Ascendis Pharma A/S (ASND) 2017 Q3 法說會逐字稿

Welcome, everyone, to the Ascendis Pharma Third Quarter 2017 Financial Results Conference Call. (Operator Instructions) As a reminder, this call is being recorded.

I would now turn the call over to Scott Smith, Senior Vice President and Chief Financial Officer of Ascendis Pharma.

Thank you, operator. Thank you, everyone, for joining our third quarter financial results conference call today. I'm Scott Smith, Chief Financial Officer of Ascendis. Joining me today are Jan Mikkelsen, President and Chief Executive Officer; and Dr. Jonathan Leff, Chief Medical officer.

Before we begin, I would like to remind you that this conference call will contain forward-looking statements that are intended to be covered under the Safe Harbor provided by the Private Securities Litigation Reform Act. Examples of such statements may include, but are not limited to, our potential to become a leading integrated rare disease company; our progress on our pipeline candidates and our expectations with respect to their continued progress; statements regarding our strategic plan; our goals regarding our clinical pipeline of rare disease endocrinology programs; statements regarding the plans for our Phase III heiGHt Trial of TransCon growth hormone; and the fliGHt and enliGHten trials; statements regarding the plans for our Phase I Trial of TransCon PTH; 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 in-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 March 22, 2017.

Today, we will discuss our third quarter 2017 financial and business results. 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.

Thanks, Scott, and good afternoon. We continue to make progress with our pipeline. As we execute on our vision to become a leading integrated rare disease company. A key step towards achieving our vision is to build a diverse pipeline of 3 independent endocrinology rare disease products that make meaningful difference in patient life. We are on track as planned with this mission. We are making continuous progress with our TransCon Growth Hormone program in Phase III as well as our TransCon PTH, and TransCon CNP programs. You will recall that all of our 3 product candidates at this time to be to provide best-in-class efficacy, safety and/or tolerability in markets with significant unmet medical needs. In addition, they also address high-value of market opportunity.

This quarter, I would like to reflect on the fundamentals behind each of our product candidates, and why we believe our internal pipeline has a higher chance of success compared to traditional drug development. It all starts with the patients. We begin our product planning process by identifying important major unmet medical needs. We reduce our pipeline risk by asking, is there an existing parent drug with already established efficacy and safety which can serve this unmet medical need, if we combine the parent drug with our TransCon technology? If yes, we will proceed. Then we have 2 questions related to product profile. First, will we create a clearly different state of product with best-in-class properties? Second, whether it'd be difficult or impossible for other to match this target profile? If yes to both questions, then we will proceed. We're also looking carefully at the clinical strategy to see if a clear clinical and regulatory pathways exist to establish differentiation from current standard of care. And of course, reiterate the market size and growth potential. Do we have a high-value opportunity with a worldwide market of at least $1 billion? For our current pipeline, we believe the answer is definitely yes.

We believe Ascendis will become a leading rare disease company by developing a high-value diverse pipeline while maintaining a higher probability of success compared to traditional drug development. The key to accomplish this is by using a parent drug with already established efficacy and safety together with our TransCon Technology, and thereby building on the known mode of action of the parent drug. We believe we have created an internal pipeline with a higher chance of success compared to traditional drug development by applying this algorithm in the building of our internal pipeline.

Let me review each of our 3 internal product opportunities. TransCon Growth Hormone is built on delivering the same active growth hormone, as daily growth hormone at the same maximum concentration and overall exposure per week that physicians have come to expect for over 30 years. We are developing TransCon Growth Hormone to have comparable clinical benefit as daily growth hormone with optimal product features and an easy-to-remember once-weekly administration. We have applied many decades of learning regarding growth hormone product designed in this program. Additionally, recent developments in the competitive landscape for long-acting growth hormone therapies have reinforced our scientific rationale for TransCon Growth Hormone, and further confirmed its market potential. TransCon PTH is based upon the status benefit of the parent compound, PTH 1-34, which has been used in hypoparathyroidism for years, either as a twice-daily injections or by infusion pump. Our candidate is designed to deliver a steady-state concentration of PTH in the physiological range for 24 hours a day, 7 days a week, thereby normalizing serum and urinary calcium. The infusion-like profile of TransCon PTH suggests it may more fully address all aspects of the disease than current standard of care. Our TransCon PTH program has been informed by decades of clinical research demonstrating the benefit of PTH infusion. We believe this candidate will be highly differentiated and will establish a new standard of care for hypoparathyroidism.

For TransCon CNP, we are working to build upon the emerging knowledge base about the important role that CNP plays to help modulate normal skeletal development and to maintain balance in the FGFR pathway. With our unique TransCon technology, we believe we have overcome the fundamental channels of using the native CNP molecule as a pharmaceutical product, including its short half-life of 2 to 3 minutes. We have demonstrated a dose-dependent effect on growth in our preclinical studies without adverse cardiovascular effect.

Again, our focus on patient outcome, and the underlying science of the CNP and FGFR pathways drives this opportunity. Our goal is to help patients and physicians manage the more disabling comorbidities such as a spinal stenosis by enhancing growth. As there is currently no FDA-approved treatment for achondroplasia and other FGFR-related diseases, this is a significant opportunity to benefit patients. Our product decisions are heavily based on deep analysis of the disease and understanding of the standard of care as well as patient needs. And our team is driven by strong passion to make a difference in patients' lives, and bring our product to patients as fast as possible.

We believe that keeping these values at the forefront of our product development activities will help us achieve our vision and establish Ascendis as a leading rare disease company.

I would turn the call over to Jonathan for a clinical update.

Thanks, Jan. We've had a very active quarter on the clinical front as we moved from 1 to 2 products in clinical trials and continued to advance all 3 of our pipeline programs. Our Phase III program for Transcon Growth Hormone is advancing nicely. The pivotal heiGHt Trial continues to enroll patients globally, and we hope to complete enrollment of 150 treatment-naive patients by the end of this year.

We're also pleased to have recently initiated the fliGHt Trial which will evaluate 150 subjects who will switch from daily growth hormone to once-weekly TransCon Growth Hormone. Additionally, this will include subjects as young as 6 months of age, some of whom may be treatment-naive. Screening of subjects has already begun. We are off to a great start with the fliGHt Trial and there's excitement among the physician community following an investigator meeting in September. This single-arm open-label trial is designed to further strengthen the safety and efficacy assessments of TransCon Growth Hormone.

It is an important component of our future regulatory submission. We anticipate that the fliGHt Trial to enroll quickly, and to be completed around the same time as the heiGHt Trial. In our discussions around the trial, investigators appear eager to offer patients the option to switch from daily to weekly therapy.

We are also preparing to launch the enliGHten Trial, our long-term extension study. enliGHten will soon be open to the first patients from heiGHt as they reach the 12-month time point. In the future, subjects from fliGHt will also be eligible for the enliGHten Trial, further broadening the long-term experience with Transcon Growth Hormone.

We also recently published a manuscript describing the structural design and rationale for Transcon Growth Hormone. This paper detailed how learnings from prior attempts to develop a long-acting growth hormone have been incorporated into our Transcon Growth Hormone program. We continue to believe in the potential of a fully active, unmodified growth hormone therapy that enables growth hormone due to its small size to diffuse freely into tissues, and activate the receptor in the same way as endogenous growth hormone.

Next, the TransCon PTH program has been progressing well this past quarter. This product candidate is in development as a novel treatment for hypoparathyroidism, designed to more fully address all aspects of the disease, unlike current standard of care. By normalizing serum calcium and phosphate as well as urinary calcium excretion, we expect to control acute symptoms of hypo or hypercalcemia while also reducing the long-term effects of hypoparathyroidism such as tissue calcinosis and renal impairments.

We recently initiated a Phase I clinical trial in Australia, which will evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of TransCon PTH in healthy adults. The trial is studying ascending single doses and multiple daily doses of TransCon PTH. The trial is progressing well and we expect to have pharmacodynamic and pharmacokinetic data to share in the first quarter of 2018. A key goal for this trial is to reproduce the infusion-like profile from our preclinical studies, which showed steady PTH exposure over 24 hours. We will also be evaluating various pharmacodynamic effects including serum calcium levels, downregulation of endogenous PTH 1-84, and assessing whether treatment reduces urinary calcium excretion in healthy volunteers. This trial will provide key insights regarding the potential of TransCon PTH as a treatment for hypoparathyroidism. If successful, we believe we can then advance TransCon PTH directly into a Phase III pivotal trial after consultation with the regulatory authorities, with the ultimate goal of helping patients who suffer from this debilitating disease.

Turning to TransCon CNP. We are advancing this product candidate for achondroplasia and related skeletal disorders. Our focus remains on preparing a regulatory submission next month, and moving TransCon CNP into the clinic next year. We recently presented the preclinical data to more broadly introduce this program at several medical conferences. We also held an expert meeting to gain input on our development program and the unique issues facing care of people living with achondroplasia. Interest in TransCon CNP is high, as there is no FDA-approved treatment, and the short half-life of CNP presents challenges to drug development.

As we approach the end of 2017, I'm very happy with the progress we are making with all 3 of our rare disease pipeline programs. We continue to receive positive feedback on each of our product opportunities from both the patient and physician communities. This further motivates our internal team as we work to bring new therapies to patients.

Now, Scott will provide a financial update.

Thank you, Jonathan. Turning to our financial results for the 3 months ended September 30, 2017. Let me review some highlights.

We ended the third quarter with cash and cash equivalents of EUR 206.3 million, and approximately 36.4 million shares outstanding. Cash and cash equivalents, includes proceeds from the completion of our follow-on financing, which closed on September 29, and raised net proceeds of approximately EUR 107.1 million. Subsequent to the quarter-end, the underwriters exercised their overallotment option increasing net proceeds by approximately EUR 16.2 million, and increasing total shares outstanding to approximately EUR 36.9 million. On a pro forma basis, including these subsequent proceeds, cash and cash equivalents, as of September 30, were EUR 222.5 million. This cash balance reflects an unrealized EUR 2.8 million finance expense due to foreign exchange fluctuations for the quarter, and an unrealized EUR 10.8 million finance expense for the 9 months year-to-date.

For the third quarter, we reported a net loss of EUR 33.9 million or EUR 1.04 per basic and diluted share compared to a net loss of EUR 18.3 million or EUR 0.72 per basic and diluted share during the same period in 2016.

Research and development costs for the third quarter were EUR 29.1 million compared to EUR 16.5 million during the 2016 quarter. R&D costs in the 2017 quarter reflect increased development cost related to new and ongoing clinical trials and manufacturing cost for TransCon Growth Hormone; increased development and manufacturing cost for TransCon PTH related to our ongoing clinical trials as well as Phase III enabling activities; increased preclinical development and manufacturing costs associated with the TransCon CNP program; and an increase in personnel and related cost due to a greater number of employees in activity in research and development.

General and administrative expenses for the third quarter of 2017 were EUR 2.8 million compared to EUR 2.6 million during the third quarter of 2016. We continue to expect our R&D cost to vary from quarter to quarter as we invest in, and advance, our wholly owned internal pipeline programs. We expect these costs to reflect advancing our Phase III program for Transcon Growth Hormone, including clinical trials and supply; validation of our commercial manufacturing process; and preparation for the introduction of the auto-injector into the enliGHten Trial; increasing cost related to our ongoing Phase I clinical trial and Phase III enabling activities for TransCon PTH, and ongoing preclinical development and manufacturing activities for TransCon CNP.

We are pleased to have successfully completed our follow-on offer in this quarter, which welcomes a number of new investors and provide additional funds to support the clinical development of Transcon Growth Hormone, TransCon PTH and TransCon CNP for which we retain worldwide of rights.

Looking ahead, with Transcon Growth Hormone and TransCon PTH already in the clinic, and with TransCon CNP moving into the clinic next year, we believe Ascendis will be very well positioned with 3 wholly owned rare disease products in clinical development, each representing a market opportunity greater than $1 billion.

Operator, we are now ready to take questions.

(Operator Instructions) And our first question comes from Jessica Fye with JP Morgan.

Just wanted to confirm the time line for the PTH update? I think you said first quarter. Could that be early in the first quarter? I think you're been suggesting very early in the year previously? And then second, just want to make sure I heard correctly that the heiGHt Trial is still on track to complete enrollment by year-end?

Yes. Thank, Jess, for the question. Related to the disclosure about the top line data from our Phase I, we are extremely dedicated to get this product as fast as possible into the patients. And we're now in a situation where we're running all the different cohorts now in the Phase I trial. And we think that we will be ready to provide -- and really, what I call, an update to give a good insight in how we can improve the target profile with our Phase I data in the beginning of the year. Potentially, it could be at the JPMorgan Conference in the early half of January, or we will have it later in the quarter. And I think Jonathan can confirm the last one.

Jess, we do remain on track to complete enrollment by the end of this year in the heiGHt Trial.

And our next question comes from Tazeen Ahmad with Bank of America.

One on PTH. Jan, how are you thinking about what the next step would be after this study results? Obviously, an area of undermet need. Do you think it can go straight into a pivotal study, for example, as long as this study's directionality goes the way you're wanting it to go? And then in terms of how you're thinking about the addressable population? We've talked a little bit about this before, but wanted to get a sense of if you've gotten a more narrowed view on whether or not you think this would be best served and, let's say, the severe population at first, or do you think this could be used across the board? And then I have follow-up on growth hormone.

Yes. Let me start on the PTH, and then I can come over to my colleagues. So yes, you are right. We're dedicated with high level of passion to get this product as fast as possible out to the patient. And I think we have a clear roadmap. And the road map would be is that we're getting the Phase I data as fast as possible. We're going to regulatory agencies. And what is, perhaps, more and more important, we are doing all the preparation for being ready to move into Phase III. We are developing everything for moving it up to manufacturing scale. So we're now running a manufacturing scale. We are conducting all the preclinical safety activities that is necessary for supporting initiation of Phase III. We're developing an optimal pen device, so we're ready to be sure that there can be optimal adherence, and the optimal compliance for the patients. Related to the clinical pathways, I could think that Jonathan will take that question. And Scott is really working dedicated and trying to find out the number of centers or patients we will take and really give opportunity to give this unique product.

So if the question is, why can we -- why do we believe we can move from Phase I to Phase III? I think we have high confidence for a couple of reasons. So, normally when you do a Phase II program, it's to establish the safety profile, the preliminary efficacy or proof of concept of your drug, the dose selection for Phase III, and immunogenicity. We arguably will have all of that settled at the end of Phase I. This is a large Phase I study and a lot of subjects. We'll have a very good view on safety. Efficacy, we will know clearly from our Phase I results since pharmacodynamics and healthy volunteers are the same as in patients, and that's been known for a while. And there's 30-plus years of experience with PTH. We'll know the dose from our Phase I study, and it's titratable in any case. And we'll know the immunogenicity from our Phase I. And furthermore, if there's any doubt at all, we will likely start our Phase III program with a sentinel cohort, and relieve any concerns from any regulatory body. Because after the first bolus of patients have gone through, we'll have a safety review meeting. And then, if all else looks good, we'll continue on. So we think it's a very compelling scientific database argument. And we'll be very surprised if regulatory authorities do not agree with us.

And then, maybe keeping in that -- with that line, do you think you'd have to have an active control versus the currently approved drug?

It's likely we will compare ourselves to standard of care, which will include calcium, vitamin D, and in some subjects likely NATPARA. So that is very likely the ultimate design. Although, we've not completed our designs of the Phase III program yet.

Okay. And then in terms of the commercial opportunity?

Yes, to the -- this is Scott. So the best studies out there indicate in the U.S. there's about 77,000 up to 115,000 hypoparathyroid patients in the United States. So we like to assume roughly 80,000 available to treat. The number in Europe, based on the best data which interestingly comes out of Denmark, is comparable to maybe slightly less than that. But just focusing on the U.S., about 80,000 patients. Per the mass general long-term follow-up study, we think the low-hanging fruit is really the 25% of those patients that have an excess rate of kidney stones, and nephrocalcinosis. That's really the low-hanging fruit, the most severe. However, if you look at some of the other studies done by NPS, such as PARADOX, you can see that patient demand is probably much higher. And in some cases, we believe that a much broader portion of these patients should be treated not just for the biomarker effects, but also for the CNS effects.

Okay, great. Thanks for all of that color. And then on the growth hormone, just wanted to get a sense on the time line. So after, let's say, the heiGHt Trial reads out, where are you in terms of kind of validating the device that you would want to use commercially? I believe in the past, you said that there might be a need for bridging studies, is that the case? And when would that be happening?

Where we want to introduce the -- our device for the patient will be in our extension trial, the enliGHten Trial. And we're already getting a lot of feedback related to the device. And I have to be -- when we're looking on this feedback, we really believe that this device is built for the future. This is a device that's not only easy to use, but also integrating essential new elements on how to build optimal adherence, like automatic data capture of doses and time of injection, which give you opportunity to build up an entire IT platform for building up adherence. So we actually believe that device is really living up to everything what we have expected. And related to, for example, the -- yes, we are running a bioequivalent trial, it's actually happening just now. It has been progressing as we had hoped for. And we are complete on track to introduce the device and to have it to be ready, and part of our initial filing.

Okay. So just to be clear, you plan on launching with the new device?

Yes, this is exactly what we want to do.

And our next question comes from Alethia Young with Crédit Suisse.

Maybe 2. Just one, as it relates to the growth hormone, have you seen any benefit like from maybe the discontinuation of the Versartis trial ending? Are you seeing interest from the sites that were there? And maybe that help you kind of fill some of the extension of such studies. And then, I guess the other question is, if you look at the NATPARA study in the Phase III, they did like a 24 week with the run-in. Do you think that's something that will be viable for you guys? Or do you think you have to study the drug longer in treatment between titration and maintenance or will there be a titration arm?

You also repeated the second question? But, thanks. The first question, with the Versartis' studies closing down, there is certainly interest at multiple sites of ours. But unfortunately, we can't enroll Versartis' patients in our trial. That's long been an exclusion criteria, not only for Versartis, but any experimental drug cannot be used in our switch trial. So these are just patients who are currently taking daily growth hormone commercially approved products. And could -- I'm sorry, could you just repeat the second question on NATPARA? Sorry.

Yes, I'm just trying to figure out if the NATPARA Phase III study, obviously where it had the run-in and you did a treatment and titration for 24 week. Is that how we should think about maybe what Phase III would like for you guys?

Yes, you should. So certainly the standard of care patients will dramatically down-titrate their calcium, vitamin D. And there'll be some subjects who are likely on NATPARA who'll do a little bit of maybe down-titrating, maybe not. But there'll be titrations throughout the entire trial, an early titration phase and then a maintenance phase, much like the NATPARA Phase III.

And as far as samples go of about 125 patients. Is that probably fair? Or would you need to do more patients since you're going from Phase I to Phase III?

Well, we haven't completely designed it yet. But it's not going to be a large program. PTH is a very well-known commodity. So we don't feel you need a huge safety database. So it will be on the smaller end of things. But we'll well powered to satisfy our primary endpoint.

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

Since TransCon HTH is the only game in town, once approved, do you anticipate that doctors will switch their patients from daily to TransCon, rapidly?

I actually think that we have been extremely, you can say, positively surprised, because when we actually run our model, we were potentially too conservative in -- we only thought that we will mainly get new patient. The feedback we're getting more and more is that, there will be many more switch patients. And I think Jonathan also see just as a huge, huge interest for having patient coming into our fliGHt Trial with switch fliGHt. And I think that just indicate the unmet medical need. So I personally believe that it will -- we will have to conservative, where we said that it will mainly be patient that are coming from naive patient at the start treatment that will be coming in on a once-weekly product. We see now because of many -- because of feedback that not only for physician but also from parents and patient that is part of that, that we actually modeling it quite different now where we forecast now for our manufacturing forecast. Actually, I'm expecting much more patients that will come from switch.

And our next question comes from Jim Birchenough with Wells Fargo.

A few questions. I guess just on -- sticking with the commercial opportunity for TransCon HTH, when you think about the switch opportunity, is there a sweet spot in terms of patients that you think are most apt to switch to your drug? And any insights into if there's patients that have a certain growth velocity that's inadequate or certain age? How do you sort of frame what you think will be the low-hanging fruit in terms of the switch opportunity?

Okay. Jim, it's a great question. And it was part of the analysis. Because what we actually sought in the beginning and what we first had in our modeling was only patient that must not getting, what we could call, the right outcome. They will be mainly the patients that will be switched. What we're now realizing by having interaction with physician, the community and other things, basic nearly all patients will be willing to switch, if you were in position that potentially just patient to have perhaps only 1-year treatment left. Perhaps they've [announced]this patient, but nearly everyone else will be really open for this switch if they can get access to our product opportunity. And that is really what we have seen now really. And this is what we're building into our forecast modeling.

And Jan, certainly the experience of some of your competitors seems to bear out your view on the advantage of a modified -- an unmodified versus modified growth hormone product. But just wanted to check that there's not a possibility that the actual pharmacokinetics of the growth hormone delivery could be at play as well. And that is, is there any suggestion that the more pulsatile nature of the daily has an advantage over a weekly? I just want to make sure what gives you confidence that beyond the advantage of having an unmodified growth hormone, that there's not some risk around the less pulsatile nature of the delivery in the different pharmacokinetics?

I think, great question, Jim. When -- in the old days of Novo Nordisk, in the '80s, we actually started already to discuss that question. And you can find really great peer review publications where we took both adult and children with growth hormone deficiency on infusion pump and compared them directly to how would the treatment outcome be after 6 months. And they were actually some of the fundamentals that were being developed to ensuring that you really were in a position that making a flat curve, which you actually doing optimal in an infusion pumps, really would give the same outcome. Another thing that supported very, very, very well is a product that is also built on an unmodified growth hormone, the product LG from a South Korean company, where that has 2, 3 years both efficacy and safety data, where they have the once-weekly dosing profile. And it's also being performed in 12 months -- sorry, 6 months in adult with growth hormone deficiency. And both of these product groups in these 2 patient groups there was no difference compared to daily growth hormone. So I'm quite sure that what you see, as the main important thing, what you can see out from the data and the science we know about it, that the only place you have seen possible to get the same outcome as daily growth hormone has been with product opportunities where you apply an unmodified growth hormone in creating the long-acting effect. And this has been illustrated by our product, but also believe that the data that is already topic for everyone from the LG also proving exactly the same thing.

And then just final question on TransCon PTH. To the extent that kidney stones and nephrocalcinosis is really -- represents the lot of the burden of disease. You need to see an effect on calciuria to move from your Phase I to your pivotal. Is that part of your go, no-go decision? And how confident are you that you'll see an effect on calciuria?

So great question, Jim. This is Jonathan. We do not need to see that in Phase I, since these are healthy volunteers. So whereas we might see a PTH effect on their kidney and see a reduction in urinary calcium, recall that they are normal, so they have endogenous PTH anyway. And as we raise serum calcium, that by itself will increase the calcium load to the kidney. And that by itself will increase urinary calcium, and the PTH effect will reduce the urinary calcium. So where that plays out, it could net-net out in healthy volunteers where you don't see a change. That said, we might actually still see a reduction in urinary calcium in healthy volunteers that are not deficient in PTH. So it's not a necessary requirement at all in our Phase I study. The infusion-like profile is more what we're looking for. The lack of immunogenicity, the consistent prolonged effect on serum calcium, those are the effects that we expect to see in healthy volunteers.

And Jonathan, just quickly, what do you expect at the primary endpoint to be of the Phase III?

It will likely be a composite endpoint that includes the 2 most clinically relevant measures, which is normalization of serum calcium and normalization of urinary calcium, that notably was not present in the NATPARA program. And we think these are those are 2 pivotal components of any composite. And maybe there'll be another element or 2, we're still finalizing it. But it will certainly contain those 2 important elements.

(Operator Instructions) And our next question comes from Joseph Schwartz with Leerink Partners.

So physicians tell us that one of the reasons NATPARA hasn't gained much traction in the marketplace is a lack of outcomes data? So as you look forward towards your Phase III, how extensive of a data package do you think you'll need to have more of an impact than NATPARA has? Do you think urinary calcium improvements alone would do it? Or do you think you could need more data than that such as kidney stone, renal survival, or surrogate biomarkers like glomerular filtration rate?

So thanks, Joe, for the question. Very good question. So the biology of PTH and the pathophysiology of hypoparathyroidism are very well understood. So I think it stands to reason for all, including the regulatory bodies, that if you control serum calcium and if you control urinary calcium, all of the downstream effects should be improved. So that does not mean we're not going to continue and collect long-term data. We clearly will. But I think the presumption is certainly going to be if we normalize those 2 factors, then all of the downstream effects should be improved. But they are important outcomes. Probably not to be captured in clinical trials, since those are multiyear outcomes, and renal failure takes years to develop, it's unlikely a clinical trial could ever show that. But I do not think you need that to be shown. As long as you normalize serum calcium and urinary calcium, the regulatory bodies will clearly connect the dots.

Okay. Okay, great. And then how physiologically relevant is a constant exposure profile like what TransCon PTH would offer in hypoparathyroidism? It's obviously been good to date in growth hormone deficiency. But I'm wondering about in hypo-PTH if there could be any drawbacks from this if there's no pulsatility which might drive anabolic and catabolic activity.

Again, a very good question. But this has been extremely well studied at the NIH over 20 years, where it's been shown by -- in multiple studies by Karen Winer, that if you maintain an infusion-like profile, then you normalize all of the issues with hypoparathyroidism. And in her earlier studies, where she didn't quite achieve that, because she used once-daily or twice-daily FORTEO, it got incrementally better. And as you approach the infusion-like profile with an insulin pump then everything normalized. So I think the data is very clear. And it's quite logical that if you're missing parathyroid hormone, you would want to replace it within the normal range to normalize all of the physiology and abnormalities in the disease, including bone marker and bone turnover.

And I'm not showing any further questions at this time. 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.