what can be achieved in achondroplasia. And I believe this data we have today is really providing the fundament for that. It started with the 26-week data. We showed them for about a half year ago. And now we have the full year data. At that time, we show an efficacy around 3x related to linear growth, which was observed compared to monotherapy when we consider the same time period. It was accommodated with what we wanted to see related to how we have improvement in body proportionality without the acceleration of bone age. No doubt, this is the first clinical trial to evaluate how really a once-weekly TransCon CNP, once-weekly growth hormone really are performing in 1-year data in achondroplasia. I would like to start on Slide 3 in the deck you can find. When I look on the growth data, they significantly exceed any historical benchmark I've ever seen in achondroplasia, creating a complete new bar for what a treatment can achieve in achondroplasia. In naive children, we saw an annualized growth velocity of 8.8 centimeters per year with an improvement in ACH height Z-score of more than 1 plus, 1.02. Remember, monotherapy for all therapy I've seen addressing basically the overactive tyrosine kinase is around 0.3. So basic -- in 1-year treatment, you basically get 3 to 4 years benefit in the combination. I think this is a new bar. In TransCon CNP treated experiences, we got 8.4 centimeter per year with an improvement in height score of 0.82. Still remember, they already have the benefit of TransCon CNP therapy. We do not -- besides that, we also demonstrate benefit beyond linear growth, which is always the aim for us. We really want to aim really addressing the comorbidities. And we saw it -- we saw already with the data we already have, we don't have all the data still top line, we saw an improvement in both body proportionality and for first time, which I've never seen before, a statistic significant increase in arm span, and really an important element of addressing comorbidity. The positive of this, all what we saw were aligned with what we saw related to height. At the same time, the linear growth was consistent with what we saw in the chronological age. So we basically don't see any acceleration. And I have to say, for first time, I think we have broken records in both our trials with SKYTROFA, we broke record with our trials with YORVIPATH. Here, we broke a new record. This is the first time I have been part of a 1-year trial where we basically have 100% of all the patients staying on the treatment. I think that illustrates basically the element of what we want to see in a treatment that really providing benefit to the patient, the physician, the caregivers that everyone stayed on treatment. And I have to say, today, all of them are still on treatment. And safety and tolerability, I think this is inherent because they stay on treatment is really consistent with what we saw for each of the product. Our key takeaway is there is a once-weekly TransCon CNP once weekly is really raising a new bar for treatment in achondroplasia, not only related to efficacy, but also related to safety and tolerability. I would now like to go to Slide 4. And I actually think this slide illustrates everything what we basically summarized related to height. We have many other slides that really addressing what we really want to achieve addressing comorbidities beyond linear growth. This slide is addressing height. So if you start with the gray curve, which are called achondroplasia growth charts. This is how a child with achondroplasia will develop through the different years. And you can see the annualized growth velocity is falling down. And then you have the 50% fractal then 95% fractal. The blue one is what we see from a normal child. And you can see that you have the 50% fractal again, and you have the third fractal and 97% fractal. So when we start with the gray box, the gray box, which have the number of 4.92 centimeter per year, you can basically see that it's naive patient, meaning is that they have never seen really treatment before, either CNP growth hormone. And you can see they represent normal children with achondroplasia because they're precisely under 50% fractal. One year after treatment, they are basically growing much more than you see in an average status child, more than 97% after 1 year, 8.8 centimeter per year. This is what I call a child with a growth, really growing to a level that you not have seen before. 8.4 going to the yellow one with the TransCon CNP, they basically have been on treatment. I think there was on average about 2.6 years. And you can see really the benefit of the TransCon CNP treatment. You can see how they have moved from the 50% nearly approaching the 95% fractal, really the benefit of TransCon CNP related to height. But when we give them growth hormone for 1 year, they are moving up to the same era that you see with the naive patients. The benefit is independent of the background. You do have CNP before or not, really the same benefit. I am really impressed by this data. It was much more than I ever have seen. And I think when Aimee come and give her presentation, you can see the durability of this treatment. It's not waning off. It's continue and continue. I believe that is one of the big surprises we saw in this trial. There is no waning off effect. When we look on what you see between 26 weeks and 52 weeks of CNP treatment and what you see on the combination treatment, the same percentage waning off, meaning is that we basically unblock the potential of growth hormone treatment in this year. So let me go to why I'm really extremely excited about this and why we made a lot of IP on this year for a long time. And it was because we have our values, the patient, the science and not the least our passion for what we do. And what we really went in and looked at, what is really the synergistic effect of different ways. And we know what the hyperactive tyrosine kinase is really doing when we look just on the growth plate because there's a lot of synergies outside the growth plates. In the growth plates, if you have a hyperactive tyrosine3 kinase, you basically are in a position that you put a brake on the proliferation inside the growth plate, meaning take a brake on really limited and when you then think about growth hormone, this is basically an accelerator for many other process inside the growth plate. But you know if you have a brake on a car and then press on the speeder, it's not moving a lot. And this is why growth hormone never, never, never really have been successful except a few places in the world as a monotherapy. When then think about you move the brake and you potentially move the brake more than you see in a normal child. And then you have the speeder on with growth hormone. This is why it's illustrated in the simplified form. So when I think about this treatment paradigm, it can be used to everything. I believe a normal child, if you get that here, that will grow to a complete different -- so from my perspective is this is a new treatment paradigm, a complete new way to look and how you really can get an integrated treatment for basic nearly every growth disorder. You don't need to find out which is the brake, what is accelerator, just give them the combination. And I think this is why I'm so enthusiastic of the data we have seen, which are really groundbreaking, complete new way to think it and open up really to give choices to patients, to physicians and their parents, what do you want really to see. That was my short introduction, and now we go over to the facts, which Aimee will do.

Thank you, Jan. I'm going to start on Slide 6, showing the design of the COACH trial. We enrolled a total of 21 patients, and that included 12 subjects who represented in purple had not been previously treated with TransCon CNP, and these patients received both TransCon CNP and TransCon Growth Hormone from the outset. Then we also included 9 subjects who were already receiving TransCon CNP monotherapy through their enrollment in a previous Ascendis clinical trial. For these patients, TransCon Growth Hormone was added on top of TransCon CNP. The primary efficacy endpoint is annualized growth velocity at week 52, which we are reporting today, and you saw already in Jan's introduction, in addition to some secondary endpoints, including change in achondroplasia-specific height Z-scores and annualized growth velocity at different time points over the course of the trial and some measures of body proportionality, including upper to lower body segment ratios. Slide 7 starts to show the demographics and baseline characteristics of the patient population enrolled in COACH. The TransCon CNP cohort in the purple column was on average, younger as expected -- excuse me, that's the TransCon naive -- the TransCon CNP treatment-naive cohort in purple was younger as expected compared to the treatment experienced cohort. So 4.7 years old versus 7.9 years old. Overall, the children enrolled were representative of the achondroplasia population and consistent with the demographics we have enrolled in prior studies. On Slide 8, we continue to show some more demographic information. As expected, you can see that the TransCon CNP treated children in the green column have now reached an achondroplasia-specific height Z-score of 1.28 after an average of 2.6 years on the treatment dose of TransCon CNP. We also see at the bottom of the table, IGF-1 SDS levels, also called IGF-1B scores. And what you can see here is that in both cohorts, their SDS scores are below 0, indicating below average for healthy children. This may reflect an impact on the growth hormone and IGF-1 access in this achondroplasia population. On Slide 9, we're showing the safety profile for the combination therapies used in this trial. I should say that the dose for TransCon CNP was 100 micrograms per kilogram per week and the starting dose of TransCon Growth Hormone was 0.30 milligrams per kilogram per week. So here, the table with safety shows that we've seen an excellent safety profile for the 2 drugs being together through week 52. In fact, the safety and tolerability looks similar to what was observed with each agent individually and the adverse events were generally mild and unrelated. As you see there, 85% were grade 1 and mild. Importantly, we saw no symptomatic hypotension, so no symptomatic low blood pressure, no fractures. These are in particular of interest given that this is a bone active drug, and we are working on the natriuretic peptide receptor. So this is reassuring. There was one subject, as you see here, who reported 2 serious adverse events, and these were both determined not to be related to study drugs. On Slide 10, we show here reassuringly, bone age remained consistent with chronologic age at week 52 and injection tolerability was consistent with that observed for TransCon CNP alone and TransCon Growth Hormone alone and all events were adjudicated as mild. Now the fun part, we'll move over to a few slides about efficacy. What we see here in terms of efficacy at week 52 clearly raises the bar. We see an inflection in growth that is sustained and consistent across multiple ways of looking at growth. In the treatment-naive cohort on this slide, the purple, who are on average a little over 4.5 years old, with the primary endpoint of AGV, we saw at week 52 that they were growing at a rate of 8.8 centimeters per year on average. This represents an increase of 3.9 centimeters per year compared to their baseline and was statistically significant with a very low p-value. The substantial improvement in growth velocity was commensurate with an improvement in achondroplasia-specific height Z-score shown on the right-hand panel. The achondroplasia-specific Z-score in treatment-naive patients increased to 1.47 from originally from being 0.46, representing a change from baseline of 1.02 standard deviation, and that represents roughly 3x the 0.3 standard deviation change we saw with vosoritide monotherapy in our Phase III trial. Again, this was statistically significant. On Slide 2, we move to the cohort that was experienced with TransCon CNP from being in the other TransCon CNP trials before coming into COACH. These results are similar. At week 52, these children, as shown in the left panel, who on average were almost 8 years old, had an annualized growth velocity of 8.42 centimeters, representing an increase of 3.28 centimeters per year compared to their baseline. This was significant. On the right-hand panel, achondroplasia-specific height Z-score reached positive 2.15 at week 52 and an increase of positive 0.86 compared to the TransCon CNP treated baseline. And this was also statistically significant. So from these 2 slides and data, we can see that the addition of TransCon Growth Hormone demonstrated a boosted growth in those children who are treated also with TransCon CNP. Now moving on to Slide 13, which Jan already walked you through earlier in this call. We're looking at growth velocity charts for average stature boys in blue there and for children with achondroplasia in gray. And this helps to contextualize the efficacy data that we saw at the week 52 primary analysis. So what we're seeing here in the COACH trial is a sustained healthy growth at a rate never seen before in children with achondroplasia. Whether they are naive or experienced CNP monotherapy, the combination of TransCon CNP and TransCon Growth Hormone results in annualized growth velocities on average that are above the 97th percentile of growth rates for children of average stature. Now I'll move over to some benefits beyond linear growth. So on Slide 14, we're showing here improvements in upper to lower body segment ratio, a measure of body proportionality in both treatment-naive kids in purple and previously treated kids in green. This is a strong indicator of the breadth of the effect of the combination and the fact that we are achieving healthy bone growth. The change from baseline in upper to lower body segment ratio is shown on the y-axis. So a reduction indicates the desired lengthening of the lower body segment of the waist and down compared to the upper, the torso body segment. For both cohorts, change from baseline over 52 weeks reaches a greater reduction than was seen with TransCon CNP monotherapy. Now moving on to Slide 15. I have a figure here showing arm span from left fingertips to right fingertips, so the arm scan across the 2 arms of the torso. This is another way to look at clinical benefit in achondroplasia and something that has been of interest to people living with achondroplasia too. Here, we see an inflection in the growth of the arm span that is catalyzed by the use of the dual agents. The effect is seen in both the treatment-naive and the TransCon CNP treated cohorts. What you can see here is that over the course of the year, these children are cutting across IsoPlex. They're cutting across the lines where they would be growing without therapy. And in this case, they're approaching the 84th percentile of arm span compared to natural history in achondroplasia. What's important about arm span getting longer, it's something that we know has been of interest to regulators and to patients. But for example, it perhaps makes it safer to cook on a range or to reach into an oven, perhaps easier to drive the things that -- with a car that doesn't need to be modified. On Slide 16, we show the durable efficacy across the achondroplasia trial. On the right panel, the gold bars, we show that TransCon CNP monotherapy, which is awaiting approval by the U.S. FDA, has established itself as a durable driver of consistent growth in achondroplasia patients in the Phase III trial. So you see there the 5.95 centimeters per year at the end of -- at week 52. In the left panel, shown in purple bars, TransCon Growth Hormone on top of TransCon CNP adds meaningfully to the benchmark set by TransCon CNP monotherapy and again shows durability between week 26 and week 52. So with that, I'll be happy to turn it back over to Jan.

Thanks, Aimee, for going through the data. When I look on the -- take the holistic view of the data, I've never seen data in achondroplasia like this here. The efficacy is out of any benchmark I ever have seen. And that is not only related to linear growth. That is important element how to really improve body disproportionality. For first time, I ever have seen data where there is a meaningful impact on arm span, one of the elements that really have been part of the treatment goal. We're still analyzing the data, getting more and more and more information. But when I see the integrated effect also related to safety, tolerability, I really see that we're building up a new treatment regime with an expectation of an outcome that is really to the benefit of the patient, the physician and caregivers where it's really highly meaningful for them. We're moving forward at what we're doing now. We started already in Q4 to prepare for a Phase III trial. We see the benefit that we basically are boosting the effect at 3x. And we really are working as fast as possible to be in a position that we really were finalizing the Phase III, get it on labeling and see the CB implemented as a standard treatment in achondroplasia and other growth disorder. Ascendis is now waiting for getting TransCon CNP as the first country here in the U.S., we're confident that is happening in the near future. With our integrated pipeline, starting with SKYTROFA, YORVIPATH and a continued investment in R&D from our platform technologies to our R&D engine really to make a sustainable biopharma. I believe here when I look just on growth disorder with both TransCon Growth Hormone, TransCon CNP in our portfolio, both of them really showing some of the most unique properties, each of them, I feel really confident that we're building up the leadership in growth disorder. Thanks so much for today, and we now will take questions.

[Operator Instructions] Our first question comes from the line of Tazeen Ahmad of Bank of America.

Congrats on the high-quality data, the 3.89 centimeters over that 52-week period is impressive. I wanted to get your thoughts, Jan, on how you're thinking about expectations for longer-term efficacy. Is there any risk that this number could potentially lower meaningfully from where it is? And how would you think about the applicability of making sure that you have this longer-term data in hand as part of the label?

Yes. What we are doing now is that we continue our COACH trial, as Aimee described, in an open-label fashion. So we will get 2 years data. When we see the safety profile, it looks exactly as we had hoped for. From that perspective, we don't see any limitation in the treatment from that perspective. When I go back and look on all my 4 children and see them growing and see when they have the grow birth and they are growing so much, is always associated with pain or always associated, we are really a little bit surprised we don't see that. But we also want not really to be in a position that we see this growth that is much more than you see in a normal child continue forever. So we believe how we potentially see a regime, which always will be a decision from the physician, a decision from the patient, decision of the caregivers. But we can see a regime that you basically always as a background, we have TransCon CNP and unique product as a background therapy and then potential for 2 years, you will boost it with SKYTROFA. Perhaps you will take a break 1 to 2 years. And then if you feel that you really need more boosting of the outcome, you will take basic perhaps 1 year, 2 years or more. So make this long answer short, we have not seen any safety concern and limit the use of it. I believe from a practical perspective, you shouldn't some way have this extremely high, you can say, efficacy for year after year after year, but in the end, it will be a decision for the physicians.

Our next question comes from the line of Joe Schwartz of Leerink Partners.

Congrats on the data as well. I was wondering if you can talk a little bit about Phase III design. Was there certain insights from the 52-week results that you were waiting on in order to guide that Phase III design? And can you talk a little bit about the device for TransCon CNP, both monotherapy and when used together with SKYTROFA?

Yes. Thanks, Joe. Let me take the last question, and Aimee can help me with the first question. Currently, what we have now is -- and this is how we are also conducting the clinical trial. We give them 2 injections every week. We have not got any complaints. We have not got any feedback related to that is a height burden or anything. I think it's totally overshadowing the benefit they see in the treatment on it. On an LCM perspective, yes, our vision is to integrate everything in a single injection. And -- but it will take some time, and we need to exactly find out how is the optimal way to have the best patient care really to do this in the most best manner for them. So this is more what you can say, the way of building up the treatment regime on it. Related to the Phase III trial is pretty standard, I have to say. Everyone - it's a 1-year trial as everyone expects to be. We cannot change the primary endpoint in any way, it got established by FDA to be linear growth. We cannot change it, but we will put a lot of emphasis on showing benefit beyond linear growth. And is everything what we see today, everything from body proportionality improvement, leg bowing, arm span that we now have seen for first time. Other thing is quality of life, which we really integrated in a best way, so we really can see that also get the benefit out from the treatment. So it's a very, very simple design. There is basically only 2 arms in it, and this is basic monotherapy and combination therapy.

Our next question comes from the line of Li Watsek of Cantor.

Congrats on the great data. Just maybe curious about the impact on comorbidities. Obviously, you've seen very nice improvement on body proportionality and arm span. Just curious, have you observed or measure benefits on quality of life metrics or muscle function and what comorbidities do you plan to measure in the Phase III?

That is an element that we're still analyzing. We're still getting more and more information from our 52 weeks data and we are still analyzing the radiological elements on it. But as I said before, Li, clearly, element that is extremely important for the patients, body disproportionality, leg bowing, arm span, that can be element related to radiological measuring on the spinal curves, how it's getting developed. There can be other things that we don't know yet. But I think, Aimee, if you have anything to add, I think I nearly got most of them today.

Yes. You got it all. Yes. Quality of life will be part of it. Physical functioning. Yes.

Good. Yes. Perhaps muscle strength, too. So there is a lot of things we're measuring into this. So we just need to find out what is the statisticarity we will use them and to be sure that we can also have it filled into the entire packet in a statistical way.

Our next question comes from the line of Yaron Werber of TD Cowen.

Congrats on the really impressive data. This is Sarah on for Yaron. So we wanted to ask about a little bit more about the Phase III trial design. You noted that there's only going to be 2 arms, the mono versus combo therapy. So just to clarify, you're not going to contemplate a SKYTROFA alone arm. And then just one more question from us, if you don't mind. So given that the CNP monotherapy is under priority review with the PDUFA date of February 28, how do you foresee the labeling and market positioning for the combination regimen once the Phase III data is out?

Yes. You can -- you are 100% right. There is an interest from regulatory agencies and there's also from physicians really to see what is really the effect on a product like SKYTROFA with its unique properties for 15% of the patients. And we are analyzing exactly how we really are doing that, but we will do that. It will be a limit single-arm trial that basically will show that just to illustrate the benefit of the combination too. So I think this is an element that we're feeling we want to do because we always want to be sure we're giving the best possible treatment regime for every patient. Related to your question about the labeling, I think the labeling for our TransCon CNP has been more or less finalized. So we cannot expect any change in any kind of the labeling of TransCon CNP being impacted with this data here. We're using the TransCon CNP IND as a continuation of this year. So we are not filing a new IND. So basically, the combination therapy will build into the CNP filing.

Our next question comes from the line of Maxwell Skor of Morgan Stanley.

Congrats on the positive update. I was just wondering, how do you anticipate payers will view the value proposition of the combination therapy, especially given the potential for higher efficacy, but also increased cost versus monotherapy?

Payer for me is a very, very broad discussion. Are you talking about U.S.? Are you talking about Italy, Germany, South Korea, Japan and everything like that because I think there will be different views from different places. We are building a global company with a global commercialization. And I think there will be a lot of different consideration in each single geographic region. For example, we see a daily CNP not being available in many, many countries today out of the never can live up to the pharmacoeconomic modeling in it. And when we see the combination therapy on a global perspective, we are 100% sure that the benefit is so unique with the combination therapy and the cost structure by adding the SKYTROFA into is not really impacting that in a highly impactful manner. So what we see here, it's opened up for a global commercialization in many countries where basic therapies addressing the achondroplasia are not available today. When we go to a specific country like U.S. I think for first time, there will be a therapy available that's really addressing what the patient want to have, addressing the comorbidities, addressing arm span, addressing leg bowing, everything what we really want to see. And I think this is why it's going to be a completely new way to think about how to treat achondroplasia.

Our next question comes from the line of Paul Choi of Goldman Sachs.

Let me also offer my congratulations on the data. With regard to the Phase III, can you comment on whether you plan to still allow patients who are treatment experienced either with growth hormone or potentially vosoritide still to enroll? And would you also potentially allow patients on background therapies such as FGFR3 inhibitors to enroll in the Phase III? Any color there would be helpful.

Why I'm a little bit stalling here because, first of all, we just are in a position where typical, you will not include other experimental drugs in any kind of protocol. So when you think about what is approved for achondroplasia today, it basically is only one product. So from a logistical point, you cannot have patients coming over for this kind of trial in this way. And as you saw, we didn't see any difference really if they were CNP naive or were on basic and CNP therapy. So we will be the most flexible to adapt. What we really some way need to consider, which I'm still struggling with on a lot of different level is we need to be sure that the experimental treatments are safe enough for us to take them into a trial. We don't want to contaminate our extremely proven safety profile with potential agents that could give a safety profile that we don't want ever to see in our trials.

Our next question comes from the line of Gavin Clark-Gartner of Evercore ISI.

Congrats on the great data. On hypochondroplasia, are you still planning to do a monotherapy and a combination study? I also wanted to confirm if you submitted the IND in the fourth quarter. And as part of that, if you confirmed that you could do a single registrational study in hypochondroplasia?

Yes. Now we start to go down in technical details. And from a technical perspective, you can say it's 2 independent trials because it's on 2 different ways we do the statistical analysis, but it's built in the same way in hypochondroplasia that we see in achondroplasia. But you're right, we are doing an active clinical development also in hypochondroplasia. There's a big difference between achondroplasia and hypochondroplasia, and this is based on the genetic mutation you have. Many of them are not in the same severity or impacted by comorbidities. And currently today, I believe many with hypochondroplasia are successfully treated with just growth hormone therapy. And this is why we always want to give choices and we're designing the trial that we really will give the choices for that. But you're right, how we do it in hypochondroplasia, Aimee, you need to correct me. It's basically 2 independent trials.

That's correct.

So for hypochondroplasia, is it going to be like a combination study versus CNP like you're planning in achondroplasia? Or is there also going to be a placebo arm included there?

Between the 2 trials, there will be some placebo, some mono and some dual therapy.

So you can say it's basically an expansion of the monotherapy at the same time, there was a placebo and a combination. So when you take the integrated value of the 3 trials, you will have 2 monotherapy, one combination and one placebo.

Our next question comes from the line of Yun Zhong of Wedbush.

Congratulations on the positive data. A follow-up question on the Phase III design. I wanted to confirm that you are still going to aim to show statistical superiority of combo versus mono? Or do you think a numerical difference could still be acceptable so that you don't have to run such a large study so that you can bring combo to approval maybe more quickly? And if you do show superiority in the long term, eventually, do you foresee both combo and mono to coexist? Or would you expect maybe combo will replace mono over time?

When we talk about specific achondroplasia, when you look at the number, I think with 12 patients, we can show statistic superiority in that. So we're not limited by the efficacy measuring. We are limited more or less by the safety part and how we also have statistic power to show benefit beyond linear growth, which are the key thing for us to do. And this is, for example, arm length. This is body proportionality. This is quality of life and many of these other things like that. And I think we need to rephrase it. The rephrasing is to say TransCon CNP is the background therapy for everyone we do. And then you add in TransCon Growth Hormone if you really want to boost it. This is like when you're flying the rocket up, then you take the booster on and then it really leaves the earth and really fly high up in the sky. And then when you're up, you remove the booster it's falling off. And I think that is the way we see it and perhaps you need many boosters to come back to the earth too. But I think that is basically how we see the treatment regime.

Our next question comes from the line of Alex Thompson of Stifel.

Congrats on the data. I was just wondering, as you envision kind of the next 12 months or so, with this strong Phase II data, potentially a publication in a journal, et cetera, whether or not you think that it would support in the U.S., for instance, utilization of this combination by physicians that might choose to do it.

That is a question I cannot comment on because I'm not deciding what a physician are using in the treatment. That is a physician's choice together with the patient and other things like that. Aimee and the team are getting ready with publication, and we'll do that as fast as possible.

Our next question comes from the line of Luca Issi of RBC.

Congrats on the great data. Maybe if I can circle back on a prior question. Again, I totally appreciate this is still kind of early days, but how are you thinking about pricing specifically in the United States? Should we simply think about the price of the 2 individual drugs combined? Or is that more complex than that? And then maybe if I can kind of check your temperature on the upcoming PDUFA date, how confident are you that TransCon CNP does get approved by the end of next month and it does not get delayed again? Any context there, much appreciated.

Let me take the last question -- last part of the question. And we have answered everything to FDA even before this year started. So we have not got any request back for them. So we're just sitting and waiting and getting the approval, we hope, as fast as possible. Related to the presentations, as I have some explained before, for years until the basic 2 LCM building into a one single injection, it basically will be likely a TransCon CNP presentation, and there will be a SKYTROFA presentation. And the patient will be taking a combination therapy, which are so common in so many other indications, for example, in the area of cardiovascular, just one thing where you have a lot of drugs being taken to benefit diabetes too and other things like that. And typically, when you look on price structure for this, it's the sum of the 2 that basically are driving the price.

Our next question comes from the line of Derek Archila of Wells Fargo.

Congrats on the updates here. Jan, I was just wondering, can you expand on your comments, I guess, on the timing of when you think like the combo will actually be used in the disease course. You talk about these periods of growth spurts. But I guess, do you presume that like long-term monotherapy will be used? Or will it be combo? Like I guess, how do you kind of envision the overall kind of treatment with the combo evolving from, I guess, early age to age 16, 18 years old?

I think what we're giving here, we're giving a patient choice and physician possibility a society possibility. If I go to some countries, I can be quite sure there will only be one therapy available. It will be the combination therapy. And you will potentially take the combination therapy for 2 years, then make a break, see, do you need it more and other things and then potentially have a cycle of perhaps 3 or 4 cycles in that because it will be the most cost-efficient way to do it. In other societies, potentially there will be a consistency, which I think will be the optimal treatment way of having a consistent background therapy of TransCon CNP, not perhaps not only in the pediatric area, but also in the adult area because there's benefit also at that stage. And then you will boost it perhaps with 3 or 4 cycles of SKYTROFA TransCon Growth Hormone dependent on how much the physician, the patients and everyone and the caregivers feel that is their desire to do it.

Got it. And just a follow-up. So I guess, do you think the physicians -- will they be looking at some sort of just the growth curve, like where they are on it or some sort of biomarker? I guess like you're talking about different cycles, but when -- like I know it's at your discretion, but like give me an example of like when they might want to do that? Because I guess when we try to think about the modeling, like how many cycles they may get of combo, that's what we're trying to understand.

Yes. I think there's a different way. First of all, this is a part why we believe TransCon CNP without doubt will be the leading product in achondroplasia treatment because as a monotherapy, providing the best outcome safety, tolerability for the patient. And now we're adding on a new dimension, unprecedented outcome with combining with a second Ascendis product, SKYTROFA TransCon Growth Hormone. And I think this is what we are providing. We are providing the menu list of how you really have an option to treat the patient in this way. So you can see it from a modeling perspective is that this is just boosting the penetration of TransCon CNP throughout the entire achondroplasia treatment regime.

One way to think about it, Derek, would be when the child starts on medical therapy. If they start early on TransCon CNP, we know that, that brings up to the growth rates of average stature helps straighten the legs, enlarge the spinal canal, that may be enough. So if you start early and you continue it through your growing career and after that might be enough. And if there is a time when they want to get an extra boost, that could be very short term versus you could consider another patient who might decide to come to medical therapy late. And so they have a shorter amount of time before they would close their growth plates. Potentially, for a patient like that, it is more urgent to treat with both for a longer time.

But don't just limit your thinking to achondroplasia here because this is how we will approach every growth disorder, so many different elements of growth disorder, 20 to 25 different diseases, and we will continue to do that. This is the way we're developing the leadership in growth disorders in rare disease endocrine.

At this time, I'd like to turn the call back over to management for closing remarks.

I would like to turn it over to Scott Smith that will have the final remarks.

Thanks so much, Jan, and thank you, everyone, for joining us this afternoon and this evening. Have a great day. Bye.

This concludes today's conference call. Thank you for participating. You may now disconnect.