Ascendis Pharma A/S

NASDAQ:ASND

Earnings Call Transcript 2019-Q2

[Operator]

Good day, ladies and gentlemen, and welcome to the Q2 2019 Ascendis Pharma Earnings Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded.

I would now like to introduce your host for today's conference, Mr. Scott Smith, Senior Vice President and Chief Financial Officer of Ascendis Pharma. Mr. Smith, you may begin.

[Scott Smith, SVP and Chief Financial Officer]

Thank you, operator. Thank you, everyone, for joining our second quarter 2019 financial results conference call today. I'm Scott Smith, Chief Financial Officer of Ascendis. Joining me on today's call are Jan Mikkelsen, President and Chief Executive Officer; Dr. Jonathan Leff, Chief Medical Officer; Tom Larson, Chief Commercial Officer; and Juha Punnonen, Head of Oncology.

Before we begin, I would like to remind you that this conference call will contain forward-looking statements that are intended to be covered under the safe harbor provided by the Private Securities Litigation Reform Act. Examples of such statements may include, but are not limited to, our progress on our pipeline candidates and our expectations with respect to their continued progress; statements regarding our strategic plans; our goals regarding our clinical pipeline; statements regarding the market potential of our pipeline candidates; and statements regarding the planned regulatory filings. These statements are based on information that is available to us today.

Actual results or events could differ materially from those in the forward-looking statements, and we may not achieve our goals, carry out our plans or intentions or meet the expectations or projections disclosed in our forward-looking statements. And you should not place undue reliance on these statements. Our forward-looking statements do not reflect the potential impact of any licensing agreements, acquisitions, mergers, dispositions, joint ventures or investments that we may enter into or terminate. We assume no obligation to update these statements as circumstances change except as required by law.

For additional information concerning the factors that could cause actual results to differ materially, please see the forward-looking statements section in today's press release and the Risk Factors section of our annual report on Form 20-F filed on April 3, 2019. Please note that our TransCon product candidates are investigational product candidates and are not approved for commercial use. The safety and effectiveness of any TransCon product candidates have not yet been established. None of the statements made on the conference call regarding our TransCon product candidates shall be viewed as promotional.

On today's call, we will discuss our second quarter 2019 financial results and provide a business update. Following some prepared remarks, we will then open up the call to questions.

I will now turn the call over to Jan Mikkelsen, our President and Chief Executive Officer. Jan?

[Jan Mikkelsen, President and Chief Executive Officer]

Thanks, Scott. Today, I would like to focus on how our TransCon Growth Hormone program is enabling us to build Ascendis as a global leading biopharma company.

This year, we achieved a major milestone with the completion of our 2 Phase III trials, the heiGHt and fliGHT trials for TransCon Growth Hormone, our once-weekly growth hormone therapy in development for pediatric growth hormone deficiency.

For untreated subjects, we reported data showing TransCon Growth Hormone demonstrated superior efficacy while maintaining comparable safety and tolerability to our daily growth hormone. We also showed it was safe and well-tolerated in subjects previously treated with daily growth hormone and children younger than 3 years of age. Based on this finding, we expect TransCon Growth Hormone to be raising the bar and setting a new standard in the treatment of growth hormone deficiency. With both Phase III trials now completed and databases locked, we are now preparing for BLA filing in the first half of 2020 and MAA filing in the second half of 2020. 2 items need to be finalized for this filing.

First, this quarter, we expect to complete our robust long-term safety packet to be included in the filing. This data set has been agreed upon with input from regulatory authorities in the U.S. and Europe. We are on track to have the last subject out this quarter for the long-term safety data set consisting of around 300 subjects for these 6 months, 120 subjects for 12 months and 45 subjects for 24 months. Second, in the coming months, we will complete the process validation activities and the associated qualifications with both.

With these 2 last pieces on track and the successful introduction of the auto-injector in the enliGHTen trial, we are now taking the opportunity to step back and further analyze all our clinical results from an integrated holistic view across both our Phase II and III trials. Our key learnings are, first, TransCon Growth Hormone demonstrated a safety profile comparable to that of a daily growth hormone. Second, TransCon Growth Hormone demonstrated superior efficacy to a daily growth hormone in the heiGHt trial, with a PK profile of release growth hormone that may indicate more efficient utilization by target tissue throughout the entire body.

Next, TransCon Growth Hormone data showed a predictable response to dose titration, which may provide a physician greater flexibility needed to successfully dose-titrate each patient to the desired clinical outcome at all stages in the treatment of growth hormone deficiency. Last, TransCon Growth Hormone data suggest the same mode of action as daily growth hormone by preserving the biological balance between the direct effect of growth hormone and the indirect effect of IGF-1 in target tissue. These results highlight the importance that a long-acting growth hormone must have the same mode of action as daily growth hormone.

By releasing unmodified growth hormone, the same molecule as daily growth hormone and endogenous growth hormone, TransCon technology is uniquely designed to leverage both the direct and indirect effect of growth hormone in the same balanced way as daily growth hormone has for this case. Indeed, it is the combination of the direct and indirect effects of growth hormones, which are the key to support the body's overall endocrine health. This includes not only heiGHt but also body composition, metabolic and cardiovascular health and even mental well-being. With TransCon Growth Hormone, we are not changing this biology. We are simply replacing what the body is missing on modified human growth hormones.

In our Vision 3 by 3, the goal is to achieve sustainable growth through multiple approaches. 2 important strategic drivers for sustainable growth for our endocrinology rare disease pipeline are global clinical reach and label expansion programs.

Let me start with the global clinical reach. Recently, I traveled to China to visit the leadership of VISEN Pharmaceuticals, our strategic collaboration formed with an investor syndicate nearly 1 year ago. After discussion with the team leading the development of TransCon Growth Hormone in China, I left confident that through VISEN, we have the local expertise and a firm plan for the development and commercialization of our rare disease pipeline in Greater China.

In addition, Ascendis is also in a unique position where we have the possibility of conducting clinical trials for our rare disease endocrinology pipeline in China through VISEN. That potential could accelerate our development time lines in the Western world.

Why is the Asian region important for Ascendis? As you may know, China and Japan are now the second and the third largest pharmaceutical market in the world. Many of the fastest-growing pharmaceutical markets are also in Asia, reinforcing the importance of this region in our Vision 3 by 3 strategy to create sustainable long-term growth through multiple approaches.

In China, VISEN has been working on development and commercialization plans for TransCon Growth Hormone. The Center for Drug Evaluation, or CDE, in China agreed that we can fully leverage our existing non-clinical packet and have no need to conduct an integrating study for Chinese subjects. Just recently, an IND was filed for our Phase III trial for pediatric growth hormone deficiency with CDE and is under technical review. This Phase III trial in China for TransCon Growth Hormone is expected to enroll around 75 pediatric subjects, and VISEN expects to begin the trial this year.

In Japan, we have met with the Pharmaceuticals and Medical Devices Agency, or PMDA, on the next step, with the goal of imitating a Phase III trial in 2020. PMDA agreed that we can fully leverage our existing non-clinical data packet, and we have agreed to conduct an integrating study to begin this year. In parallel, we are actively working to develop a Phase III protocol, including around 40 pediatric subjects expected to be initiated next year.

In South Korea, we sought advice from the Ministry of Food and Drug Safety on the next step. They also agreed that we can fully leverage our existing non-clinical data packet and move directly towards regulatory submission and marketing application without further clinical trials. By establishing a global reach across our program, we believe that we will be able to build and maintain a competitive advantage as we are building a growing biopharma company.

Label expansion is another important element in our Vision 3x3 strategy for creating sustainable long-term growth for our rare disease endocrinology pipeline. For TransCon Growth Hormone, the first indication for label expansion will be adult growth hormone deficiency. For this indication, we expect to combine open label expansion and global clinical reach in one single program. We expect to initiate a global clinical trial next year for subjects with adult growth hormone deficiency in collaborating with clinical sites in the U.S., Europe and selected countries in Asia.

For commercialization of our rare disease endocrinology pipeline, we are dedicated to bring our product opportunities all the way to a patient as quickly and as broadly as possible. By building a pipeline of at least 3 independent high-value product opportunities in rare disease endocrinology, we believe that we are creating the levers, synergy, economy of scale needed for our own commercialization. We have already started this process in areas like North America and European countries, where we're driving towards commercialization with the filing of our first regulatory submission for TransCon Growth Hormone next year.

The promise of our TransCon platform is clear. The TransCon Growth Hormone results have validated our ability to move from an innovative idea, all the way to a successful Phase III development program of a unique product candidate. This validation of the TransCon platform gives us increased confidence in both our rare disease endocrinology pipeline programs that we will also set a new standard with TransCon PTH and TransCon CNP and the growth potential of the development of product candidates with TransCon technologies in all the therapeutic areas such as oncology. With our progress this quarter, we are one step closer to establishing a broad global reach for TransCon products and one step closer towards achieving our Vision 3x3 goals.

Let me now turn the call over to Scott for a financial update.

[Scott Smith, SVP and Chief Financial Officer]

Thank you, Jan. Turning to our financial results for the 3 months ended June 30, 2019, let me review some highlights.

For the second quarter, we reported a net loss of €58.9 million or €1.25 per basic and diluted share compared to a net loss of €22.8 million or €0.55 per basic and diluted share during the same period in 2018. The second quarter 2019 net loss included some unrealized noncash loss of €8.2 million compared to an unrealized noncash gain of €21.3 million in the 2018 quarter due to foreign currency exchange rate fluctuations.

Research and development costs for the second quarter were €43.8 million compared to €40.2 million during the same period in 2018. Higher R&D costs during the 2019 quarter reflect increased personnel and infrastructure costs due to growth in headcount to support development of our product candidates.

For TransCon Growth Hormone, costs were lower, primarily due to a decline in manufacturing and clinical trial costs following the completion of our Phase III heiGHt trial. For TransCon PTH, costs were slightly lower, primarily due to a decline in costs for preclinical research and costs to develop our pen device, which were partially offset by higher costs associated with our Phase II clinical trial. For TransCon CNP, costs were slightly higher, primarily due to an increase in manufacturing costs and clinical trial costs related to our ACHieve study and ACcomplisH trial, which were partially offset by lower preclinical costs. Other R&D costs were higher, primarily due to activities to support our oncology therapeutic area.

As a reminder, our R&D expenses, including manufacturing-related expenses, vary from quarter-to-quarter, reflecting timing of ongoing development activities. General and administrative expenses for the second quarter of 2019 were €11 million compared to €5.2 million during the 2018 period. These higher costs primary reflect an increase in personnel and site costs as well as costs of building out commercial capabilities. We ended the second quarter with cash and cash equivalents of €690.4 million and 47,545,204 ordinary shares outstanding.

As a reminder, our quarterly ending cash balance may be impacted by a combination of items, including exchange rate and working capital fluctuations, which, this quarter, led to a net positive impact on the ending cash balance. During the quarter, we continued to execute on our Vision 3x3 strategic road map in our recent initiation of the Phase II ACcomplisH trial for TransCon CNP.

Looking forward over the near term, we plan to complete long-term follow-up for TransCon hGH this fall as agreed to with the FDA and EMA as we progress towards a BLA filing in the first half of next year; continued growth of our endocrinology rare disease pipeline through label expansion of TransCon hGH into adult GHD and initiation of the Phase III trial of TransCon hGH in China to through VISEN Pharmaceuticals; report Phase II TransCon PTH data by year-end; continue executing on the TransCon CNP ACcomplisH trial as we march toward discovery and effective dose in 2020; advanced oncology product candidates toward first IND or similar filing in 2020; and continue to expand our global reach for our endocrinology rare disease pipeline.

Operator, we are now ready to take questions.

[Operator]

[Operator Instructions] Our first question comes from Josh Schimmer with Evercore.

[Josh Schimmer, Evercore]

As we approach the Phase II TransCon PTH data, something maybe you can help frame the unmet need for us in terms of the number of patients in the U.S. with hypoparathyroidism, that the general split between severe hypo-PTH patients, perhaps more mild and moderate, and where NATPARA, from your understanding, has been able to make inroads in penetrating into market and where it hasn't and the extent to which you think TransCon PTH can succeed where NATPARA has not.

[Jan Mikkelsen, President and Chief Executive Officer]

Thanks. Josh, as always, a good question. So what we have as data in our slide, as a research, we gave an overview about the patient group that we would like to some way cover in our Phase III study. And if you look in the numbers we gave from the U.S., there was about from 70 to 110 in the U.S.; in Europe, it was about 90,000 to 200,000; Japan, for about 25 to 32; and South Korea, between around 12,000. So you can see, in average, it is more than 200,000 patients, that we have to believe our global Phase III program really will have the opportunity to really cover.

And the question you are reflecting is how large of this proportion of patients will we actually would expect to treat. And I could always turn it back to what I call the rare disease. If I look on the completion, if I look on how this patient group are basic, are not really can function, all the what I call the short-term symptoms, which I think is very well-described in our survey and from our research data, but also what is really the long-term complication, just what you see that has the weight of, really, the complication, find faults and other things. So we're really dealing with what I call really as severe. More than 35% cannot really manage to keep a job. So we're really talking about both short-term symptoms or long-term complications.

And to address a part of your last question before I come to the final conclusion is I also think you cannot compare TransCon PTH to NATPARA because you are comparing 2 different compounds with complete 2 different clinical profiles. What we want to do in TransCon PTH is basically develop a true replacement therapy. And what do I mean with that? I mean that we give back to the body exactly the needed molecule, identical molecules that it really needs. That is the first requirement of a true replacement therapy. But I think where we have and will be highly differentiated compared to NATPARA is in the second part of what I think is exactly as potent as a true replacement therapy, is to both raise it back in the right physiological way. And what we want to do, and this is what I think is the really clear agreement both to regulatory agencies, to just reading the literature related to treatment of the disease, is that you need to give it back in the physiological level where you have PTH, in the physiological level 24 hours, 7 days a week.

So therefore, when I see what that really results by having a true replacement therapy, it will basically mean that you basically can remove all the supplements and take them to a level where you basically will see the same amount of supplement being given as you see in a normal population. You will normalize urine calcium. You will normalize phosphate. You will basically recall the normal life. Today, how do we do that? We give them infusion pump on children -- or patient that is. So I personally believe that the majority of these patients should be treated with TransCon PTH that have hypoparathyroidism. Would that happen? Definitely not. Not all of them will be treated. But I believe that a large portion of them, and it could be between 30% to 63% of these patients are suffering somewhat, that just from a pharmaco-economic calculation and then seeing the patient need, there should be a treatment.

That was a long answer for this short question.

[Operator]

Our next question comes from Tazeen Ahmad.

[Tazeen Ahmad, Bank of America Merrill Lynch]

Jan, I'm sorry if I missed this in your prepared remarks, but when you submit your application for GHD next year, is it your anticipation that there will be an outcome for it?

[Jan Mikkelsen, President and Chief Executive Officer]

Tazeen, that is not really my decision. This way, we are trying to somewhat to position us in the way we write the BLA, that I think we're trying to take any kind of theoretical consideration that we can think about and build it into the BLA, so we're trying to be proactive when we describe it. For example, the analysis we did related to the patterns between the indirect and direct effect of growth hormone was actually somewhat part of that effort to really show that we are the only long-acting growth hormone that you ever have seen, where we basically are keeping the same balance between direct and indirect effect.

And I could think this is some other thing. So when you go back to our slide that you can see the key learnings from our TransCon treatment files, it is basically, in some way, somewhat the summary that is a part of the BLA statement. That summary will be giving the fundamental, really to have a strong position. You can ask me on a personal level, do I believe that is a reason in the data I see that, that should be in outcome? I don't believe that. And we can also ask Jonathan, our CMO, and hear what he will answer for this question.

[Dr. Jonathan Leff, Chief Medical Officer]

I will very much agree. I think the data that we've generated to date is really unambiguous. And often, when it's ambiguous and not quite clear, that leads to advisory committees. So our hope is that we would not have an advisory committee. Of course, if there is one, we'll be there, we'll be prepared.

[Tazeen Ahmad, Bank of America Merrill Lynch]

Okay. Great. And then another question, also on GHD. You're planning on applying in the U.S. in the first half of next year and then Europe in the second half. Is there any difference in what each of the agencies is asking for in terms of data that you would need to submit?

[Jan Mikkelsen, President and Chief Executive Officer]

No. This is basically exactly the same type that will be filed in place, I should think as I've never seen such a great alignment between all the agencies, both in U.S. and Europe. There basically have been no discomfort in what we will provide in the data packet.

[Operator]

And our next question comes from Jessica Fye with JPMorgan.

[Jessica Fye, JPMorgan]

I had a few on PTH. I'm going to say them all at once. First, can you help us think about what the typical calcium dose might be for patients enrolling in the PaTH Forward trial, acknowledging the 400-milligram BID minimum and where you think that might end up after optimization of supplements to get calcium into the normal range?

Second, can you maybe just set expectations for that Phase II data set around whether investors should expect to see statistical significance on the primary endpoint versus just clear separation? And lastly, sort of related to that, is it possible that the highest dose might not end up with the best response rate? Should it push patients above the normal range on some calcium?

[Jan Mikkelsen, President and Chief Executive Officer]

I think Jonathan will take the first question, and I will continue.

[Dr. Jonathan Leff, Chief Medical Officer]

Okay. So we would expect that patients that are in the PaTH Forward trial would typically require 1,000 milligrams of calcium or more. Some of these patients, as you know, sometimes require 2,000 or even more, but somewhat in that range. And after treatment with TransCon PTH, even after a short period of 4 weeks, we would expect a great majority of those to taper off calcium to the degree of, well, taper off Vitamin D for sure. And most of them will taper off calcium, except that all of us require about 500 to 700 milligrams of calcium in our diet. So many of them might end up on those low doses of calcium, which would be typical of all of us.

[Jan Mikkelsen, President and Chief Executive Officer]

So going back to how we have designed our Phase II trial. And often, when we talk about a Phase II trial, at least from the scientist's view, we try to conduct a Phase II trial in such a manner that we basically can derisk it before we move it into the Phase III trial. This is where we actually like to be just where we were with the TransCon Growth Hormone. Some thought it was a big surprise, but basically, what we had in our Phase II trial got repeated in our Phase III trial. This is why we, in some way, are allocating the same endpoints that we want to use in the Phase III trial also into our Phase II trial.

The question you're asking is are we powered sufficiently enough to basically, to hit the statistic significance in our Phase II trial. And often, we are in a position that we first really can't answer this when we haven't done it, but what we're getting if we're getting the strategic power to, really, to be in position to design the Phase III trial so we can have a high level of insurance that we will hit the statistic power in our Phase III trial. So therefore, the goal for the Phase II trial is basically not to hit the statistic power. If we do it, I don't know, but this is not really the goal on it, but I do not know.

The second question you have is, yes, you could be right. It could be, and I think it could be likely that the highest dose, the 21-microgram dose, will be a too-high dose as a starting dose. But this is how we actually are exploring it. It could be 15, is the optimal starting dose. We don't believe that the optimal starting dose will be much lower than 15 because we know, in average, there will be a use of PTH when you use infusion pump, which is about the 15 level. So therefore, we believe that it will be highly likely it will be under that.

So therefore, potentially, the 15 or 18 could be the optimal starting dose, and the 21 could be too high. And what we will basically be seeing in that is there will be some patients that will be hypoglycemic, but it's still showing that it's a highly titrable compound and we have the right property to get a single patient adjusted to the right level depending on the severity of the disease and what is the optimal types of limit that is for this patient.

[Jessica Fye, JPMorgan]

Okay. Great. And I just have one more if I could on growth hormone. I appreciate the comment on manufacturing earlier in the call. Can you please just elaborate a little bit on that topic and ideally share a little more detail to help us understand the remaining steps that need to take place for you to file the BLA and also to launch TransCon Growth Hormone?

[Jan Mikkelsen, President and Chief Executive Officer]

Yes. So basically, the 2 missing parts we have now, the first part is the last patient out we still have in this quarter related to locking the safety database that we have proposed and agreed with the authorities, and that is happening this quarter. The second part is that we, in the coming months, we will be finalizing the 3 independent validation batches. And when they are finalized, we need to be quite sure that we are getting all the reports or the quality statement is being made, and then we basically can compile the last part of the BLA. It's not like we're writing -- have been writing the BLA for the last 10, 12 months now. And people are extremely resource-demanding and getting all this BLA written. And so we basically have a rolling way to do it, and we were being in a position that the 2 largest pieces is the 2 last and probably writing together at last.

[Jessica Fye, JPMorgan]

Okay. Thank you.

[Operator]

Thank you. Our next question comes from Michelle Gilson with Canaccord Genuity. You may proceed with your question.

[Michelle Gilson, Canaccord Genuity]

Hi. Thank you for taking my question. I wanted to go back to a comment that you made, Jan, on regulators recognizing TransCon PTH as a physiologic PTH replacement. Can you just talk a little bit about what you would be looking for as far as TransCon PTH's profile, what you need to show and either in both the Phase II and Phase III to show that TransCon PTH confers an advantage over supplements perhaps?

[Jan Mikkelsen, President and Chief Executive Officer]

I actually think that -- so Michelle, that's a great question because this goes back to the fundamental of this product opportunity. The fundamental is that how do you have the optimal treatment we're seeing today is either by NATPARA, either by FORTEO, by really an insulin pump that provides a steady-state level of PTH, 24 hours, 7 days a week. And what we showed in the Phase I setting, we showed that we basically mimic not only the PK but all the expected PD effects of a continuous infusion in healthy volunteers. What we're doing now, we're basically moving up and showing that in our Phase II trial, where it will not be in healthy volunteers but in adult patients with hypoparathyroidism. That is what we're doing in there.

What we can see in this state, I think we will see exactly the same thing I'd expect to see with an infusion pump. We will see that, basically, we can't be in a position where we can withdraw all the supplements, which you are basically doing on day 1 for the patient when you start the infusion pump. I also believe we can see exactly the same thing that you see with an infusion pump in patients with hypoparathyroidism, is that you see a normalization of urinary calcium. And that is indicating exactly the physiological effect you expect to see and with having just a person that's providing the normal physiological PTH level, 24 hours, 7 days a week.

So when I go back and say, yes, we will not only see it highly differentiated against the extent of it here, but we also can already see it highly differentiated against a product like NATPARA, which basically, only 50% of them managed to withdraw all the activated Vitamin D, only the 25% managed to withdraw the calcium supplement. And this we already can establish on our Phase II trial.

[Michelle Gilson, Canaccord Genuity]

I guess, and in terms of what regulators are looking for in terms of, I guess, showing how TransCon PTH might have an effect on renal complications and quality of life bone complications, do you think those things can be elucidated in the Phase III study?

[Jan Mikkelsen, President and Chief Executive Officer]

Accessing the clinical development people have really decided very well because what is happening with these 40 patients, they're going on to extension study. In this extension study, you will have the opportunity really to see how we address long-term complications. So you're 100% right. What we basically see in the study, we can see some kind of symptoms, a short-term symptom. We can see effect, and then what we can see on long term we will see in the extension study. And Jonathan, you can see, you have developed a great patient reported outcome, at which a really, will be unique to really, to be relate excitement, the benefit we see from the therapy.

[Dr. Jonathan Leff, Chief Medical Officer]

Yes. I mean, I don't have a lot to add. In the short-term Phase III studies, the goal is to manage calcium, to manage, both in the blood and in the urine, and to greatly reduce or completely reduce vitamin D and calcium. That's a practical outcome we can show in the short-term Phase III trial. And for the longer term, as Jan said, we're developing the questionnaires that will inform us on all of the long-term complications.

[Operator]

Our next question comes from Jim Birchenough with Wells Fargo.

[Jim Birchenough, Wells Fargo]

Congrats on all the progress. A few questions. Maybe just starting with TransCon Growth Hormone. Jan, you did very good at predicting the positive outcome you've had with TransCon Growth Hormone and the benefits of an unmodified growth hormone. Could you maybe speak to the other side on the risk of a modified growth hormone and maybe in the context of OPKO data we're going to get later this year and how much of a risk do you see that data being? And how predictive do you think the biology of a modified growth hormone will be in them being able to match what you've done and maybe what we should think about as we look at their data?

[Jan Mikkelsen, President and Chief Executive Officer]

When we analyzed, started the, our long-acting growth hormone, we analyzed what is really the consequence of infusing a molecule enlargement principal exactly as OPKO 2. And basically, instead of have it at the balance between indirect effect and direct effect, you're basically eliminating a large part of the direct effect. And you saw that very, very, very clearly in the OPKO trial in Phase III in adult growth hormone deficiency because there, you have truncal effect as the primary endpoint.

Truncal the mode of action is such that you need, basic to have the direct effect to see this benefit in growth hormone treatment. So when I go back and seeing, and starting with the Phase III trial, and look and there product opportunity, what we have see and that basic phase in the Phase III trial method growth hormone deficiency.

So from a theoretical perspective, from a Phase III data, we know already now they are in a position that don't have the same benefit that you really would have on what I call the integrated effect of growth hormone treatment, ensuring that you're getting the right body composition, the cardiovascular effect, the mental effect and also, all the things that you expect to see in a growth hormone treatment.

Going then to the specific trial, the specific trial. And what you will see on the primary endpoint is height velocity, potentially. And I think they have a fair change to be non-inferior to daily growth hormone, but who really cares honestly. Because you already have proven that you cannot get the integrated effect on all the effect you want to see in a growth hormone treatment. The other part that you should ask as a question. They need to disclose everything from BMI. They need to disclose all the body composition effect that you also want to see.

They also need to show that you are in a position that they really can titrate up to the relevant benchmark for them in the U.S. market, and that is not what they're comparing themselves to now, the 0.24 milligram per kilo per week because this is what they're comparing to with our European dose. They need to, somebody convince them.

Can you also get the expected effect compared to a U.S. dose, which are 0.30 to 0.35 and they selected the highest Phase II dose in their Phase II trial. So there have no data that suggest that everybody can do it. And I think it's really highly doubtful that can drive a mainly idea of one-driven growth effect up to that effect. And then you have all the other effects, somewhat typical, we start to see like edema where you have something high-growth hormone activity because of this indirect or lack of direct effect.

[JimBirchenough]

That's very helpful, Jan. And then maybe just on the PTH program. Just in terms of the protocol for reduction in calcium and vitamin D supplement patients. How much, can you help describe, is the protocol if there's some discretion for investigators, is there any risk that some physicians or investigators won't dose titrate down the calcium and vitamin D as aggressively as others? So if you could just speak to that aspect of the trial.

[Jan Mikkelsen, President and Chief Executive Officer]

Jonathan, will you?

[Dr. Jonathan Leff, Chief Medical Officer]

Jim, it's very prescribed in the protocol. There's a very specific algorithm. There's a chart basically on the serum calcium level, they're instructed to reduce. So I think there's very little risk that they will not reduce. There's a little bit of discretion into how fast and whether they reduce the vitamin D or the calcium but by and large, it's pretty well prescribed in the protocol.

[Jim Birchenough, Wells Fargo]

Great. And maybe just finally on CMP. Again, your Phase IIs have been high or designed to be highly derisking in approaching Phase III as with the case with TransCon Growth Hormones. What are you looking for in Phase II results for CMP in achondroplasia? What would be a good result that you think would be derisking for the subsequent Phase III?

[Dr. Jonathan Leff, Chief Medical Officer]

The first thing is, are obvious when we are having a pediatric Phase II is safety. We need to show that we have a safe compound. All what we are seeing in all preclinical model, what we're seeing in our dose acceleration study in [indiscernible] is extremely safe product. We are not seeing basic anything. So really from that perspective, we feel really, really on a safe ground. No cardiovascular risk. Nothing we have seen. What we believe we can see in our Phase II trial in children with achondroplasia is we will start to see the efficacy. And the efficacy, we want to see, and the ultimate goal of TransCon CNP, is to do a normalization of the pathway between the hyperactive FPR3 and CMP. And we do that by selecting in [indiscernible] of the second downstream of the activated FPR3 pathway. And I believe, and what we have seen in animal models and what we have seen from other places, this is really possible to basic to do a yin and yang normalization of these 2 pathways. What dose we need to have to achieve that, that is what we want to identify in our Phase II trial. And I actually think there will not be one single dose. I think, you will see the same thing that you see a lot of if we're doing GHD in the disease. You'll see some are mild, some are more in the middle, moderate, and some are really severe. And I actually believe you'll basically see that for some patient, perhaps we need to give them more CMP than other patients.

So what I hope to see on a fixed dose basis is that we can measure really what we're doing at the primary endpoint, heiGHt velocity as a way to see the effects of CMP. And I expect that we'll be very, very meaningful, and by meaningful, I mean, it's not just 1 to 2 centimeters because you can already achieve that partly by giving growth hormone treatment in that kind achondroplasia to date. We mean that's what we see, for example, in the beginning of growth hormone treatment moving up to an 8 centimeters or some that range. I actually think we have huge ambition for this product because I have to believe we have the tools by continuous exposure of CMP really to normalize this pathway.

[Operator]

Thank you. Our next question comes from Tiago Fauth with Credit Suisse. You may proceed with your questions.

[Tiago Fauth, Credit Suisse]

Hi, thanks for taking the questions. So just to follow up on the CMP. So in terms of news flow from the Phase II, have you guys established a plan for any interim data releases? What are we going to see? When is this first data point that we might see there? And are we planning on not disclosing any biomarker data to help establish that profile? And perhaps, as a follow-up, Jan, the preclinical data, what is the evidence in humans perhaps, if there is any, that CMP may lead to that outsized growth relative to perhaps a shorter half-life CMP alternatives that are in clinic right now? Thanks.

[Jan Mikkelsen, President and Chief Executive Officer]

That's a lot of good question related to the underlying signs and priority with CMP. And I should think that CMP, even if we have known the molecule for 20 years, it's really, really developing there. I just found that people are now to do genetic testing about CMP molecule mutation and they're active finding and some mutation in the CMP molecule result that have major effect on what I'd call the entire growth. And so there's no doubt CMP is potentially one of the most powerful hormones that ever have been identified with (inaudible) growth.

So going back to some of the questions, because I would like a lot of questions. One of the things was related to biomarker, yes? We are reiterating different kind of biomarkers. Today, there is not really any great biomarkers that is a surplus. Surplus DMP is not really a biomarker for efficacy. The growth rate is more mainly the effect on the cardiovascular system and nothing to do for what you see in the growth rate. There is different quality markers that can be related and the evaluating also different biomarkers, and this is where we need to have the associated what I call the clinical outcome compared with the biomarker to show before either come out and say, now we have a validated biomarker that can be use either to predict outcome or the guidance for giving the optimal dose because it's basically established to date. So that is one question. You have some more? I forgot some of them now.

[Dr. Jonathan Leff, Chief Medical Officer]

In the interim data.

[Jan Mikkelsen, President and Chief Executive Officer]

The interim data is a good question in this way. We will in position where we see some active doses. We will be in a position that we have the opportunity to look at that, but we will have that part of the dose escalation.

[Operator]

And our next question comes from Alethia Young with Cantor Fitzgerald.

[Alethia Young, Cantor Fitzgerald]

A couple. One, can you talk about your PEGylation technology versus some others in the past? I get this question a lot from clients. And what do you think are the key considerations for regulatory approval? Also, as it relates to the adult growth hormone trial, I don't know if you're ready to discuss, but can you talk maybe a little about size and endpoint and design of that study. And I just wanted to clarify on PTH, the FAST-Forward study study, we'll get all 40 patients of data at the end of the year, and will we also get kind of any longer duration that exist beyond kind of what exist what's characterize in ClinicalTrials.gov.

[Jan Mikkelsen, President and Chief Executive Officer]

Let me start from the last question. We're still aiming of being a position to provide the top line data in the end of the year. We're still in a position that we will move the patient over in an extension study, so that there will be long-term data. So for example, you can nearly add 6 months to the data, then there will be 6 months data. So I expect that in the middle of next year, we will have 6 months data from the extension study, and then we will continue where we will have on predetermined, the integral, we will readout of the at least 40 patient that will be in the study.

Related to our TransCon technology. Yes, you are right. Ascendis Pharma is built on TransCon technology. We are basically the only company that has what I call technology platform that provide what we call the TransCon technology with our basic and predictable sustained release of our product. No one basic has that. You see other company trying to mimic that product. You can see, for example, Nexia have tried to do it in the PEGylated IL-2 with our basic very, very, very complicated way to make a product of IL-2. And so other technology platform is not really existing in the same level as you've seen with our TransCon technology. And this is why we have really a unique position is.

And the technology platform is very, very different compared to other technology platform that had been used. If you go to the protein area, you have protein fusion that had been used and we already have seen the issued by protein infusion, both related to change of mode of action but also immunogenic potential on the permanent PEGylated product. We also have seen that complete different technology platform where you have an entity that is basic and consisting of the target drop, link and the carrier, and is also have the element of restricting the distribution volume. So when we talk about the technology platform and how we differentiate it to become clear to our technology platform, everything from encapsulation technology, permanent PEGylation, protein infusion, no one really can be compared to the TransCon technology.

[Dr. Jonathan Leff, Chief Medical Officer]

And she asked about the adult program.

[Jan Mikkelsen, President and Chief Executive Officer]

The adult program.

[Dr. Jonathan Leff, Chief Medical Officer]

So we're finalizing the details of the adult program, but we've not yet completely harmonized across all the different regions and regulatory bodies. So it's a little premature to talk about the specific details and study design of the adult program.

[Operator]

And our next question comes from Liana Moussatos with Wedbush Securities.

[Liana Moussatos, Wedbush Securities]

Do you plan to partner the entire pipeline, including oncology with Visen in China? And can you remind us the terms for pediatric growth hormone?

[Jan Mikkelsen, President and Chief Executive Officer]

What we did within China was that we made a collaboration where we provided the 3 endocrinology product: TransCon Growth Hormone, TransCon PTH, TransCon CNP. So Visen Pharmaceuticals is basic limited to what we call endocrinology. We have not done any kind of partnership at all with our, for example, oncology pipeline, or they're not any way are limit and any kind of geographic regions.

The partnership with VISEN Pharmaceuticals is that we have a 50% ownership in the entity and associated and the pre-mark was that it give us a unique opportunity, not only for being a position that we gave our 3 product opportunities developed and commercialized in China, but we also as Ascendis Pharma have an opportunity to conduct clinical trials for our product, for example, in achondroplasia, in China to VISEN Pharmaceuticals. So we really believe that having this kind of positive approaches take us in there, really unique. At the same time, we also have what we call a potential upside that VISEN Pharmaceuticals could go public as an independent company either in Mainland or in Hong Kong sometime in the future.

[Operator]

And our next question comes from Adam Walsh with Stifel.

[Adam Walsh, Stifel]

A couple here. Just on TransCon Growth Hormone. You mentioned, Jan, that you've been proactive in identifying any potential review issues upfront and writing them into the BLA. That's terrific. And I think you gave an example earlier, but I wonder if you could elaborate on that in terms of what are the potential review issues, if any, that you see, and how are you approaching that in terms of the BLA filing? And then just one other, with respect to label expansions for TransCon Growth Hormone and do additional pediatric indications like Turner or SGA, can you just clarify for us the approach that you'll be taking there, whether you intend to pursue formal label expansion studies or how you'll go about accessing those patient populations.

[Jan Mikkelsen, President and Chief Executive Officer]

Yes, Adam. And I have to think that you're going up and saying is, first of all, my overall conclusion is that I really cannot think about an issue without accessing that I should be concerned about. But what we really have done in our basic slide deck is that we have tried to say what is our key learnings and accessing that is the main important part we have done in our evaluation. So I have to think that we are in a position is that we have really thought through. We have not seen anything that really give us some concern. We wanted to prove that we have the same balance between the direct and indirect effect because we know that by having that, we really some way can be in a position that we can, in some way, build on over the last 15 to 20 years what I call safety, efficacy on it.

I think, Jonathan, on his people, have really gone through all the major, you can say, safety part of the entire trials we have made, not only our Phase III trials but also, our Phase II trial. And I have to think, Jonathan, if you can come up with your conclusion.

[Dr. Jonathan Leff, Chief Medical Officer]

Sure. So I mean the growth hormone as a class has some safety issues that have been well described over the years, like slipped capital femoral epiphysis, benign intracranial hypertension, arthrosis, swelling, so we look at all of those. We've not seen those in our program, but those are sorts of the proactive issues that we'll describe very carefully to show that we've not seen them, and those are the kinds of issues that the agency surely will be looking for.

[Jan Mikkelsen, President and Chief Executive Officer]

Related to your second question, we have a really working a lot with all our commercial strategies, and Tom and his team have got their mask on, how can they build a leading brand in less than 3 years. And one of the complete bag is, what is the balance between Phase III trials and Phase IV trials? How are we balance the different indications? And I'd like to think like what you see first is where we have a proactive Phase III trial happening, and that is the first label expansion we'll do, they will be in adult, the growth hormone deficiency. So I have to think when you look on all the other indication where we -- growth hormone be used, you will see a mix of the team, Phase IV trial and Phase II trials. And this is how we basically built and expand the growth hormone market in the future. Growth hormone adult is interesting because it's under-penetrated, perhaps it's only penetrated down to 15% to 20%. And we believe potentially, if we conduct a really successful Phase III trial in adult growth hormone deficiency, we can drive an expansion of this market. And there is other indication where we potentially can see there is a huge benefit to make a Phase III trial potentially, we can facilitate an expansion of this specific market segment.

[Operator]

Thank you. And our last question comes from Joseph Schwartz with SVB Leerink. You may proceed with your question.

[Joori Park]

Hi. I'm Joori dialing in for Joe. Thank you for taking our question. I'm wondering if you can expand on the percent of patients with IGF-1 standard deviation greater than 2 and 3 for the Phase III fliGHt Trial that you provided at your R&D day. Could you provide the number or the percentage of patients with consecutive observations greater than 2 and 3 standard deviations in your fliGHt Trial?

[Jan Mikkelsen, President and Chief Executive Officer]

The question you have is need to be a little bit more reflecting back of the data we are providing. For example, if you go back to our current slide deck and go to the new data we are providing, how we show we can basic titrate up and down, and it gives you a little bit of a perspective about the IGF-1 levels you see in the patient group with our fliGHt Trial. So if go to Slide number 29, and then you can see that when we, we look on these patients, the 29 patients that went to a down titration. And these 29 patients went to an average growth reduction of 0.045-milligram per kilo per week. And then before we would like to see what is really the demographic of this patient group. And when we look at them, where we're on daily growth hormone dose of 0.28-milligram per kilo per week, this is basically the same growth, the average of the entire fliGHt was 0.29. That's a little bit 0.01.

But when you look at the baseline IGF-1 STF, you can basically see the ability and what kind of excursion because you can, basic from a mathematic model, you can calculate out from the ST. The baseline IGF-1 is based on daily growth hormone was 2.0, meaning is that you're going to see the frequent effect that is higher on 3, that is higher on 4. This is patient that is on daily growth hormone.

So you can always say that it's typical what you see in a U.S. population where you'll see more than 30%, 40% of all measuring being done on IGF-1 higher than 2. What we also saw, we saw because we take them on a 0.24-milligram per kilo per week dose, they basically are in a position that they get higher IGF-1 because they're a much more effective compound. We have with about 40% to 50% more effective.

And what we can see, you just lower the dose, with the 20% and then you basic at 0.2406. And if you were in a position, then your basic will lower again, with 20%, then they will be reacted down to the starting dose. So this is how you function in the clinical system today, how you really are, as a physician, will have the product. You look holistic on the patient, do you really look on the age, the gender, looking on what is the time before the growth rate close. Perhaps, I only have a treatment opportunity to 1 to 2 years, I want to keep the optimal benefit to the patient, a new treatment according to that.

[Operator]

That concludes our question-and-answer session. Ladies and gentlemen, thank you for participating in today's conference. This does conclude today's program, and you may all disconnect. Everyone, have a wonderful day.