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Edited Transcript of ASND earnings conference call or presentation 1-Apr-20 8:30pm GMT

Q4 2019 Ascendis Pharma A/S Earnings Call

HELLERUP Apr 17, 2020 (Thomson StreetEvents) -- Edited Transcript of Ascendis Pharma A/S earnings conference call or presentation Wednesday, April 1, 2020 at 8:30:00pm GMT

TEXT version of Transcript

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Corporate Participants

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* Dana Pizzuti

Ascendis Pharma A/S - SVP of Development Operations

* Jan Møller Mikkelsen

Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director

* Scott T. Smith

Ascendis Pharma A/S - CFO & Senior VP

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Conference Call Participants

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* Adam Anderson Walsh

Stifel, Nicolaus & Company, Incorporated, Research Division - MD & Senior Analyst

* David Neil Lebowitz

Morgan Stanley, Research Division - VP

* James William Birchenough

Wells Fargo Securities, LLC, Research Division - MD and Senior Biotechnology Analyst

* Jessica Macomber Fye

JP Morgan Chase & Co, Research Division - Analyst

* Joori Park

SVB Leerink LLC, Research Division - Associate

* Li Wang Watsek

Cantor Fitzgerald & Co., Research Division - Research Analyst

* Michelle Lim Gilson

Canaccord Genuity Corp., Research Division - Analyst

* Tazeen Ahmad

BofA Merrill Lynch, Research Division - VP

* Vasiliana Vireen Moussatos

Wedbush Securities Inc., Research Division - MD of Equity Research

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Presentation

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Operator [1]

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Ladies and gentlemen, thank you for standing by and welcome to the full year 2019 financial results and business update conference call. (Operator Instructions) Please be advised that today's conference is being recorded. (Operator Instructions)

I would now like to hand the conference over to your speaker today, Scott Smith, Senior Vice President and Chief Financial Officer at Ascendis Pharma. Please go ahead.

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Scott T. Smith, Ascendis Pharma A/S - CFO & Senior VP [2]

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Thank you, operator. Thank you, everyone, for joining our full year 2019 financial results conference call today. I'm Scott Smith, Chief Financial Officer of Ascendis. Joining me on today's call is Jan Mikkelsen, President and Chief Executive Officer; Tom Larson, Chief Commercial Officer; Dr. Juha Punnonen, Head of Oncology; and Dr. Dana Pizzuti, Head of Development Operations.

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 risk factors -- 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 most recent annual report on Form 20-F.

Please note that our TransCon product candidates are investigational product candidates and are not approved for commercial use. As investigational products, the safety and effectiveness of the TransCon product candidates has not been reviewed or approved by any regulatory agency. 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 full year 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.

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [3]

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Thanks, Scott, and good afternoon, everyone.

In 2019, we continued to make progress towards our strategic goal to become a leading biopharma company, as outlined in our Vision 3x3. Today, I will review some of our major achievements and progress in 2019 and provide an update on our pipeline and outlook for 2020.

To start with the overall conclusion, I'm proud to announce we are currently still on track to see our stated 2020 cohort milestones. There are several reasons why the pandemic situation has had little impact on our near- and long-term milestones.

Firstly, Ascendis' global structure. We are operating through cross-functional teams across different geographic regions and time zones. We know how to work with each other and have established decision-making procedures without the need to meet in person.

Secondly, diversification of our business partner and operation across multiple geographic regions. As a global company, we have diversified our supply chain and clinical research across multiple geographic regions. This has enabled us to avoid concentrating too much risk in one geographic region or one vendor.

Next, our ability to adapt. One of our key leadership competence is managing complexity and dynamic decision-making. Our team of around 400 people across Europe and the U.S. has demonstrated passion and commitment to achieve great things in their persistent pursue of our milestones.

And finally, it is our employees, the people we have hired and their dedication to our core values and focus on our Vision 3x3. These core values, such as being patient focused and scientific driven, are embedded in our culture. I'm proud to say to have contributed greatly to the decision-making and problem-solving that keep us on track.

Over recent weeks, I have seen many examples of this as we have adapted to the current situation and worked to find solutions to challenges for our trial to proceed, for investigators and subjects to receive clinical drug supply and for us to meet time lines, all while being mindful on everyone's safety. Our progress is possible because of our team, our ability to adapt, a strong focus on our values and vision and the support infrastructure we have in place. Even so, we are very proud about what we achieved in 2019. We aim to accomplish even more in 2020.

Let me review the status of our pipeline programs. Starting with TransCon growth hormone, we are on track with our plans to submit the U.S. BLA filing in the second quarter and the MAA filing in the fourth quarter, both for pediatric growth hormone deficiency. We have executed a robust Phase III program, evaluating the potential of TransCon growth hormone in both treatment-naïve and treatment-experienced subjects. Remember that TransCon growth hormone is the only, long-acting growth hormone in clinical development that release somatropin, with the identical amino acid sequence and size to daily or endogenous growth hormone. By releasing somatropin, TransCon growth hormone is designed to maintain the same mode of action as daily growth hormone and attempts to preserve the biological balance of direct and indirect effects of growth hormone. We believe this is the reason for the positive outcome of our clinical data to date.

Results from the pivotal Phase III heiGHt Trial demonstrated superior efficacy, as shown by statistical significant increase in annualized height velocity at 52 weeks and a safety profile comparable to daily growth hormone. As reported January, heiGHt subjects who originally received TransCon growth hormone and enrolled in our long-term extension trial, enliGHten, and were treated for an additional 26 weeks, for 78 weeks in total, maintained the superior growth with TransCon growth hormone compared to the patient who started on GENOTROPIN and switched to TransCon growth hormone at week 52. And the safety profile for TransCon growth hormone across all 3 of our trials is consistent with the safety profile of daily growth hormone.

Our auto-injector has now been used by more than 160 patients. And we have positive feedback from sites and patients regarding their experience. We are on track with TransCon growth hormone. We have completed manufacturing of PPQ batches. We have completed the development of the auto-injector and are on track for commercial availability. We have had 2 pre-BLA meetings with the FDA related to CMC and for clinical, nonclinical packages. And we are now working towards completion of our BLA filing as planned during Q2, followed by MAA in Q4.

But we're not stopping there. We expect to create sustainable growth for TransCon growth hormone by global clinical reach or pursuing new indications. For global clinical reach, in China, VISEN has initiated a pediatric growth hormone deficiency Phase III trial. And in Japan, we plan to initiate a pediatric growth hormone deficiency Phase III in the fourth quarter.

Related to pursuing new indications for TransCon growth hormone, we announced yesterday that we have submitted an IND amendment to initiate our global adult growth hormone deficiency Phase III trial, the foresiGHt Trial. We plan to begin worldwide enrollment later this year. Our aim is to demonstrate the benefit of TransCon growth hormone in adults with the primary objective to evaluate change in trunk fat to further highlight the advantage of a long-acting somatropin.

For product supply so far, we are producing according to our plan to be ready for our launch. And we have not seen a direct impact of the pandemic on our commercial production.

Finally, our commercial organization is on track for our launch in the U.S. in 2021. We truly believe we are raising the bar and have established a new benchmark in growth hormone replacement therapy with TransCon growth hormone.

Turning to TransCon PTH, we are developing a true PTH replacement therapy designed to sustain physiological levels of PTH 24 hours a day, 7 days a week with once-daily administration. What does it mean to be a true replacement therapy? It means that TransCon PTH is designed to normalize serum and urinary calcium levels, serum phosphate and bone turnover and to remove standard of care, which is activated vitamin D and high-dose calcium supplements. We believe this is the optimal product candidate to address both the short-term symptoms as well as the long-term complication of hypoparathyroidism.

In November, we announced expansion of the TransCon PTH Phase II PaTH Forward Trial to expand the enrollment with subject previously treated with NATPARA in the U.S. The decision was made in response to the NATPARA recall. Final enrollment in our Phase II trial was 59 subjects, including 17 subjects previously treated with NATPARA.

Now let me remind you of the Phase II trial design. Subjects in the fixed-dose portion of the PaTH Forward Trial received a specific fixed dose of 15, 18, or 21 micrograms or placebo once daily for 4 weeks. The trial has a composite primary endpoint: the proportion of subject with normal serum calcium, normal urinary calcium, off activated vitamin D and taking less or equal to 1,000 milligram per day of calcium supplements. We choose this composite endpoint because it is a measurement of the treatment of the disease in the absence of standard of care. All 4 components are correlated, reflecting the underlying biology of HP and PTH regulation of serum and urinary calcium and phosphate.

In addition to evaluate the safety and efficacy, a fundamental purpose of this Phase II trial in the 4-week fixed-dose period is to find the optimal starting dose for TransCon PTH and establish the algorithm for complete withdrawal of standard of care. Why is this important? Because to have a true replacement therapy, it is essential to remove standard of care. To be clear, we are not developing TransCon PTH to be an adjunct therapy like NATPARA, which is used in addition to standard of care. But our goal is to establish TransCon PTH as a treatment for HP. The PaTH Forward Trial is being conducted with a ready-to-use prefilled pen device. That is also our intended commercial presentation.

And finally, we're also including patient-reported outcome in the trial, which will strengthen our overall value proposition for TransCon PTH. Following the 4-week blinded period, subjects in the PaTH Forward will then enter the open-label extension, where they all receive TransCon PTH. The open-label extension is very important for informing how TransCon PTH will work in Phase III and then in the real world, as each patient will be titrated to their preferred PTH dose.

There will be evaluation at different time periods, including after 6 months, which is the expected treatment period for a Phase III trial. Following 6-month treatment at the maintained dose, they will be evaluated on a composite primary endpoint as expected for Phase III trial: the proportion of subject with normal serum calcium, normal urinary calcium, off activated vitamin D and taking less or equal to 500 milligram per day of calcium supplement. 58 subjects continue into the open-label extension study.

Now looking ahead, we remain on track to report top line results from the trial data this month in mid-April. The result we are most eager to see is the number of subject who have been able to withdraw from standard of care, both at the 4-weeks endpoint and after transition into extension. Already, we had a preview of soft data in January. The first 8 subjects who completed 4 weeks of follow-up in the open-label extension portion had completely discontinued standard of care, meaning they no longer required supplement to control the calcium. This finding reinforced our target product profile for TransCon PTH as a true replacement therapy.

Finally, after the top line Phase II data, we will report the long-term 6-months data from the open-label extension portion of PaTH Forward later this year in Q3 based on the planned Phase III endpoint, a key indicator for success in Phase III and the longer-term benefit of TransCon PTH.

We also remain on track with our plan to initiate a global Phase III trial in North America, Europe and Asia in the fourth quarter of this year. We've just successfully completed our ethnobridging study, supporting Phase III development in Japan, showing no difference in PK profile between Japanese and [non-]Japanese population. We are very encouraged by the results we have seen so far in this program and the potential for patients to receive a true replacement therapy, removing current standard of care and create a new treatment standard for HP. We are excited to share the top line data with you in the coming weeks.

Moving to TransCon CNP, the achondroplasia signaling defect is well understood. We are now seeing the reported Phase III clinical data with another CNP compound that further has validated this pathway and the benefit of CNP despite a much shorter half-life. Data also suggests that if you only have exposure of CNP for a limited amount of time, the effect will not be as strong as with continuous exposure. This is where biology suggests how TransCon CNP can make a difference. If a pathway is abnormally activated, firing 24 hours a day, 7 days a week, it needs to be counterbalanced with a continuous drug exposure, 24 hours, 7 days a week. That is the concept that we have demonstrated in our Phase I data. We showed TransCon CNP has a half-life of 120 hours with no serious AEs reported at doses up to [150] micrograms per kilo.

These Phase I results support our target product profile. Our global Phase II ACcomplisH Trial is evaluating the safety and efficacy of TransCon CNP and escalating doses of 6, 20, 50 or 100 micrograms per kilo in up to 60 children between the age of 2 to 10 years of age with achondroplasia. The primary endpoint of ACcomplisH is annualized height velocity. And key secondary endpoints include change in body proportionality, other comorbidity and patient-reported outcome. We continue to work towards escalating sequential dosage cohort throughout the year while ensuring the safety in subject during the current pandemic and access to site staff for future monitor basis. You could ask, when do you expect to see an effective dose of TransCon CNP? Will it be in 2020 or 2021? The answer is we do not know. It depends if 6, 20, 50 or 100 micrograms turned out to be an effective dose. It could either be this year or next. We have to run the trial to find out.

Through our strategy of expanding global reach, we are working with VISEN Pharmaceutical to expand our clinical program in China, where ACcomplisH China is on track to be initiated in the fourth quarter of this year. This is an example of how quickly the environment can change. And with VISEN now operating full speed ahead, our ability to leverage clinical development in China is accelerating the TransCon CNP program globally.

In achondroplasia, we really want to address the comorbidity of this disease. With continuous exposure, we believe we can restore balanced growth and affect not only height but also address the comorbidities of achondroplasia. This is where we see the potential of TransCon CNP.

Finally, in oncology, our aim is to create best-in-class oncology therapies by building on the same scientific principles we applied to our 3 independent rare disease endocrinology products. We do this by applying both systemics and intratumoral TransCon technologies for clinical validated pathways to improve outcomes. We are building a diversified high-value pipeline addressing multiple indications, where products are currently limited by suboptimal efficacy and systemic toxicity. This is how we identified our first 2 differentiated R&D candidates, TransCon IL-2 beta/gamma and TransCon TLR 7/8 Agonist. We are on track with these programs and plan to submit an IND or equivalent for our first oncology program in the third -- fourth quarter of this year.

As I think about how Ascendis has achieved all this great achievement in 2019 and now in 2020, I think about the adaptability and resourcefulness of our organization. The ability of the company to continue to execute on our goal is the true reflection of the dedication and flexibility of the Ascendis employees, especially during the environment. I will say that it's a challenging time. But drug development is always challenging, and we always look for the best people to solve the issues. It is the positive attitude and spirit to face this challenge every day year in and year out, our values and this corporate culture that drive us to move ahead with our pipeline program, so we can make a meaningful difference in patients' lives.

Now let me turn the call over to Scott before we open up to questions.

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Scott T. Smith, Ascendis Pharma A/S - CFO & Senior VP [4]

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Thank you, Jan.

Turning to our financial results for the full year ended December 31, 2019, we reported a net loss of EUR 218 million or EUR 4.69 per basic and diluted share compared to a net loss of EUR 130.1 million or EUR 3.17 per basic and diluted share during 2018.

Now let me run through some key components of these results. Research and development costs for 2019 were EUR 191.6 million compared to EUR 140.3 million during 2018. R&D costs in 2019 reflect continued advancement of our pipeline, with the primary drivers of the R&D increase including, for TransCon growth hormone, costs of manufacturing PPQ batches and initial costs of building commercial inventory; for TransCon PTH, costs associated with our Phase II PaTH Forward clinical trial; for TransCon CNP, costs associated with our ACHieve natural history study and ACcomplisH clinical trial; costs related to continued build-out of our oncology therapeutic area; and finally, an overall increase in personnel and related costs.

General and administrative expenses for 2019 were EUR 48.5 million compared to EUR 25.1 million during 2018. These higher costs primarily reflect an increase in personnel and related costs as well as continued build-out of our commercial capabilities.

Other income and expenses included an unrealized noncash gain of EUR 7.7 million compared to an unrealized noncash gain of EUR 20.7 million in 2018 due to foreign currency exchange rate fluctuations. And we ended 2019 with cash and cash equivalents of EUR 598.1 million. Please refer to our latest 20-F filing for additional information.

Turning to 2020, we expect increased expenses as we continue to advance our endocrinology rare disease pipeline, expand our activities in oncology and continue to invest in the TransCon technology platform. We expect R&D costs will include, for TransCon growth hormone, commercial inventory build and preparation for launch which will be expensed to R&D until BLA approval, clinical trial costs primarily related to the ongoing Phase III enliGHten Trial in pediatric growth hormone deficiency and the Phase III foresiGHt Trial in adult GHD, costs associated with ongoing development of our proprietary auto-injector and connected health platform and preparations for the BLA filing which we anticipate in the second quarter of 2020 and the MAA filing in the fourth quarter of 2020; for TransCon PTH, ongoing costs associated with the Phase II PaTH Forward clinical trial and preparation for initiation of a global Phase III clinical trial in adults in the fourth quarter; for TransCon CNP, ongoing costs associated with our ACHieve natural history study and ACcomplisH Phase II clinical trial; for our oncology therapeutic area, costs to advance our preclinical product candidates, including costs for supporting our first IND filing expected in the fourth quarter; and finally, increased headcount and infrastructure costs related to our growing organization.

We expect SG&A expenses will include continued investments in personnel, systems and infrastructure to support our rapidly progressing portfolio and growing organization, and continued build-out of our commercial capabilities to support key prelaunch activities as we approach a potential approval and launch of TransCon growth hormone.

For 2020, we expect that capital expenditures will increase compared to 2019 as a result of investments to expand our TransCon growth hormone commercial manufacturing capacity and expansion of our facilities footprint, including for our oncology R&D organization. We were pleased to report great progress during 2019 and look forward to providing updates on our planned milestones for this year.

As Jan mentioned, we're fortunate to have the capabilities in place to adapt to today's rapidly changing environment. This includes the ability to staff personnel in the optimal geography, rapidly adjust our supply chain to address both the macro environment and the changing competitive landscape and continue to execute while working remotely.

In summary, during 2020, we remain on track to achieve the following milestones: for TransCon Growth Hormone, submit the BLA filing in the second quarter and the MAA filing in Europe in the fourth quarter and initiate a Phase III clinical trial for pediatric GHD in Japan in the fourth quarter; for TransCon PTH, report top line Phase II PaTH Forward data in mid-April followed by 6-month open-label extension data in the third quarter and initiate a global Phase III clinical trial for adult hypoparathyroidism in the fourth quarter; for TransCon CNP, through our strategic investment, we continue supporting VISEN Pharmaceuticals as they work to initiate a Phase II clinical trial for achondroplasia, ACcomplisH China, in the fourth quarter; and lastly, in our oncology therapeutic area, submit our first IND or equivalent by the end of the year.

We are executing on our goal of building a diverse pipeline of potential high-value, innovative drug candidates in multiple therapeutic areas, and we look forward to updating you on our progress for both our endocrinology rare disease and oncology portfolios as we continue to move forward during the year.

Operator, we are now ready to take questions.

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Questions and Answers

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Operator [1]

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(Operator Instructions) Our first question comes from the line of Jessica Fye with JPMorgan.

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Jessica Macomber Fye, JP Morgan Chase & Co, Research Division - Analyst [2]

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I have 2: first is on growth hormone; second is on PTH. First, on growth hormone, have you heard back from PDCO on your PIP? And if not, when do you expect to hear feedback from them? Second is for the PaTH Forward top line results, will you tell us the proportion of patients who met each of the individual components of the composite primary endpoint? I think in prepared remarks, you mentioned that you're most excited to see the proportion of patients able to withdraw from standard of care. Is that a result that you'll provide in addition to the primary endpoint?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [3]

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Thanks, Jess. Thanks for the question. I will start initially, and then Dana, she will take over. So let me start with a little bit about the PIP. The PIP is one of my love story cornerstone because I am from Europe and it has been really interesting for me to talk with a lot of U.S. investors about PIP and what is very meaningful of PIP and what is the entire procedure for PIP. So I have to think this is really great it's coming up again. And I have to say I was really extremely positive surprised because if I look on the traditional way that how the PIP Committee have dealt with a long-acting growth hormone, they are just giving a waiver, meaning is that they basically have said that they don't believe that is really providing a benefit to current therapy, or it could be potentially looking on a safety perspective or other things like that.

So all other long-acting growth hormone, to my knowledge, that either have been done with protein infusion or other things like that, some of them was permanent PEGylated or anything, got just what we call a PIP waiver. And this is basically not a great thing to have when you basically have a pediatric program. So from our perspective, a PIP waiver was very fast to get. It takes only -- this is the first interaction, you get it, so then you're over. And what we actually observed, which was very, very positive for us, was that we actually have now a constructive dialogue with them how really to interact and how to make a program that's also fulfilling the need for the pediatric or the PIP part on it.

I do not know if you have anything to add around that, Dana?

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Dana Pizzuti, Ascendis Pharma A/S - SVP of Development Operations [4]

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Sure. Yes. This is Dana. As Jan mentioned, we did receive initial feedback from PDCO. And basically, they requested more information. And what they had requested was fairly consistent with what we were planning to do with the program. So until -- and we have submitted the responses to the PDCO questions at the end of March. And so we are waiting to hear their assessment of that. Again, the process will still take another couple months to get a final opinion from them, which will probably come at the end of June. So -- but right now, so far, they haven't made any indications that we would receive a waiver.

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [5]

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Which we believe is extremely positive. [They] see the benefit of the TransCon growth hormone in a pediatric population. And this is the first time they ever have done that. And I say this is basically because our superiority, the safety and tolerability, preclinical package, everything what they have seen with us give us a pretty good comfort on our pathway forward in Europe.

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Dana Pizzuti, Ascendis Pharma A/S - SVP of Development Operations [6]

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And just to be a little more explicit about it, the outcomes are to get an approved PIP, which is what we are aiming for, or you get a waiver if they cannot conclude that the benefit and risk is acceptable for the pediatric population. So...

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [7]

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And just related to your second question, yes, it is the plan that we will have analysis related to each [symptom] of the elements. So you will see how many of patients of the 59 patients -- and great to hear, all 59 patients continue throughout the entire treatment period. We really didn't lose one single patient, which I think is pretty good. And we will give you the data how many of the patients where we could make complete withdrawal of activated vitamin D. And I think this is really, really important for us also to share that with you.

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Operator [8]

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

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Tazeen Ahmad, BofA Merrill Lynch, Research Division - VP [9]

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Jan, maybe a couple on growth hormone. Can you remind us what additional steps still need to be completed in order for you to be ready to file your European application later this year? And then the second question also on growth hormone. Can you give us an idea because you're now going to try to gather some data on the adult population, what is the current use of, let's say, the daily growth hormone therapies in the adult population in the U.S. right now? And what kind of overall market opportunity do you think you could have with the adults?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [10]

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Yes, I think -- good, good. I think, Dana, will you take the first one on the European application?

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Dana Pizzuti, Ascendis Pharma A/S - SVP of Development Operations [11]

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Sure. Yes. With respect to the requirements for the MAA, there are some additional submissions that you need to make that are included in the module 1 of that documentation. One is about having an approved PIP, okay? But the second is about our risk management plan and also the pharmacovigilance safety master file, okay? So there are these additional requirements over and above the U.S. requirements. And we're working to address those and have concrete plans in place to be able to meet our time line for that submission.

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [12]

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Going to the adult growth hormone deficiency trial, I do believe when I look on TransCon growth hormone, this is a trial which I'm just as thrilled to get started because when I look on the other long-acting growth hormone that's with potential in the same area as us. Why I say potential because they have never shown that they have the same benefit as TransCon growth hormone. But if you look at the [Norditropin], in their adult growth hormone deficiency trial, if you look on the Novo product that showed same IGF-1 level but basically 50% of the outcome, what we want to show that we can see the same benefit on a complete different endpoint and this is more a metabolic effect, but you also use this metabolic effect in the pediatric treatment on it. So the 2 things are linked together.

Even in the pediatric, you measure it, what I call height velocity as the primary endpoint. Obviously, you cannot use that in an adult population. But you do it in this way, you're looking truncal fat and you can say that it's a vertical way to measure something. But it's basically showing about how well can the growth hormone come out in the target tissue and really combine the right benefit in the target tissue. And this year, what's typical is the truncal fat compartment. And I'm really looking forward to see that because we basically believe we will see a huge differentiation compared to some of the other long-acting growth hormone. But this is also a really relevant endpoint in the pediatric segment.

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Tazeen Ahmad, BofA Merrill Lynch, Research Division - VP [13]

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Okay. Now I guess, how big is the adult population right now in the U.S.?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [14]

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Yes. That is basically what we typically say of -- that's about 10% of the entire growth hormone market. But then you can say, is that a market segment that is under-penetrated? When I look at the pediatric growth hormone segment, I will say it's well penetrated. If I talk about the adult growth hormone deficiency, it's highly less penetrated. Some people believe that it's only about 15% to 20% penetrated. And there is a huge opportunity in this segment if you really can move the treatment paradigm up to a new state, meaning once-weekly treatment with really much, much easier to get an adult population also to adhere to and, at the same time, show really a good effect. And that is what we will like to see in our adult growth hormone deficiency trial.

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Operator [15]

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Our next question comes from the line of Michelle Gilson with Canaccord Genuity.

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Michelle Lim Gilson, Canaccord Genuity Corp., Research Division - Analyst [16]

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I guess I was just wondering if you could maybe walk us through the titration regimen for the long-term extension study. Could you just let us know, is it primarily based on serum calcium? And also help us understand what does it mean that so many patients were able to completely remove standard of care and maybe what we can read through that to the Phase III study as patients get to an individual titration regimen?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [17]

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Thanks, Michelle. If I go back and say why is it possible for -- see -- that we see this high level of removal of standard of care is, we are providing the same profile that you see and observe through a lot of clinical data by applying a PTH product, either FORTEO or NATPARA, in an infusion pump.

In an infusion pump, where you basically can ensure that you are in the physiological level 24 hours, 7 days a week -- all the data from studies where you use an infusion pump at either of these 2 PTH product, you basically observe the same thing that you basically can withdraw completely all the standard of care. So when I look on our expected outcome because we saw that in our Phase I data that we could basically mimic this physiological curve of PTH in healthy volunteers, we expect that we will see the same thing in patients, too. And we also expect that we will see the same effect of it. The only question we have is, is the 4-week long enough to get all the patient off or not? What we at least know now when we looked at the first patients in 4 weeks in the open-label extension study, it was clear, basically, all of them was out of standard of care. So from that perspective, we know this product is functioning, from this dataset, how we really designed it to be.

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Michelle Lim Gilson, Canaccord Genuity Corp., Research Division - Analyst [18]

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And then you -- given that this 4 weeks appears to be long enough, the NATPARA Phase III study had 12 weeks of titration and 12 weeks of maintenance, and you indicated that you're planning to update us in third quarter on 6-month follow-up, but would maybe a 16-week follow-up, given that that titration period so much shorter, be relative -- or be relevant from like a regulatory perspective, especially if you're able to show urinary calcium and bone turnover biomarkers normalizing, like we saw in the NIH study?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [19]

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I have to think the element which I actually would wait longest for will be the bone markers to ensuring that we basically are normalizing the bone turnover. Because if you look on naïve patients that have not seen PTH for a long time, they have a much higher bone density. And when you start to initiate normalized PTH, you will see a much larger bone turnover because they basically are turning the old bone over to what we call much more normal bone structure. By doing that in this position, I will think that bone marker are elements that will take longer time for that. But I actually believe that why we -- so should test this about the 6 months is because the 6 months is more or less reflecting the treatment time that we expected to have in a potential Phase III trial. It's the 6-months data. And at that time, there is stabilization of a lot of the element we also wanted to see.

And this is why we took the 6-month data out as it's an essential element in Q3 this year. You can be potentially right. 3 months could also be extremely relevant for serum phosphate, urinary calcium or serum calcium and all other, what I call element to measure. And this is -- everything is up for discussion, and we can always make a cut point if we think that is relevant to do. But this is also the element we will love to talk with the regulatory agencies about.

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Operator [20]

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

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David Neil Lebowitz, Morgan Stanley, Research Division - VP [21]

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When you look at the 17 patients that were previously on NATPARA, are you going to break out those patients separately or will be completely blended into the various cohorts that they are included in?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [22]

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They are most dependent on what endpoint you're looking at. If you're looking on the primary endpoint, no. If you're looking on change in potential bone markers, change in BMI, yes. Because they are coming from a completely different background and because NATPARA is basically an osteoporosis compound being repositioned into the HP or hypoparathyroidism segment, so it functions like FORTEO, providing a highly anabolic effect. So there we're coming in with a complete different, you can say, background related to both bone marker and bone density. From that perspective is that when we look at this kind of endpoint, yes, it will be separated out. If you look on the primary endpoint, it should have no difference.

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David Neil Lebowitz, Morgan Stanley, Research Division - VP [23]

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So clearly, with respect to what we're going to see in 2 weeks, then, it's not like they will see much from that population, and that would be more likely at the 6-month time point?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [24]

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Or later on, 3 months on other things. But I think it's very, very important that we're showing that we can see the same effect in the 2 patient populations. And we really believe that -- showing that they have the same starting dose, the same algorithm is essential because then we can broaden out the entire demographic part of the patient, saying it's independent on you just switching directly from a short-acting or you have never seen a short-acting PTH product before. You can transfer by this proven algorithm both patient populations in a safe manner over to the TransCon PTH product.

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Operator [25]

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

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Joori Park, SVB Leerink LLC, Research Division - Associate [26]

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I'm Joori Park dialing in for Joseph Schwartz. I guess my first question is, for your TransCon PTH Phase II data expected in mid-April, could we -- are you planning to provide additional OLE data at that time point? Or is it mostly just going to be the 4-week fixed-dose data?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [27]

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It will be mainly the 4-weeks data. We have not decided if we're coming with further data cut at that time. We currently basically have cleaned all the data and ready to the lock of the databases related to the primary endpoint. So from that perspective, this is our main focus.

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Joori Park, SVB Leerink LLC, Research Division - Associate [28]

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Okay. Great. And then my second question is, could you speak to the frequency of clinical visits in the OLE study for TransCon PTH? So it seems like vitamin D and calcium supplements are tracked via electronic diary, which could be easily accessible remotely. But how often do patients need to go into the clinic to get their serum and urinary calcium checked on? Could this be done remotely, if they had to or have like a nurse come to the patient's home or things like that?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [29]

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That is exactly what we're implementing now. So we're implementing, if it's not possible basically to come to the hospital, we're also trying to make a completely new procedure for clinical supply, where we basically are in a position that we are not being dependent on hospital and other things like that. And this is how we have an adaptive design of clinical trials now to ensuring that we can still keep all the patients in our trial, ensuring that they get the drug on time but also ensuring that we are in a position that we have the right follow-up. And this is what we're doing by patient to patient all the time.

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Operator [30]

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Our next question comes from the line of Jim Birchenough with Wells Fargo.

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James William Birchenough, Wells Fargo Securities, LLC, Research Division - MD and Senior Biotechnology Analyst [31]

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Congrats on all the progress in this environment. So just on the PTH program, just on the NATPARA group who've been previously exposed, could you maybe talk about what differences we might expect from their baseline? If they've been on NATPARA previously but that was an adjunct to calcium, vitamin D, would we assume that their baseline calcium vitamin D levels are similar to the other group? Or are there some differences we should consider?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [32]

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I think the patient group is not that different between how they really started out from that perspective. So we've not seen, to the current knowledge I have, any kind of difference from that perspective aided to what you call clear demographic difference.

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James William Birchenough, Wells Fargo Securities, LLC, Research Division - MD and Senior Biotechnology Analyst [33]

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And then just in terms of the potential difference between a short acting and a long acting with the TransCon PTH, in terms of hypocalcemia, theoretically, would you expect lower risk of that with the TransCon PTH over the daily? Is that something you're tracking and something we should consider?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [34]

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Definitely. We believe that we expect to see a much, much more stable level, and this is basically -- you just imagine, in the beginning of the day, you have a major burst of PTH, providing huge retention of calcium in the kidney system. That disappear after 6 to 8 hours. Then you have a prolonged effect of mobilization from the bones, which have up to about longer time, which are longer than the PK profile. At that time, you basically have no PTH in the kidney on a short-acting PTH, so we basically dump all the calcium immediately from the serum out in the urine. Often, that perspective, it's really, really hard to control anyway the serum calcium. What we provide is basic solving 2 major elements. Constant level of PTH, meaning is that even it has been designed so, there is a 30% difference between peaks with trough. And therefore, we advise to give it in the evening because during the night, you sometime -- you see on the normal curve of PTH, you have about 20%, 30% higher PTH level because you get less calcium from the food. This is how we have designed it.

The other part that's very, very essential, if anything the patient by any mistake forget in 2 or 3 hours, 1 day to get their PTH product, with TransCon PTH, we're not going to crash. They still will have sustained level of PTH, meaning is that they can manage to get the dose in the right time without need to move to the emergency room because they crashed and not having any kind of having a hypocalcemic episode.

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Operator [35]

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Our next question comes from the line of Alethia Young with Cantor Fitzgerald.

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Li Wang Watsek, Cantor Fitzgerald & Co., Research Division - Research Analyst [36]

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This is Li on for Alethia. So for TransCon growth hormone, can you just talk about where it is manufactured? And then do you guys have any notable findings from your recent CMC meetings with the FDA? And then for the PaTH Forward Trial, it seems like there is a slight delay for the data readout. Just wondering, is it related to COVID-19?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [37]

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Let me just go through the first one. I will take the first one, Dana will take the second one, and Scott will take the third one. So I think when you look at the manufacturing supply chains we have, it's basically built in a way where we both are securing our manufacturing to a dual strategy. So what I'm describing now is one of our pathway.

So we basically have a pathway where we produce a link. But it's not really how you produce it because what you're building up, you're building up storage capacity on 2 different geographic regions, in 2 different places, to ensuring that you always have storage capacity for a long time manufacturing if there is any kind of delay in the manufacturing. This is one of the principle in what we call robust supply chain. So first of all, you have one place you produce, then your place of storage, then you have a running supply chains. And it's typical having 2 different geographic region to ensure that. And this is basically how we have built it up. So currently, our manufacturing for this primarily is at Switzerland, Japan and the U.K. And we have not seen any kind of delay in any of the sites in any of the manufacturing. Dana?

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Dana Pizzuti, Ascendis Pharma A/S - SVP of Development Operations [38]

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Right. For the CMC meeting that we had with the agency, which was back in the beginning of December, there really weren't any problematic issues at all. A lot of it was related to the location of certain sections in the application. And then we were able to provide a little bit more of an education about our device and how that works and how we've tested it. But again, there wasn't really anything controversial or problematic that would affect the ability to file the application.

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Scott T. Smith, Ascendis Pharma A/S - CFO & Senior VP [39]

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And then, finally, we're exactly on track as we disclosed 4 months ago in January at JPMorgan with the data. So no difference. No change. All on track.

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Operator [40]

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Our next question comes from the line of Liana Moussatos with Wedbush Securities.

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Vasiliana Vireen Moussatos, Wedbush Securities Inc., Research Division - MD of Equity Research [41]

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About how long do you think the adult trial will last? Do you think you could have data by the end of 2022 or more likely 2023?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [42]

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We will disclose that in -- I expect later in the year when we're starting the recruiting, we get the sites up running and over time when we see the initial recruitment. As soon as we see the initial recruitment, we basically can give a much better prediction when we expect it to be fully enrolled. But we actually see a great assessment for this product here because -- and we -- typically, as we're doing in all our trials, we go really broad out, a lot of different countries, a lot of different sites because this is one of the capabilities we have in our global thinking that we manage, can open sites everywhere in the world. And by doing that, if there is some problem in one region, we will just switch recruitment over to another region to ensuring we are on track with the time line we want to be on.

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Operator [43]

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Our next question comes from the line of Adam Walsh with Stifel.

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Adam Anderson Walsh, Stifel, Nicolaus & Company, Incorporated, Research Division - MD & Senior Analyst [44]

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My first one -- actually, I have 2 on TransCon PTH. And first one is, in talking to doctors, a lot of them stress the importance of whether or not their patients are symptomatic. And I know you're using a PRO tool to kind of measure symptoms. Will it be too early to see symptoms in the 4-week blinded portion of the trial?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [45]

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I think we -- it's a good question. What we are -- I'm just going back and thinking about when did we see it in the infusion studies and how early was that reported, and I'm not 100% sure how early they can see it in the reporting. There were some patients that explained that, yes, you can see it pretty much immediately because typically this is not dependent on calcium regulation. It's a direct effect of the liberated PTAs directly into the cognitive or the brain part on it. So it is a good question, and I cannot answer it yet.

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Adam Anderson Walsh, Stifel, Nicolaus & Company, Incorporated, Research Division - MD & Senior Analyst [46]

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No worries. I have a follow-up. They've also talked a little bit about -- obviously, nephrocalcinosis is a big problem in these patients, and that's something that they're keenly interested in the urinary control of calcium. And some have suggested that one way of looking at that kind of shorter term is using cross-sectional DEXA or ultrasound measurements to kind of see that. At what point -- first of all, will you be doing that? And second of all, at what point in time is the earliest time point that you think you might be able to have some imaging that could support the actual long-term benefit to the kidney as opposed to just the urinary calcium measurements?

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Jan Møller Mikkelsen, Ascendis Pharma A/S - President, CEO, Member of Executive Board & Executive Director [47]

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Exactly. This is why we -- basically on baseline, we really have a proper testing about all the element you're talking about. To be quite sure, we are in a position when this patient go over in the open-label extension study, we can follow them. And I would think a realistic potentially we can start to see something after 6 months. And perhaps we need 12 months, but it's exactly why we actually are making the demographic baseline now really also to see the long-term effect.

And this is not only on real impairment we're looking on. We're also looking on normalization of bone density, normalization of bone markers and all of this other element that is important to be quite sure you also see a way to address the long-term complication this patient group have. Sure, nearly all of them have really short-term symptoms and the short-term symptoms I think we can address very, very, very fast. The long-term complication which basically all of them have, too, we also will try to address them. And -- but some of them, because they are, by definition, long-term complications, it would take longer time to basically measure a meaningful impact. But I also believe, to going back, Adam, is that people in the field of renal damage have a pretty high level of confidence if you have a positive impact on urinary calcium, it also will end up having a positive impact on the kidney functional system.

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Operator [48]

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Thank you. We have no further questions at this time. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.

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Scott T. Smith, Ascendis Pharma A/S - CFO & Senior VP [49]

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Thanks a lot, everyone.