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

Good day, and thank you for standing by. Welcome to the Fourth Quarter and Full Year 2024 Ascendis Pharma Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to Scott Smith, Chief Financial Officer. Please go ahead.

Thank you very much, operator, and thank you, everyone, for joining our full year 2024 financial results conference call. I'm Scott Smith, Chief Financial Officer at Ascendis Pharma. Joining me on the call today are Jan Mikkelsen, President and Chief Executive Officer; Sherrie Glass, Chief Business Officer; Jay Wu, President, U.S. Market; and Aimee Shu, Chief Medical Officer. Before we begin, I would like to remind you that this conference call will contain forward-looking statements that are intended to be covered under the safe harbor provided by the Private Securities Litigation Reform Act. Examples of such statements may include, but are not limited to, statements regarding our commercialization and continued development of SKYTROFA and YORVIPATH for the U.S., European and other markets as well as certain financial expectations; our pipeline candidates and our expectations with respect to their continued progress and potential commercialization; our strategic plans, partnerships and investments; our goals regarding our clinical pipeline, including the timing of clinical trials and results; our ongoing and planned regulatory filings and our expectations regarding the timing and the results of regulatory decisions; expected market developments and our exploration of market opportunities in therapeutic areas outside of endocrinology rare disease. These statements are based on information that is available to us today. Actual results may differ materially -- 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 today, February 12, 2025. TransCon Growth Hormone or TransCon hGH is approved in the U.S. by FDA and in the EU has received MAA authorization from the European Commission for the treatment of pediatric growth hormone deficiency. TransCon PTH is approved in the U.S. by the FDA for the treatment of hypoparathyroidism in adults. And the European Commission and the United Kingdom's Medicines and Healthcare products Regulatory Agency have granted marketing authorization for TransCon PTH as a replacement therapy indicated for the treatment of adults with chronic hypoparathyroidism. Otherwise, please note that our product candidates are investigational and not approved for commercial use. As investigational products, the safety and effectiveness of product candidates have not been reviewed or approved by any regulatory agency. None of the statements during this conference call regarding our product candidates shall be viewed as promotional. On the call today, we will discuss our full year 2024 financial results, and we'll provide further business updates. Following some prepared remarks, we will then open up the call for questions. With that, let me turn it over to Jan.

Thanks, Scott, and good afternoon, everyone. 2024 was a favorable year for Ascendis as we achieved key milestones that set us up to deliver strong growth and value creation in 2024 and beyond. With SKYTROFA firmly established as a high-value growth hormone brand in 2024, volume grow sustainable with revenue reaching around EUR 200 million on a 6.5% market share of the total growth hormone market in the U.S. and around 45% of the total U.S. long-acting growth hormone market based on third-party prescription data. With further penetration in pediatric growth hormone deficiency and a planned commercial launch across multiple indications and countries, we expect sustained value creation for the TransCon Growth Hormone franchise in the coming year as outlined in our Vision 2030. Importantly, YORVIPATH, the only FDA-approved treatment for hypoparathyroidism in adults, is now launched in the U.S. and has already begun to establish itself as the new standard of care. Given the long-standing need for a treatment option like YORVIPATH, we are seeing significant early demand in both the patient and physician communities. And we are pleased with the pace of payer approval so far. The large global population living with a significant hypopara disease burden underscores the potential for YORVIPATH to grow into a multibillion-dollar product over time. Rounding out our endocrine rare disease portfolio. TransCon CNP clinical data demonstrated it could be a highly differentiated product with a unique profile that represent a major step forward in the treatment of achondroplasia and other growth disorder. We believe that once-weekly TransCon CNP data demonstrating superior linear growth and benefits beyond linear growth, supporting our proposed label for treatment of achondroplasia. For this reason, following our pre-NDA meeting with FDA, we are on track to submit an NDA to FDA this quarter, followed by MAA submission to the EMA in the third quarter of this year. All 3 of these endocrine rare disease medicine demonstrate the value of our TransCon technology platform and its potential to address major unmet medical needs with highly differentiated products. We are also bringing the TransCon technology platform beyond endocrine rare diseases in large patient population through our collaboration with Novo Nordisk in metabolic diseases such as obesity, type 2 diabetes and cardiovascular diseases, in ophthalmology through the creation of Eyconis. We have also expanded the TransCon technology platform to incorporate protein degraders, a very promising area where we believe that new -- the new TransCon technology platform will expand our pipeline with additional potential blockbusters. We entered 2025 with a very strong financial position with a cash of EUR 665 million on our balance sheet, including the $100 million upfront payment that we received from Novo Nordisk last month. As a result, we are in a strong position to invest in commercial uptake and new product development to drive continued revenue growth. Let me review our key programs in rare endocrine disease in more detail. In the U.S., SKYTROFA was launched just over 3 years ago. Today, it's the treatment of choice and at the same time, growing the growth hormone market. Importantly, with the pediatric growth hormone deficiency indication alone, we are currently addressing only half of the existing U.S. growth hormone market. Both are on path to expand SKYTROFA's addressable market in multiple ways. Near term, we expect U.S. approval in adult growth hormone deficiency this year with our PDUFA date on July 27. Longer term, we will investigate SKYTROFA in additional therapeutic areas through a basket trial, including idiopathic short stature, SHOX deficiency, Turner syndrome and SGA. In the third quarter of this year, we plan to submit an IND application for this basket trial to the U.S. FDA. Planned commercial launches across multiple countries. In 2024, SKYTROFA volume increased 84% in the United States with premium net pricing of 3x compared to once-daily growth hormone. SKYTROFA achieved revenue of around EUR 200 million in 2024, supporting the potential for it to become a blockbuster product over time. Moving to YORVIPATH. 2024 was a critical year for YORVIPATH with commercial availability in Europe starting early in 2024 and then this past December in the U.S. With YORVIPATH also available to named patient programs, patients in multiple continents living with hypoparathyroidism can begin to assess this long-awaited treatment option. Hypoparathyroidism represent a large global market opportunity for Ascendis to address a major unmet medical need for an effective and well-tolerated treatment option. To create durable, long-term leadership for YORVIPATH, we are building this market by educating physicians about the well-documented limits on risk of conventional therapy and the clinical benefit seen with our PTH treatment. In the U.S., we estimate there is about 70,000 to 90,000 patients with chronic hypoparathyroidism, most of whom are currently using conventional therapy of oral calcium and active vitamin D. Our claims analysis demonstrate that 10,000 to 15,000 of these U.S. patients are uncontrolled and 30,000 to 35,000 are partly controlled. We believe YORVIPATH can sustain growth over a long time as the vast majority of patients with hypoparathyroidism qualify for PTH treatment per the current international guidelines. Less than 2 months in the U.S. YORVIPATH launched, initial demand is strong with 908 patients with prescriptions as of February 7, 2025. This includes prescription for 539 unique prescribers in around 44 states. Nearly 80% of the enrollments are new to YORVIPATH, the majority of whom are switching from conventional therapy, with the remaining being existing patients from the TransCon PTH clinical trial or expanded access program. Discussion with payers are ongoing. And as expected, with a novel specialty product, we estimate the majority of insurance approval will take about 4 to 8 weeks. We are pleased with the initial pace of insurance approval across commercial and government payers and have shipped reimbursed drug to patients in around 35 states. Outside U.S., we remain on track for decent commercial launches in what we call Europe Direct countries, where we expect to add 5 or more countries this year. We also expect launches in multiple international markets in 2025, further expanding our global reach where we have signed 8 exclusive distribution agreements covering 50-plus countries so far. YORVIPATH is a unique product. Our broad and extensive clinical data include 3 successful Phase III trials in the U.S., Europe, Japan and China, covering diverse disease groups, including post surgery, autoimmune, ADH1, idiopathic hypoparathyroidism. Last year, we presented 3 years data from our Phase II PaTH Forward trial. And later this year, we plan to present 4 years data demonstrating excellent patient retention and sustained serum calcium control and bone health, sustained reduction of calcium phosphate product independent from conventional therapy and normalization of 24-hour urinary calcium [ excretion ]. The data also showed sustained improvement in kidney function. Switching to TransCon CNP. Achondroplasia remains a disease with high unmet medical need, and we believe TransCon CNP has the potential to be a highly differentiated treatment option. In the pivotal ApproaCH trial, TransCon CNP demonstrated significant improvements in linear growth and body proportionality compared to placebo as well as benefit beyond linear growth. As one example of benefits beyond linear growth, we have shown data demonstrating significant improvement with TransCon CNP treatment on leg bowing, a common and [ debilitating ] complication in achondroplasia that can result in pain, impaired physical function, need for corrective surgery and a negative impact on quality of life. TransCon CNP has shown a safety and tolerability profile comparable to placebo with low frequency of injector site reaction, all of which were mild, and no evidence of hypotension effect, supporting TransCon CNP potential as a best-in-class treatment for achondroplasia. Following our productive pre-NDA meeting with FDA, we plan to submit an NDA for the treatment of achondroplasia during the first quarter of 2025 and submit an MAA for treatment of children with achondroplasia to the EMA during the third quarter of 2025. We believe TransCon CNP will be setting a new bar for treatment of achondroplasia. To further raise this bar for linear growth and other clinical benefit, we are also working on a combination treatment of TransCon CNP and TransCon Growth Hormone in achondroplasia. Ascendis is uniquely positioned to bring these 2 once-weekly medicines together in a combination treatment, providing 2 different modes of action to potentially improve outcome in achondroplasia and other growth disorder. We look forward to sharing top line week 26 results from Phase II COACH trial of TransCon CNP in combination with TransCon Growth Hormone, which we expect in the second quarter of 2025. Additionally, during the fourth quarter of 2025, we plan to submit an IND or similar to investigate TransCon CNP alone or and in combination with TransCon Growth Hormone for the treatment of hypochondroplasia. Looking to how we are expanding our pipeline in endocrine rare disease. We are expanding into additional product candidates beyond our first 3 successful medicines as we disclosed at the JPMorgan conference. In addition, we continue to broaden the reach of our platform outside endocrine rare disease and [ through ] collaboration in therapeutic area affecting much greater patient number. For oncology, our internal development continues to focus on TransCon IL-2 beta/gamma aiming for accelerated approval in one or more indication. In early '24, we announced the formation of Eyconis to explore the development of TransCon-based therapies in ophthalmology. In November, we announced a multiproduct collaboration with Novo Nordisk covering metabolic and cardiovascular diseases with a lead program to develop once-monthly TransCon semaglutide. This entitled us to escalating tiered mid-single-digit royalties on global net sales of approved products. Finally, as I mentioned earlier, we have expanded TransCon to incorporate protein degraders, a technology with very promising potential within as well as outside rare endocrine diseases. Ascendis today, with approved commercial product, a strong pipeline and guided by our values of patient, science and passion, is positioned to continue driving rapid and sustained growth in the years ahead. I will now turn it over to Scott Smith.

Thanks, Jan Mikkelsen. The progress we made in 2024 enables us to head into 2025 with the financial and organizational strength to execute on our strategic priorities, which are: to successfully launch YORVIPATH on a global basis; to build on SKYTROFA's leadership position in pediatric GHD by expanding the U.S. label to adults while maintaining its premium net pricing of 3x compared to daily growth hormone; and to submit TransCon CNP for approval to treat achondroplasia in children in the U.S. and the EU. I will touch on some key points surrounding our fourth quarter and full year financial results, but for further details, please refer to our 20-F filed today. SKYTROFA volume increased 37% in the fourth quarter of 2024 compared to the fourth quarter last year, while reported revenue was EUR 58.5 million compared to EUR 64.2 million reported in the fourth quarter of 2023. In the fourth quarter this year, SKYTROFA revenue benefited from volume growth and a favorable sales adjustment of EUR 4.6 million attributable to periods prior to January 1, 2024, which was offset by higher sales deductions compared to the same period the prior year. Backing out this favorable sales adjustment, SKYTROFA revenue was approximately EUR 54 million for the quarter. Sequentially, SKYTROFA volume increased 16% in Q4 compared to Q3, while pricing was stable. We expect revenue growth to continue to track closer to script growth unless payer mix changes substantially as there have been no major contracting changes compared to Q4 last year. Shifting to YORVIPATH. As previously reported, fourth quarter YORVIPATH revenue increased to EUR 13.6 million, bringing total 2024 revenue to EUR 28.7 million. As Jan noted, the launch of YORVIPATH in Germany and Austria in 2024, together with the initial demand in progress with reimbursement in the U.S. so far in 2025, has been very encouraging. We expect that YORVIPATH will have a significant impact on our financial profile in 2025. While it is early in the launch, we look forward to sharing data on parameters like enrollments, prescribing HCPs, time to reimbursement, et cetera, to provide more detail on launch dynamics. More importantly, everything we are seeing in the early launch phase supports our view that over time, we expect YORVIPATH to be the standard of care for patients with hypoparathyroidism and to become a multibillion-dollar product. Closing off the top line. Total revenue for the fourth quarter was EUR 173.9 million, including revenue recognition of the $100 million upfront fee related to our collaboration with Novo Nordisk as well as other revenue from partners. To be clear, although we recognize the $100 million from Novo in 2024 for accounting purposes, the cash was received after year-end in January. Total revenue for the full year 2024 was EUR 363.6 million. Turning to expenses. For the fourth quarter, R&D costs totaled EUR 79.3 million compared to EUR 90.9 million during the fourth quarter of 2023. The 13% decline was largely due to lower external development costs for TransCon Growth Hormone and TransCon PTH as well as the Eyconis spin-off. SG&A expenses in the fourth quarter of 2024 totaled EUR 80.2 million compared to EUR 64 million during the fourth quarter of 2023. The EUR 16 million increase was due to higher employee costs, including the impact of additional headcount supporting global commercial expansion, most of which came toward the end of the year. Similarly, we spent more on external commercial costs to support launch activities and plan to continue to do so in 2025 with the global launches of YORVIPATH. Total operating expenses were EUR 159.5 million for the fourth quarter of 2024, a 3% increase compared to EUR 154.9 million during the fourth quarter of 2023. Total operating expenses for the full year 2024 were EUR 598 million. Net cash financial expenses for the full year 2024 were less than EUR 1 million, while net finance expenses for the full year were EUR 74.4 million, driven primarily by noncash items. We ended 2024 with cash, cash equivalents and marketable securities totaling EUR 560 million compared to EUR 399 million as of December 31, 2023, including the $100 million upfront payment from Novo Nordisk that was received in January 2025. Cash at the end of '24 would have totaled EUR 655 million. Finally, as separately announced, we expect to use approximately $25 million in the first quarter of 2025 to preserve approximately 200,000 ADSs held as treasury shares. With that, operator, we are now ready to take questions.

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

Congrats on the strong YORVIPATH script number and breadth of prescribers. I have one question with a few parts, mostly just confirming some stuff. First, can you confirm that the 908 figure is unique patients and not like cumulative scripts including refills, for example? Second, can you just confirm how many of the EAP and OLE rollover patients are now included in that 908 number? I want to make sure I heard you. I think you said it was 84% new to YORVIPATH, 16% from the EAP and OLE. Lastly, I think you reiterated that you continue to expect the majority of insurance approvals will take 4 to 8 weeks. Can you just confirm that's actually what you're seeing now that you've been in the U.S. market for coming up on 8 weeks?

Thanks, Jess, a lot for the questions. I think we can confirm nearly all the answers. So Jay and Sherrie, will you confirm all the numbers, just to be sure?

Happy to. Jessica, thank you for the question. The first part of your question, from an enrollment standpoint, we can confirm that is unique patient enrollments, so not cumulative repeat. I think the second question you asked was the percentage of patients that are coming over from either the EAP or clinical trials versus those that are new to YORVIPATH. So about 20% of the 908 is existing patients from TransCon PTH EAP or clinical trials and then 80% of patients are actually new to YORVIPATH. And then the third question that I think we heard you ask, Jessica, is more around the 4 to 8 weeks. That is our estimate of what we think it should take. But keep in mind, too, that based on the time frame for which the drug has been on market, it is still a very nascent period of time where, for many of the patients enrolled, that time period hasn't actually occurred yet, right? So we'll need more time to get a better sense of that, but that is our initial estimate today.

For my follow-up, can you provide the YORVIPATH patient number outside the U.S.?

We have not broken that number down. It's still increasing as we expected to do. We are still only in Europe Direct countries, full commercial in Germany and Austria. We have our AP2 program in France, a nonpromotional program that also is enrolling reimbursed patients and then we have our international market [ in this way ]. And the patient numbers are increasing to exactly as we have expected, but we have not broken down the numbers.

Our next question comes from Tazeen Ahmad with Bank of America.

Jan, could you provide any color on how many of the 908 scripts that have been written have now been converted to patients on actual therapy? And can you give us also any color that you might have on what proportion of these patients may have had previous experience with NATPARA? And then I have a follow-up.

Yes. The question you are addressing is a question where we still lack all the information to give you and really the concrete answer that you want to have. What we have done in our market research, we have looked a lot on claim data. And we have defined patient group, which we call the 10,000 to 15,000 patients, which we will call not controlled on standard therapy or conventional therapy, and this patient group is basically seeing the physician at least 4 times a year. And they also will have one thing more in common. They have at least one hospitalization related to the disease. And we also know the limitation in really -- that is in seeing an endo. So out from that perspective, just by the random process when you can see an endo, we actually believe that many of the patients that we see of the 908 actually are coming from the group which we define as more uncontrolled in this. We don't have a positive definition if that is true or not, but that is all expectation in this. The second question you raised about how many patients we have on therapy now is a number we are waiting, some way, to come out with until we feeling we have sufficient, good enough data to give you a solid number because we are now in the initial part of our, you can say, journey of getting them 100% reimbursed. We were extremely positive on the broadness of having reimbursed patients, both from the commercial setup but also for the government side. And we basically are getting reimbursed patient every place from. And when you see the broadness on the state, we're covering with about 35 different states, we're really coming out in all different states. We're also feeling that we are in a very, very strong position. The vast majority of the patients are on-label. And basically, they are also fulfilling exactly the criteria that justifies for them to be on a PTH treatment. So we are really highly positive on the development we have seen in the reimbursement spectrum.

Okay. And then I just wanted to clarify, I think you had said that you were considering providing sales guidance for YORVIPATH for the full year sometime in the middle of the year. Does that -- still the plan?

I think -- Tazeen, I think we would like to give you guidance when we believe in the numbers. And I think that is the criteria we take up. So depending on how we see the numbers going and how we see different regions, we will come up with what we call revenue guidance exactly when we're feeling that we feel a bit confident. Scott always like to give up a lot of numbers. So you can hear in his list and what he said in the prepared remarks that he will come up with a lot of elements that can give you the best possible fundament to build up a solid model in your own way. Comment from you, Scott?

Yes. We will -- as we said, we're excited to continue to share with you the underlying parameters driving the launch, and we plan to do that in the quarters ahead.

Our next question comes from Gavin Clark-Gartner with Evercore ISI.

Congrats on the very strong progress so far. Just had one question on YORVIPATH and one on CNP. For YORVIPATH, how have your discussions with payers gone so far? And what are your assumptions for how some of the prior authorization criteria may read? Specifically wondering if you think it's going to be different than the label. And kind of on that same line, maybe you could just remind us your contracting or gross to net assumptions. That's the first one. On the CNP side, for the CNP plus growth hormone combo data coming in the second quarter, can you just remind us your expectations, specifically on AGV?

Yes. I think Jay will come with some flavor about the contracting [ situation ]. But also, as I said before, I've been lucky to see most of the [indiscernible] criteria. And I have been really pleased how they are aligning to the labeling. But I believe Jay will come up with comments related to the commercial contracting landscape.

Yes. So thank you for the question. As you can expect for any new launch, we are still in the early stages of establishing policy with payers. So just as an example, most medical policies right now for our large national players haven't even published a policy yet, right? So our conversations have all been productive to date, really focusing on the clinical value proposition of the drug. As you can see and based on our data from our array of clinical studies, we feel really positive about the benefit that we can convey to the patient community, and we're having great conversation around that. Specifically, your question around prior auths and what that might look like, we're expecting and, again, as part of those negotiations and discussions, wanting to ensure that the standard PA is consistent to label, both in terms of reauthorization time lines, tests that may need to be conducted to ensure that, again, it is consistent with label. So while many of those plans and policies still need to take some time to come into fruition, we're feeling encouraged by those conversations.

So the CNP question is always looking in the crystal ball because you asked me, Jan, what is your expectation to data you have not really seen? And it's the first time, to my knowledge, everyone have done a combination trial in achondroplasia, a Phase II trial, [ which see ] TransCon CNP and Growth Hormone. And why I think it's really, really interesting because it's 2 different compounds become very different physiological mode of action. And if I ever believe in science, which I always do a lot, it should be a great combination because it's synergistic pathway. And when I look on what you can do when you address the hyperactive tyrosine kinase systems that you have in achondroplasia, you can do that with either the tyrosine kinase inhibitors, you can do it by CNP as short-acting or, you can say, continuous exposure. I think it's easier to saturate the annualized height velocity in this part of the integrated effect you expect to give as a treatment option in achondroplasia. One of them that's easiest to hit is basically the annualized height velocity. And when I look on all the data, it's likely are going at around 5.5 to 6.0 on annualized height velocity, which basically are reflecting a little bit what the science also would say. You are removing a [ brake ] and you restore normal growth, so out from that perspective. And this is why I love the growth hormone because -- what is growth hormone? This is like sitting in a car and then you suddenly get rid of the speeder. [ Some may take ] a little bit on the speeder, get the brake off and then you really can move. And this is why I feel this combination will give good results. And I look forward to the results as much I can ask you, what would a good result be.

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

Wanted to add my congrats on the strong YORVIPATH launch as well. Just curious, for these 900-plus prescriptions, what proportion of these patients have more severe versus more moderate diseases? And if you can share any early trends of compliance and initial titration, whether it's consistent with your clinical trials.

Yes. It's a question we tried to address with before. But I think, Sherrie, you're also sitting with a lot of data. Potentially, you can, in some way, describe the limitation that we have in our dataset. We need to answer that question today.

Sure. And thanks for the question, Li. So what -- we don't actually have data in terms of the enrollments on patient severity. What we do know though is a couple of important things. One is that, as Jan said earlier, the most severe patients are going most frequently to the endocrinologists. So by that practical matter of them getting into the office to get the prescription, it's likely that we have severe patients initially getting some of the first prescriptions. And as Jan also mentioned, there are a number of those uncontrolled patients in the U.S. There's 10,000 to 15,000 of them and then a number more of people who are partially controlled. So to the extent that we are starting to see some of the first patients being the more uncontrolled and severe patients, we know there's still a tremendous amount of room for expansion beyond that.

Our next question comes from Derek Archila with Wells Fargo.

This is Eva on for Derek. Congrats on the progress. A quick one from us on YORVIPATH. So can you provide some color on what type of docs are prescribing YORVIPATH? Are these like high-volume docs? Or are you starting to get some docs from the community? And as a follow-up, how long do you expect patients will take to convert from drug in the EAP over to paid drug?

Yes. Let me take the last question before I turn it over to Jay or Sherrie. What is happening in our EAP program, the last packet they got was a 3-pack of basic 3 months, and some of them got them in December to -- and January. So the 100-plus patients that we are converting from our EAP clinical trial over will likely come into commercial drug starting in February and then the majority in March. So that was the second question. And I think -- Sherrie or Jay, who will take the -- will you start, Jay?

Sure. Happy to start. I think the question around prescriber breadth, I think, as we mentioned before, 539 across 44 states. We're seeing that pretty broadly across all different types of physicians across all deciles. Naturally, you would expect directionally physicians that are treating perhaps a greater number of patients, right? We're naturally also focusing on them quite heavily. So from a field standpoint, we're actually over 50% reach for a lot of our priority physicians. So I think naturally, you're going to see some directional lean in that direction. But more importantly, what you're seeing is a broad outreach and broad interest across the provider community, agnostic of decile.

And maybe I'll just add to that, that what is really exciting is that we see that we're broadening a lot beyond the NATPARA prescribers. So of the 539 physicians, only about 200, a little less than 200 had prescribed NATPARA. So we see that we're really broadening our reach.

Our next question comes from Yaron Werber with TD Cowen.

I got maybe a couple of questions, Scott, for you. And then I don't know, Jan, if you want to take the next one. I think, Scott, you said that towards the end of the year, you could be -- you could reach profitability on a cash basis. Does that still sort of hold? And what would drive that? How do we -- is it going to be YORVIPATH is the biggest driver? And then secondly, as you think about reimbursement for YORVIPATH, are you expecting, with time, prior authorizations? Or are you expecting not to have any prior auths?

Okay. I think Scott would like to say something.

Yes. I think you're exactly right. YORVIPATH will be a big driver of the ability to cash breakeven. It's a strong launch in Europe for us. Obviously, we're off to the races here in the U.S. And it's a very profitable product. So I think we agree that, that will be a strong driver of breakeven potential this year.

Yes. But I also believe you need to look that U.S. is the numbers we're giving you today. But we basically have a global effort. And we also are, some way, seeing that end of this year, we're starting to take into a much, much higher gear in our Europe Direct countries. We also see the international market is starting to really, really get engaged. I expect that it will be a major event for '26 where all the countries will come in mainly with full year launches in -- for many of them, but '25 will be where we start in both the Europe Direct in at least 5 countries more but basically also our international market. So the U.S., sure, is a fast market, is a fast penetration we can get because it's so large single market. So sure, it will dominate in the beginning of the year. But just remember, the number of patients outside the U.S. with hypopara is so much, much, much larger, perhaps four-, fivefold than what you have in the U.S. The second one, will you take that, Jay?

Yes. Sure. I mean from a prior auth standpoint, I think the question was what do we expect for YORVIPATH. It is a specialty product, and I anticipate there to be some basic questions, even if it's as simple as who's prescribing it, right? I think -- whether it's an endocrinologist, whether it's a nephrologist, et cetera. And I think secondly, what you're going to see and should expect is there's going to be wide heterogeneity across what you'll see across both national and regional plans. I think as we alluded to before, we are seeing approvals across commercial payers, public payers. And even absent of there being a formalized policy at some of the large national payers, we still submit generic prior auths to seek exception through that policy. So again, some of this will take time to evolve and some of that we would expect to change. But we will see probably a wide range across the various plans.

Our next question comes from the line of Joseph Schwartz with Leerink.

I'm Joori Park dialing in for Joe. I believe in the last earnings conference call, you mentioned that in Germany, physicians are prescribing YORVIPATH to about 1 to 2 of their patients, whereas in the U.S., you are expecting physicians to prescribe the drug to 2 to 3 of their patients. And based on the metrics that you provided today, it seems like on average, each physician is prescribing the drug to a little over 1.5 of their patients. So I was just wondering if you're still expecting each physician in the U.S. to prescribe YORVIPATH to about 2 to 3 of their patients. And where does it go from there?

Yes. I think in some way, I accept what I said and I stand by what I said before. And I think the pattern we see now is an early launch. I have seen and follow some of the physicians that was part of our EAP and clinical trial. And one -- some of these physicians have been already making prescription up to 20 patients. So no doubt the [ broadness ] of that will come. But in some way, this is in early launch, 1 to 2 months in the launch. So I will expect that to see and come in the future.

Okay. Great. That's helpful. And then a clarifying question. Are there any -- are any of the 908 prescriptions included in the YORVIPATH sales from 2024, considering the drug was available mid to late December?

Scott?

I mean strictly speaking -- so we did ship a very small amount in December. It was basically immaterial to the total.

Yes. So in practical, no.

Our next question comes from the line of Kelly Shi with Jefferies.

Congrats on the great quarter. On manufacturing front, how should we think about the capacity to meet the increasing demand of YORVIPATH throughout the year?

Yes. I think one of the things we have been very, very proud at Ascendis is really our robust supply chain. We have seen how we have managed to go up in high demand on the shortage of the daily growth hormone and could fulfill all requirement for all [ wishes ] for having, for example, the SKYTROFA brand. And when I look on the YORVIPATH, we're using the same solid supply chains, the same infrastructure. We followed the same way. I personally get a weekly report on every compound in every region, in every place where we are selling product, how many months there is on storage. And we, some way, are taking that as a really serious thing because we will never be in a position that we will go short. And that is our vision, and I hope we never come to this positioning.

Our next question comes from the line of Ellie Merle with UBS.

Congrats on the launch progress. Just in terms of how we should think about the U.S. YORVIPATH script cadence, I guess, sort of what's the latest that you're seeing in terms of the cadence of new starts? Are you sort of seeing a steady number of adds each week? Was there a bolus upfront? How should we think about this going forward? And second, just a follow-up on reimbursement. I know you said you're seeing approvals across a number of plans. But could you characterize maybe sort of the number of scripts that have been covered so far and sort of any trends that you're seeing in terms of ease of reimbursement, say, between the moderate patients versus the severe patients and your expectations there?

I think the question related to what we call controlled to partly controlled and -- patient, we have, in some way, answered this to our best of knowledge. We have no clear data of the patients that is -- already have received a prescription. We have a gut feeling, and the gut feeling is that we believe many of them belong to the uncontrolled part because they see the endo in a much higher frequence than anyone else. Related to the pattern on prescription, we are not breaking it down in weeks or anything. This is something we are following [ where we are tight ]. And we would like to see a pattern being developed. We don't believe there's really a huge bolus coming in because there is not a huge availability of the [indiscernible] really to come in and say, oh, I just want to have an appointment, run into an endo and now we have a prescription. It's not like [indiscernible]. Like Aimee is sitting here. If you want to see Aimee, our CMO, at Stanford, it takes how many weeks now, Aimee?

12.

12 weeks to see her. So it takes a little bit of time to get an appointment. So we don't believe that it's a lot of built-up demand. It's patients that come in and have the need to be in a treatment. And I think it's pretty obvious for me, when I see the benefit that all the patient gets, everyone should have a treatment option and come on PTH like everyone on type 1 diabetes should have insulin. This is a hormone replacement therapy in this perspective. Related to the reimbursement system, I do not know, Jay, if you have further comments compared to that.

Yes. As we mentioned before, because this is such early days, I don't think we would be able to draw a meaningful pattern or trend based on just a few weeks that we've been in here. I think I go back to the statement we made before. We are seeing approvals across all -- both commercial and public payers, but fully recognizing too that because many policies aren't in place, a lot of these cases are exception-by-exception basis. And we believe that after at least a few more months, we'll have a better sense of how these policies shake out and what that more stable trend should be.

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

First, on SKYTROFA, you had the PDUFA date coming up this summer for the adult growth hormone deficiency. I'm just curious, how should we be thinking about that in terms of what that market opportunity actually presents?

Yes. I think Aimee can explain on the unmet medical need that really exists in adult growth hormone deficiency. From my perspective, there's 2 key things I really -- some way, are reflecting over a lot. First of all, it's an area with extremely low penetration. To our best knowledge, it's under 5%, 6%, 7%. So you can say there is a huge opportunity for growth. And the other thing is that has been a huge burden basically, to be in the treatment with daily growth hormone. But Aimee, you can explain and tell about what is really the unmet medical need, the burden of having adult growth hormone deficiency.

Sure. Happy to do so. So many people arrive at growth hormone deficiency in adulthood following something involving organically the brain, right, so a brain tumor or brain cancer or its treatment, either surgery or radiation. That's at least 50% or more. So many of them, because they are missing function of the pituitary gland, are taking many hormone replacements. And growth hormone is just one on that list. So they have oftentimes said, if I -- if it's something we can make simpler, right, that the community could provide more simply to them, they would -- it is something they would consider, knowing that it adds to their metabolic health and overall endocrine health, right? But of course, their first priority always are the 2 lifesaving hormones from the brain, that is from the adrenal gland and the thyroid gland. So those you can't forget, and those are pills. So after that, they are willing to think about injectable, less frequent therapies, knowing it is good for their overall health. We could admit that growth hormone deficiency is not immediately life-threatening the way that if you don't take thyroid or adrenal replacement is. So we think we're in a nice sweet spot here. If it's hormone that should be replaced and if it meets patients' expectations, we think there would be [indiscernible].

And just jumping over to YORVIPATH. I'm just curious as to thoughts on potential competing pivotal data coming out this year and how you think the market ultimately might evolve.

Yes. If you reflect on pivotal data, I don't think there is anyone else than one compound, the [indiscernible] compound. And to our best knowledge, when we talked with [indiscernible], their last patient in was in the beginning of November. So I'm still waiting to see the results of the pivotal trial. It's a small trial with a little bit more than 100 patients. So it shouldn't take too long time to clean the data and come up with the top line data. But I have not seen anything else. When I go back to the science at one of our key values, this is not a hormone replacement therapy. This is a substitution of the long-acting effect where you basically are placing part of the receptor system into a fixed position and therefore, have a long-acting effect. It's not even reflecting the normal biology where you are basically activating both the PTH 1 receptor and the PTH 2 receptor. And by doing the different mode of action, you already are -- from the data, can see that it can now substitute, as in hormone replacement therapy, element on where you see it's not restoring normal function, for example, in the kidney, both with -- for example, related to phosphate excretion. See, for example, it cannot lower a key element like calcium phosphate complex. You also see the unnatural activation to the activating system in the bone and other organs. And then I'm not talking about the hemogenic potential that is in the compound. So we are looking forward to see the data. We would like to see the data, and we hope one day that will come out. They should be out there now because it's so long time since the last patient came into the visit.

Our next question comes from Paul Choi with Goldman Sachs.

Congrats on the early launch success with YORVIPATH in the U.S. My first question is on YORVIPATH. And as we look at consensus numbers, The Street is modeling less than 900 patients in the U.S. for this year. And you've already exceeded that in terms of scripts. So I was just wondering, recognizing that you're not giving guidance and not -- and the reimbursement is a work in progress, just your level of comfort with The Street, a revenue number for the full year possibly, or any color around that would be great. And my second question is regarding CNP and the hypochondroplasia program that you plan to file an IND for later this year. Are you planning to do any run-in activities ahead of that possibly at some of the centers just to potentially help accelerate the timing of that study and enrollment? Any color there would be helpful.

Yes. Let me take the first part together with Aimee because we are really dedicated to be the leader in growth disorder. And when we see the 2 cornerstones we have, TransCon Growth Hormone and TransCon CNP, we really will do the best for the patient in [indiscernible]. How can we design an optimal treatment in this way? And what we're doing now in hypochondroplasia is design what is really the pathway forward for us. Is it then just a TransCon CNP treatment? Or will it be a combination treatment between TransCon CNP and TransCon Growth Hormone? And we are now in a position that we are starting the discussion with regulatory agencies. But I think Aimee can give you a little bit of background why we, some way, think that when we're moving into hypochondroplasia, it's one of many growth disorders we actually would like to focus on. And the actual design can also be a different state process.

So -- exactly. We are taking the time to give hypochondroplasia the opportunity it deserves. While some of hypochondroplasia overlaps highly with achondroplasia and the genetic variant arises on the same FGFR3 receptor, the gene changes are very different along that whole receptor. And we are understanding that hypochondroplasia has a unique phenotype. It's a broader phenotype and very unique. So along those lines, we are still figuring out -- it's an active process, what's the population of interest to us, where we can benefit from them, and therefore, the different ways to find a regulatory path forward, which I think gets to your question about how much time do we put in into the run-in. So I couldn't tell you now as we are still figuring a lot of this out. But I think the condition and other conditions of short stature, especially on the skeletal dysplasia genetics side, right, deserve a very good, thorough understanding to find the best way to accomplish.

And we are in this position that potentially we will start both trials at the same time, CNP and then combination trial. And then we will basically evaluate the data and find out that potentially we will go for an approval for both. And then they can choose the optimal treatment from the physician, how they best can serve the patient needs in this way. If they really want to have a much more extensive linear growth, likely, the combination therapy will be the preferred option. Related to your last -- first question, I think we said in Scott's prepared remarks that we are not giving any guidance, as you correctly said. We would like to give you as much as possible what we can call elements we are using in our own modeling and giving that as fast as we can give it with all the different [ goals ] to ensuring that you have the best possible modeling that you can do. And I think Scott is always open for discussion. He's extremely extroverted, like to talk with people. So I think if there is any element of model discussion, I think he likely will engage in it.

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

I guess on YORVIPATH, I wonder if you could talk a little bit about how titration is working in the real world with patients, whether that requires additional visits with their HCP, et cetera, if this is done at home. And then maybe could you talk a little bit about your expectations around gross to net stability in 2025 for SKYTROFA?

Aimee, would you take the first?

Sure. The first question was about titrations with YORVIPATH. From what we've heard so far, right, this is in the domain -- this is the sweet spot for endocrinologists. They know how to titrate medicine. So we are -- but that being said, I'm not sitting on the shoulder of each prescriber, and I can't see what they're doing week-to-week. I think so far, they have found it straightforward to follow. They have gotten the guidance that they wanted. And the only times we may have touch points with them will be as we go further along and one switches from the medium-dose pen to a high-dose pen or a low-dose pen. But we don't have that insight yet. But from what we're hearing just anecdotally, it's what endocrinologists know how to do.

At least what we have seen now by being in market in Germany for one year now, we are not seeing any issues to the titration and patient-physician feel that is not complicated and easy element to do it. And they're getting up on conventional therapy exactly at the same speed that we saw in our clinical trials, which surprised me a little that they were doing in the same speed as we do when we have much more regional framework for a patient to come into and talk with the physician. It's same thing happening in real life. They're out of conventional therapy extremely fast.

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

The first one on YORVIPATH. So when you report first quarter earnings, are you going to break down sales to tell us how much is coming from Europe, how much is from U.S., please?

That's a good question. We will decide when we come to that state exactly how we report the data.

Okay. Then a follow-up question on SKYTROFA. I believe what I heard was that the adjustment has largely been over for 2024, but you haven't really given any guidance unlike in January last year, you put out the guidance for 2024. And are there any uncertainties surrounding SKYTROFA? Is that related to the adult launch or more related to the pediatric market, please?

Yes. Thanks for the question. So we expect revenue growth to continue to track closer to script growth going forward, unless, of course, there's payer mix changes -- substantial payer mix changes. And this is primarily because there's been no major contracting changes compared to last year -- Q4 last year.

That's all the time we have for questions today. This concludes today's conference call. Thank you for participating. You may now disconnect.