Ascendis Pharma A/S (ASND) 2017 Q4 法說會逐字稿

Welcome, everyone, to the Ascendis Pharma Year-end 2017 Financial Results Conference Call. (Operator Instructions) I will now turn the call over to Scott Smith, Senior Vice President and Chief Financial Officer at Ascendis Pharma. Sir?

Thank you, operator. And thank you, everyone, for joining our year-end 2017 financial results conference call today. I'm Scott Smith, Chief Financial Officer of Ascendis. Joining me on today's call are Jan Mikkelsen, President and Chief Executive Officer; 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 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 statement section in today's press release and the Risk Factors section of our Annual Report on Form 20-F filed today.

On today's call, we will discuss our year-end 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. Jan?

Thanks, Scott, and good afternoon. A year ago on the 2016 call, we focused on our strategic vision for becoming a leading rare disease company. The vision included expanding our pipeline from 1 to 3 rare disease endocrinology candidates: TransCon GH, TransCon PTH and TransCon CNP. During 2017, we continue this transformation of Ascendis from a company with a single product in the clinic to having a pipeline with multiple rare disease candidates in clinical development.

You will recall that our 3 endocrinology product candidates are created by the same unique combination of our TransCon technology, together with our algorithm for product innovation. Our rare disease endocrinology pipeline is built on parent stock with established safety and efficacy, which is expected to provide a higher success rate compared to traditional drug development. This expected higher success rate is becoming evident as we further derisk our pipeline by successful clinical progress.

Our organization continues to evolve [carefully] as we prepare for our programs to advance to the clinic and towards commercialization. We are executing step-by-step on our plan to build a leading integrated rare disease company.

I would like to briefly review the profits with each of our product candidates. Our TransCon Growth Hormone program continued to advance in Phase III. We completed enrollment in our pivotal heiGHt Trial and initiated 2 supporting Phase III trials. We also continue the development of our patient-friendly auto-injector, which we expect to be ready at launch.

In addition, we published our Phase II results and other data to build awareness of our potential best-in-class program. Given changes in the competitive landscape during 2017, TransCon GH has moved to a potential first-to-market position in the latest wave of long-acting growth hormone products for pediatric growth hormone deficiency. We are well positioned in this market, and we expect top line result from our heiGHt Trial in the first quarter of 2019.

For TransCon PTH, we initiated our Phase I trial last year. Since January, we have been reporting and sharing data from both the single and multidose cohorts. These positive data reinforce our preclinical findings, supporting the target product for TransCon PTH as a true replacement therapy. By restoring PTH to physiological levels for 24 hours a day, both serum and urinary calcium should be normalized. We expect to complete this trial in the second quarter, and we will report data at medical conferences and business updates. We expect to initiate Phase III in the first quarter of 2019, pending regulatory discussion data this year.

For TransCon CNP, we submitted regulatory filing in Australia and have now received approval to initiate a Phase I trial as planned. We are trying to dose subject during the second quarter and have top line data in the fourth quarter of this year.

As I reflect on the year, one significant achievement is the translation of TransCon PTH preclinical data into clinical data, once again, highlighting the predictability of our TransCon platform technology. This gives me a high level of confidence that TransCon CNP has the potential to realize its target product profile. We expect to report the clinical data in the third quarter this year, supporting our goal to provide patients with FGFR-related diseases, an effective treatment without cardiovascular risk.

All 3 of our candidates are now advancing to (inaudible) phases. The product profile and data so far has been well received by both the medical and patient communities. It is clear that our pipeline address significant unmet medical needs.

I would also like to remind you that each of our internal pipeline programs is wholly owned without royalties to third parties. We are building our commercial infrastructure and putting in place the key function requiring to support prelaunch activity and commercialization of our differentiated product candidates.

You may recall that one element of our Vision 20/20 is to pursue additional new therapeutic area. We are eager to develop the same kind of high-value pipeline we have developed for endocrinology in other areas. We plan to address unmet medical needs using the same equipment we use for our current pipeline. While we're advancing our rare disease endocrinology pipeline and achieving our stated milestone, we also remain on track to this part of the vision. Thank you for your support during a super year from Ascendis.

I would now to turn the call over to Jonathan.

Thanks, Jan. 2017 was a defining year for our pipeline. We now have 3 product candidates advancing in development and we have met all of our stated milestones. With this growing pipeline, we're maturing as a company and expanding capabilities in our clinical and regulatory organizations.

Our Phase III program for TransCon Growth Hormone is progressing well. We completed enrollment of 161 subjects in the pivotal heiGHt Trial, exceeding our original target and further strengthening the statistical power of this noninferiority trial. The Data Safety and Monitoring Board has extensively reviewed our safety data and recommended continuing our program as planned.

At the recent ENDO conference in Chicago, we presented a poster summarizing the baseline demographics of heiGHt Trial subjects. The poster concluded the demographic profile is generally similar to the daily growth hormone cohorts of 4 recent Phase III registration trials. Based on final subject enrollment, we calculated the trial's statistical power for noninferiority to be well over 90%, even based on conservative assumptions.

Our Phase III single-arm open-label fliGHt Trial is also well underway. Our plan is to recruit 150 subjects who will switch from daily growth hormone to once-weekly TransCon Growth Hormone. The fliGHt Trial is enrolling briskly, and we are extremely pleased with the strong interest from sites, most of which are also participating in the heiGHt Trial. Investigator enthusiasm for the trial also suggests strong interest among patients treated with daily growth hormone to switch to our long-acting therapy. We believe this is an encouraging indicator of the unmet need for long-acting growth hormone treatments. We expect to complete enrollment in fliGHt in the third quarter of 2018.

We also recently initiated the enliGHten Trial, our long-term extension study with the initial subjects from heiGHt rolling over in recent months. Feedback from sites has been encouraging, and we expect the vast majority of subjects finishing the heiGht and fliGHt trials to enroll in enliGHten. As Jan mentioned, we anticipate top line results from the heiGHt Trial during the first quarter of 2019. Based on expected availability of data from heiGHt and the supporting Phase III trials, we are on track towards our stated goal of a database lock for the entire clinical program in the third quarter of 2019.

Turning now to TransCon PTH. We have made exciting progress with this program in the past year. As a reminder, TransCon PTH is in development as a true PTH replacement therapy for hypoparathyroidism, designed to more fully address all aspects of the disease. Following initiation of our Phase I trial last year in healthy adults, we are thrilled with the interim data so far that supports our target product profile, a convenient therapy that restores PTH to physiologic levels with an infusion-like pharmacokinetic profile.

We believe that by replacing and maintaining PTH levels for 24 hours a day, TransCon PTH can normalize serum calcium and phosphate as well as urinary calcium excretion. Such a product may not only control acute symptoms of hypo or hypercalcemia but also may help reduce the long-term effects of hypoparathyroidism, such as tissue calcinosis and renal impairment. Currently available treatments do not fully address all aspects of the disease.

In January, we presented initial findings from the single ascending dose, or SAD, portion of the ongoing Phase I trial. Pharmacokinetic data from these SAD cohorts demonstrated a half-life of approximately 60 hours, supporting an infusion-like profile with daily administration and reinforcing our prior preclinical evaluations and modeling. Importantly, this half-life is a substantial increase in duration compared to subcutaneous administration of PTH 1-34 and PTH 1-84, both of which have half-lives of only a few hours.

Finally, the SAD data also showed sustained and dose-dependent elevations of serum calcium levels lasting more than 72 hours with low inter-subject variability.

Earlier this month in a late-breaking poster at ENDO, we presented additional data, notably, results from the multiple ascending dose, or MAD, cohorts. These data further reinforced our target product profile for TransCon PTH. Following 10 daily doses, free PTH levels showed a flat infusion-like profile and a low peak-to-trough ratio over 24 hours.

The MAD cohorts also showed a predictive pharmacodynamic response, suggesting the ability to titrate patients with hypoparathyroidism into the normal calcium range. For example, measurable increases in serum calcium levels were demonstrated with repeated administration at both the 12 and 16 microgram daily doses.

Finally, the results from the SAD cohorts show the expected effect on renal calcium reabsorption with maintenance of a normal fractional excretion of calcium, which is important to minimize the long-term adverse effects of the disease and its treatment on renal function.

As you may be aware, PTH controls serum calcium via several mechanisms. First, it acts to release calcium from the skeleton; second, PTH facilitates the conversion of 25 hydroxy vitamin D to 125 dihydroxy vitamin D, the active form, which in turn, acts on the intestines to increase calcium absorption. Finally, presence of PTH is required to act on the kidneys to reabsorb calcium from the urine into the bloodstream and decrease reabsorption of phosphates.

For patients with hypoparathyroidism, continuous presence of PTH should allow control of urinary calcium. This is critical, given the fourfold greater risk of long-term renal disease and the high rates of hospitalization for these patients.

In terms of safety, TransCon PTH was generally well tolerated across the likely clinical-dose range. We're extremely pleased with the emerging data from our TransCon PTH trial. We believe that our initial results support our plan to advance directly into a Phase III study, pending discussions with regulatory authorities.

Our third product candidate, TransCon CNP, also continues to advance as a potential treatment for achondroplasia and related skeletal disorders. In December, we completed regulatory submissions in Australia to enable our first-in-human Phase I trial for TransCon CNP, which is expected to begin dosing healthy adult subjects during the second quarter. The trial will evaluate safety, tolerability and pharmacokinetics with the goal of identifying safe doses for future efficacy trials. We expect top line data to be available in the fourth quarter of 2018.

As you know, there's a high level of interest in development of treatments for achondroplasia from the medical, patient and regulatory communities. To this end, FDA is planning to hold an advisory committee meeting to discuss drug development for the treatment of children with achondroplasia. We look forward to the panel discussion as it will help inform our TransCon CNP program. We will be interested to hear the views on defining clinically meaningful outcomes that could help improve patients' lives.

2018 has started off with strong momentum across all 3 of our rare disease endocrinology programs. We have a pipeline of products designed to address unmet needs, and we have assembled a very committed and experienced development team. We look forward to achieving our milestones and bringing these product candidates closer to patients during the coming year.

Now Scott will provide a financial update.

Thank you, Jonathan. Turning to our financial results for the full year ended December 31, 2017, let me review some highlights. We ended 2017 with cash and cash equivalents of EUR 195.4 million on a reported basis. In February this year, subsequent to the December 31 year-end, we completed a follow-on financing, further strengthening our cash position as we advance our pipeline. Net proceeds from this February 2018 financing were approximately $242.5 million or approximately EUR 196.8 million, based on exchange rates as of the date of the financing. Combined with our year-end cash balance, this financing ensures that Ascendis is well capitalized to pursue our Vision 20/20 to become a leading integrated rare disease company.

As of December 31, 2017, the company had 36,984,292 ordinary shares outstanding. As of today, including the February 2018 financing, the company has 41,523,765 ordinary shares outstanding.

For the full year 2017, we reported a net loss of EUR 123.9 million or EUR 3.68 per basic and diluted share compared to a net loss of EUR 68.5 million or EUR 2.58 per basic and diluted share during 2016. The 2017 loss reflects an unrealized noncash EUR 13.7 million finance expense due to foreign currency exchange rate fluctuations for the year.

Research and development costs for 2017 were EUR 99.6 million compared to EUR 66 million during 2016. Higher R&D costs in 2017 reflect an increase in manufacturing and clinical costs related to preparation for and execution of the Phase III clinical program for TransCon GH, including the heiGHt, fliGHt and enliGHten trials; ongoing development of our proprietary auto-injector for use with TransCon GH; an increase in costs related to the Phase I clinical trial; and activities related to Phase III initiation, including manufacturing and device development for TransCon PTH; and preclinical development costs associated with TransCon CNP.

General and administrative expenses for the 2017 year were EUR 13.5 million compared to EUR 11.5 million during 2016. This is primarily due to an increase in G&A personnel.

During 2017 (sic) [2018], we expect an increase in R&D expenses as we continue to advance our wholly owned internal pipeline programs and invest in the TransCon technology platform. R&D expenses will include, for TransCon Growth Hormone, costs associated with our Phase III clinical supply and manufacturing of validation batches, which we expect to be used for commercial supply; costs associated with the ongoing Phase III clinical program, including execution of the heiGHt, fliGHt and enliGHten trials; and costs associated with ongoing development of our proprietary auto-injector for use with TransCon GH.

For TransCon PTH, R&D will include Phase III enabling activities, including nonclinical talks, manufacturing, regulatory and device development activities and the ongoing Phase I clinical trial. And finally, for TransCon CNP, R&D will include ongoing Phase II enabling activities, including nonclinical talks and manufacturing; and costs associated with the Phase I trial, which is expected to dose the first patients in the second quarter this year.

We expect to make meaningful progress on each of our wholly owned rare disease pipeline candidates in 2018 and sharing new developments with you on all 3 of our programs over the next 12 months. Key upcoming milestones include TransCon PTH Phase I data from all SAD and MAD cohorts, TransCon CNP Phase I data, regulatory discussions and agreement regarding design and initiation of our Phase III program of TransCon PTH, and top line data from our heiGHt Trial of TransCon GH.

Our goal is to continue to leverage our TransCon technology to create a pipeline of internal proprietary products. As we disclosed to you during our February 2018 financing, we intend to use a portion of the net proceeds from that financing to apply our algorithm for product innovation to expand our pipeline, including potentially into new therapeutic areas.

Operator, we are now ready to take questions.

(Operator Instructions) Our first question comes from Jim Birchenough with Wells Fargo Securities.

Congrats on all the progress. A couple questions. I guess, first, you alluded to it, Jonathan, but the heiGHt and fliGHt rollover into enliGHten, could you quantify it? It sounds like there's a pretty decent rate of rollover, but are you be able to quantify that for us?

So far, every subject who has completed the heiGHt Trial has chosen to enroll into enliGHten. Now we've not provided exact numbers yet, but it's been 100% so far. And I expect it to remain very close if not at 100%.

And then maybe just on TransCon PTH, with the 60-hour half-life, is there any possibility of spacing at the dosing less than once daily? And I'm just wondering, with once daily dosing, do you expect to achieve an optimal steady-state? Or again, does it make any sense to spacing out the dosing further?

Jim, it's a pretty interesting question, but I think it's mainly going back to the old question, how do we build up optimal adherence for our patient population. And the general rule has always been that you like to have an -- the treatment administration that is still something that a patient really can remember. And it comes back to daily administration, weekly administration, monthly administration. So therefore, even we believe we can develop and the treatment administration that can support perhaps thrice-weekly injections, potentially once-weekly injection, we think it's very, very important to start with a daily administration because it give us this opportunity to be in a position that we can titrate in an optimal manner. The fast and best way to really to get the [maintenance] treatment that is optimal for the patient. And then we can discuss potential later on that if you have stabilized the patient, we can move them on to once-weekly product opportunities, more like a kind of life cycle management opportunity.

But from that perspective, we believe that the daily administration -- and we -- one of the more, really I think, appealing element of our long half-life, about 60 hour, is that if a patient, by any means, forget to take the administration just for one day, they are in a position that they're not suddenly losing completely the PTH level, but you will have a sliding scale of less and less of PTH. So you're not sitting in -- suddenly in a situation where you're having a hypercalcemic episode.

And maybe one last question, if you'll allow me. It strikes me that for the TransCon PTH program that your differentiation versus things like NATPARA are on the urinary calcium side, but that's also a differentiator from -- of calcium and vitamin D supplementation, which is more broadly used. So the question is, do you think in a Phase III, you'd incorporate an arm where you have vitamin and calcium D -- vitamin and calcium supplementation?

So another good question. So we absolutely will compare ourselves to the first-line therapy, which is calcium and vitamin D. And you're right, lack of control of urinary calcium is a major problem there as well as for NATPARA. So we will clearly incorporate control of urinary calcium as an important component of our endpoints because we feel it's a very important aspect of the disease. It's not been well addressed so far.

Just to add in, Jim, we also believe that if we go away on secondary point, secondary point could be more a normalization of bone marrow because it could be also be with -- suddenly, it could be that you have a much more healthy bone metabolism. And I actually believe that's other element where we can see a benefit of the profile we're providing and having PTH always in the physiological level for 24 hours a day. But we're quite sure that easiest and perhaps the most important one is definitely the urinary calcium, and that is, as Jonathan said, it's really one where we see a huge differentiation to all standard-of-care treatment, including NATPARA.

Our next question comes from Jessica Fye with JPMorgan.

Can you talk about your estimate for the standard deviation and heiGHt velocity in the Phase III growth hormone trial? Or maybe just what it's been in other recent Phase IIIs? And then sticking with growth hormone, you reiterated the time line for database lock for the clinical program in 3Q '19. Is -- beyond that kind of clinical data, what are the remaining gating factors to think about that you would need to knock out prior to filing? Is it accruing more long-term experience? Is it manufacturing? And can you also remind me of where we stand in terms of incorporating the auto-injector into the growth hormone clinical program?

Jonathan here. So for the standard deviations, the exact numbers I don't know that are critical, but I'll tell you what our approach was. So our approach was to take our own experience from Phase II. Take the standard deviations that we actually saw in our hands. Realize that we were expanding from 40-some-odd sites to about 90 sites. And when you do that, the standard deviation typically improves -- sorry, expands, enlarges, worsens. And then we looked at the standard deviation from other published studies and kind of just took all of that into account. And I tend to be relatively conservative when I power studies, so I looked at standard deviations that were on the conservative side in coming up with our numbers, and that gave us a number of 150 subjects. And then, of course, even from there, we overrecruited. So we went beyond that. So that's kind of the general approach that I have taken in designing the heiGHt Trial with the team here.

And for the auto-injector question, we are going to incorporate the auto-injector into the enliGHten Trial sometime early next year. So patients, when they're in the extension study, will begin using the auto-injector at some sites.

So Jess, going back to your -- last of your question. Just to clarify one thing, we expect -- and this is our plan to have the auto-injector ready for launch, so it would be part of our filing document. We think this is an essential part of providing an optimal treatment for the patient, the growth hormone deficiency but also be having the auto-injector available.

Related to the filing date, this is something we have been executing on for a long time now. We have 3 different elements that we -- as far as a group, we have 3 different elements just to be quite sure that is more in small packets. One packet is related to the preclinical safety. It's basically done. We're starting and writing that up now, finalizing everything. The report's done. What Jonathan just disclosed was in Q3 next year, we will have all clinical data that is necessary for supporting a filing in both the U.S. and in EMEA ready.

The last part of that is the validation batches. And you can see from Scott's talk, we already are executing on the validation batches because we -- it will be part of our commercial production that will be out coming after patients. We still are locking the last time line of the last part of the validation batches. And assume, as they are really locked down to days, months, we can give you the basic -- the date for the filing. But we also feeling that we want to be very transparent, and we want to keep milestones and being quite sure we can live up to them. As has we (inaudible) -- have not really locked down the last part of that, the manufacturing steps. I think it's much better that we will come to you and say this will be our filing date.

Okay, understood. And then on CNP, just as we anticipate that data in the fourth quarter, can you talk about the extent to which we can feel comfortable reading across from the PK data for PTH, for example, to that program in terms of your ability to replicate what you're seeing preclinically? And are there any biomarkers that you can evaluate in the healthy volunteers for the CNP product?

I can take the first part, and then I'll move it over to Jonathan to take the second part of the question. First part is that what we have seen for all product opportunities that has been developed with TransCon technology are pretty unique and really great translation from preclinical data, specific primate data into humans. That is not only for PTH. We have seen it -- we have seen for all our product opportunities.

Yes, sure, it gave us -- confident that we hope that will be a great translation. We have at least the [ops] with us not against us because we have seen it every time. There can be coming out product-specific elements that we have never considered. We think we have really started and analyzed the fundamentals in each single product opportunity to really deep level, and we feeling that we think that we have a great chance to see the same translation that result with PTH also for CNP. Jonathan will address what we're trying to get out of that trial and also what we expect to see of PD markers.

So we'll certainly get a full safety profile from healthy volunteers. We'll get a tolerability profile. We'll get the infusion-like profile that we expect as we saw with PTH as well to see in that study. In terms of biomarkers, there are some biomarkers, such as cyclic GMP, that we can measure both in urine and serum. There's also some experimental biomarkers of bone metabolism that we're considering as well. And then finally, I would say that if we don't see a drop in blood pressure, which we are not expecting to see and we have not seen preclinically, that would allow us to push the dose to higher levels where we might really optimize our efficacy signals in those children.

(Operator Instructions) Our next question comes from Alethia Young with Credit Suisse.

This is Derek on for Alethea. Congrats on all the progress for the quarter. I guess I have 2 questions from me, if I may. My first one is about the FDA advisory meeting on achondroplasia. Can you provide some color on what are your thoughts about your expectation, the different possible outcomes from the meeting? And how those could affect your TransCon CNP development plan?

Sure, so thanks for that question. We're really looking forward to this. And we think it's a great sign that FDA has called for this meeting because, in their briefing materials, it looks as if they are really, really focused on what are clinically meaningful endpoints in these children, and what kinds of study designs are required to establish that. And that has long been our passion as well. We really want to make a difference in this disease state. And we're really focused on what are the clinically meaningful endpoints. We have our own ideas about that, and we certainly are going to follow with great interest as the panel discusses that. No matter what happens, it will clearly inform our plans, and we think they're likely on the right track.

We also believe that the timing is perfect for us. We're in a position now where we're really deciding how we really will develop our TransCon CNP in the late-stage clinical development, and getting this kind of input is the right timing because we can integrate it into our plans.

And I think kind of the obvious question is, how important is height, if at all? So you might grow more, but does that really correlate with the real unmet need in this disease state? So we look forward to that discussion. We certainly have our own views on that topic.

The other question on the PTH part, can you walk us through how the fraction calcium excretion is calculated? I know there's a chart you see. Percentage of 1% to 2%, you can maintain that level. I'm wondering what's the expectation for that number. And how's the data compared to expectation?

Sure, so fractional excretion of calcium is just that. It's what percent of calcium that's delivered to your kidney is actually excreted and how much is reabsorbed? So -- and that is a formula that you can just look up, but it involves a measurement of urine and serum creatinine and then making a ratio of that and urine and serum calcium levels. So those 4 components you plug into an equation and you get the fractional excretion of calcium. Now normal fractional excretion of calcium is about 1% to 2%.

And I think the really critical part to understand in our poster, and it explains what we're seeing in our data, is really that the figure in our poster that shows that if you were to clamp a calcium level of 10.3, and this has been done in previous literature, and you look at the fractional excretion of calcium in normal volunteers, it goes up to that 6 to 7. And that is because in normal volunteers, where you falsely elevate their calcium level to 10.3, you completely suppress their own endogenous PTH. So those healthy volunteers have no PTH presence in a hypercalcemic blood level.

What happens then is your calcium gets dumped by the kidney because there's no PTH present to reabsorb. Now you turn to our study, and when we raise the calcium levels with a PTH level of 100 microgram single dose to 10.5 or more, similar to that other published study I told you about, you would expect fractional excretion of calcium to go up to 6 to 7, but in fact, it remained normal because, in our study, we had continuous presence of PTH at the kidney. In fact, this is just a wonderful representation of how important it is to have PTH present 24/7. In the presence of PTH, you don't dump calcium, even when your calcium level is abnormally high. Does that answer your question?

Yes, yes.

As I show no further questions in queue, I would like to conclude today's conference. Thank everyone very much for their participation, and you may all disconnect. Have a wonderful day.

Thank you, everyone. See you. Bye-bye.