Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE)
Q2 2016 Earnings Conference Call
August 08, 2016, 05:00 PM ET
Ryan Martins - VP, Strategy & IR
Emil Kakkis - CEO & President
Shalini Sharp - CFO
Eric Schmidt - Cowen and Company
Gena Wang - Jefferies
Joseph Schwartz - Leerink Partners
Adam Walsh - Stifel
Heather Behanna - Wedbush Securities
Yigal Nochomovitz - Citigroup
Arlinda Lee - Canaccord
Brittany Turner - JP Morgan
Kennan MacKay - Credit Suisse
Mike Guo - SunTrust Robinson Humphrey
Carol Werther - H.C. Wainwright
Good day ladies and gentlemen and welcome to the Ultragenyx Second Quarter 2016 Financial Results and Corporate Update Conference Call. At this time, all participants are in a listen-only mode, Later we will conduct a question-and-answer session and instructions will follow at that time. [Operator Instructions] As a reminder, this call may be recorded.
I would now like to introduce your host for today’s conference Ryan Martins. Please go ahead.
Thanks David. Good afternoon and welcome to the Ultragenyx Pharmaceutical Financial Results and Corporate Update Conference Call for the second quarter of 2016. We have issued a press release detailing our financial results which you can find on our website at Ultragenyx.com.
I am Ryan Martins, Vice President of Strategy and Investor Relations. With me today also are Emil Kakkis, Chief Executive Officer and President and Shalini Sharp, Chief Financial Officer.
I would like to remind investors that this presentation contains forward-looking statements within the meaning of the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995, including but not limited to statements regarding plans with respect to our translational research program, the expected release of data from clinical studies; the initiation of additional clinical studies and the designs of the same; plans regarding ongoing studies for existing programs; the expectation of increased expenses over future quarters; our belief about adequacy of current cash resources to fund our operations; our intent to file for conditional marketing authorization and the timing of expected decisions regarding approval from regulatory authorities.
These forward-looking statements represent our views only as of the date of this call and involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the clinical drug development process, such as the regulatory approval process, including with respect to the MAA we filed seeking conditional approval from EMA with respect to Ace-ER, whether the Phase 3 results for Ace-ER will in fact confirm or mirror the results from the prior Phase 2 study, the timing of our regulatory filings and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations and the availability or commercial potential of our drug candidates.
For a further description of the risks and uncertainties that could cause actual results to differ from those expressed on the forward-looking statements, as well as risks relating to our business, see our Quarterly Report on Form 10-Q for the quarter ended March 31, 2016, filed on May 10, 2016, our quarterly report on Form 10-Q for the quarter ended June 30, 2016 that will be filed soon and our subsequent periodic reports filed with the Securities and Exchange Commission.
I will now turn the call over to Emil.
Good afternoon everyone and thank you for joining us. I will start by discussing our recent progress and milestones and Shalini will give you an overview of our second quarter financials.
We've continued to execute and moved our clinical programs forward to the second quarter of 2016. We are pleased to announce data from our first Phase 3 program for rhGUS just last month. We received breakthrough therapy designation with KRN23 in pediatric patients aged one year and older and also completed enrollment in 2 Phase 3 studies for Ace-ER and KRN23 in adults.
The success in the clinical development activity is also complemented by our ongoing efforts to build our early stage translational research program. Our recent partnership with Takeda is a significant additional step in building our robust pre-clinical program, along with a number of other partnerships that we have completed over the past twelve months.
For our rhGUS product intended to treat MPS 7 we presented data from the Phase 3 pivotal study last month at the MPS symposium in Bonn. Study which enrolled 12 patients between the age of 9 to 26 met the primary endpoint of reducing the urinary GAG excretion after 24 weeks of treatment. We saw a 64.8% reduction from baseline with a p-value of less than 0.0001. Urinary GAG reduction data from rhGUS is at the high end of what we've seen with other enzyme replacement therapies in which urinary GAG reductions ranged from approximately 40% to 75%.
Because of the small population of available patients and their limitations to prevent them from being able to complete certain tests, we developed the Multi-domain Responder Index or MDRI to assess clinical impact. The MDRI scores the summation of minimally important changed scores from six clinical domains. By using the MID, we can filter out smaller changes up and down and basically add together the big movers of benefit or decline in different clinical domains. Overall the MDRI score demonstrates a mean improvement of 0.5 domains with a p-value of 0.0527.
Turning to safety, all patients did experience treatment emergent adverse events most of which were mild to moderate in severity. There were two serious adverse events, including one Grade 3 treatment-related anaphylactoid event that resulted from an infusion rate error and one Grade 2 unrelated events from an accidental injury. There were no deaths, no treatment discontinuations or missed infusions due to adverse events.
In summary, we’re encouraged by this data that showed a significant urine GAG reduction, signs of clinical improvements in a very heterogeneous patient population, and an excellent safety profile for an enzyme replacement therapy.
As a reminder for this program in the EU, the primary endpoint is urine GAG reduction and some evidence or trend improvement in the clinical endpoint to support a favorable benefit risk ratio will also be needed for approval. In the US there is no primary endpoint [indiscernible] totality of the clinical data appreciating the heterogeneity of the disease. Based on this data we are in the process of planning to meet both the FDA and EMA this year to discuss our plans to submit a biologic license application in the US and marketing authorization application in the EU both in the first half of 2017.
We currently believe that the urinary GAG effect combined with the evidence of clinical effect and safety profile we observed is sufficient to meet the final criteria but we need to meet with authorities first in terming these precisely.
I will spend now a few minutes on recent highlights from our KRN23 program. In June the FDA granted breakthrough therapy designation of KRN23 for pediatric patients ages one and older with XLH based on the Phase 2 pediatric XLH data and other KRN23 data. We're encouraged by this designation for the first potential disease specific treatment option in development for patients with XLH. We’ll keep you apprised of our discussions with the FDA as we work with them to bring this potential new therapy to XLH patients the soonest possible.
Our KRN23 program in adults with XLH also continue to progress. We completed enrollment of 134 patients, above our plan of 120 patients in the Phase 3 randomized double blind placebo controlled clinical study designed to assess the efficacy and safety of monthly KRN23 in adult XLH patients who are experiencing pain at screening. The primary endpoint of the study is a comparison between active and placebo groups for the change of serum phosphorus levels from baseline through 24 weeks. Many adult patient with XLH have substantial disability, pain stiffness due to complications from their disease which will be evaluated through the secondary endpoint. The key secondary endpoint is a change from baseline of the brief pain inventory question 3 or BPIQ3 which looks at pain at its worst in the last 24 hours. This endpoint consists of the change in the mean of the BPIQ3 for the eight days up to including the study visit days as baseline week 12 and week 24.
Use of pain medications is also being monitored. Additional secondary points will also evaluate stiffness, physical function and other patient reported endpoints based on disease burden we've observed in adult XLH patients. We expect to have data from the study in the first half of 2017. We’re also enrolling patients in a 48 week open label bone quality study to evaluate the effect of KRN23 on the underlying osteomalacia. Enrollment is going well and we have expanded the study from 10 patients to 14 patients.
For Ace-ER, in July we completed enrollment of 89 patients in the randomized double blind placebo controlled 48 week pivotal Phase 3 study. The primary endpoint of the study is a comparison between active and placebo treated patients for the change from baseline to 48 weeks in the composite of upper extremity muscle strength as measured by handheld dynamometry. We’ll also look at GNE myopathy-functional activity scale, a disease-specific patient-reported outcome that includes measures of mobility and upper-extremity function, a composite of lower extremity muscle strength, and other measures of lower-extremity muscle strength and function. The Phase 3 study design and primary endpoint were based on feedback from the FDA and the EMA and we expect the data from the study in the second half of 2017.
We’re also continuing to develop and expand our preclinical program. Our strategic collaboration with Takeda which we announced in June provides us with a robust source of new product candidates and will help achieve our goal of bringing a new therapy into the clinic every one to two years. The most advanced product opportunity is approaching clinical stage development and the partnership includes option to license with up to six other Takeda product candidates for rare disease over the five year of research collaboration.
I’d like to now go through our upcoming milestone for the rest of the year. For KRN23 in the Phase 2 pediatric XLH study we are expecting the 40-week data in 52 patients and 54 week data in 36 patients in the second half of 2016. This will include rickets score data of RSS and RGI-C from all patients, a high growth velocity from patients who have received 54 weeks. We’re planning to initiate a Phase 3 in pediatric XLH patients shortly which will include the RGI-C rickets score as the primary endpoint and will include a reference arm of oral phosphate and vitamin D therapy.
In the second half of the year we expect to have a full 24 week bone data from the first 8 patients in the Phase 2 study in TIO, or tumor-induced osteomalacia. We plan to file a conditional marketing authorization in the EU for the treatment of XLH around the end of 2016.
Moving on to UX007, in the second half of the year we expect 78 week data from our Phase 2 study in long chain fatty acid oxidation disorders with close screening in our Phase 2 seizure study in Glut1 deficiency syndrome patients. We enrolled up to 40 patients and its data are expected in the second half of 2016. We plan to initiate a randomized placebo controlled Phase 3 study in approximately 40 patients with movement disorder phenotype Glut1 deficiency syndrome in the second half of the year.
Based on discussions with the FDA, we are working on further substantiating the clinical meaningfulness of Glut1 disorder -- movement disorder events captured by a patient diary prior to finalizing the study design. For Ace-ER in GNE myopathy, the CHMP opinion on conditional marketing authorization application in Europe is expected in the second half of 2016, followed a decision of European Commission in the first half of 2017.
I'll now turn the call over to Shalini to provide an overview of our financial results.
Thank you, Emil. We issued a press release earlier that included a financial update which I will briefly summarize.
Total net loss for the second quarter of 2016 was $56.9 million or $1.46 per share basic and diluted compared with $29.8 million or $0.83 per share basic and deluded for the second quarter of 2015. For the six months ended June 30, 2016 net loss was $109.7 million or $2.81 per share basic and diluted compared with a net loss for the same period in 2015 of $51.2 million or $1.46 per share basic and diluted. This reflected cash used in operations of $84.6 million in the first half of the year compared to $34.9 million in the first half of 2015. We continue to expect increases in cash used in operations quarter over quarter for the balance of the year and into 2017.
Net loss for the first six months of 2016 included approximately $25.5 million in non-cash charges with stock based compensation of $21.1 million, amortization of premiums on investment securities and depreciation and amortization. We expect stock compensation expenses to continue to increase over time.
Our operating expenses were $58.1 million for the second quarter of 2016 and $11.7 million for the first half of the year. R&D costs accounted for $43.3 million or 75% of our operating expenses. Our three Phase 3 program accounts for the greatest proportion of R&D costs. As a reminder, we share KRN23 development costs 50:50 with Kyowa Hakko Kirin. Costs for our multiple pre-clinical translational research programs are increasing as well as programs advance toward the clinic.
OpEx continues to increase due to the conduct of multiple late stage clinical studies. Manufacturing costs related to the clinical supply of multiple programs, increased regulatory activity across the programs, early stage investment in our U.S. and European commercial infrastructure and patient identification efforts, general and administrative expenses to support these activities and increases in stock based compensation expenses. Our expenses will continue to increase as we invest in advancing multiple product candidates into Phase 3 clinical studies and developing and expanding our pre-clinical stage portfolio.
This quarter the company recognized revenue for the first time with $17,000 in named patient sales for rhGUS. We expect named patient sales to remain negligible for the balance of 2016 as well as into 2017. Emil provided regulatory timing updates for Ace-ER, rhGUS and KRN23 during his remarks. Given review timelines as well as the lengthy process of obtaining reimbursement in European countries we expect little to no revenue from these programs in 2017.
We ended the second quarter with $441.8 million in cash, cash equivalents and investments on the balance sheet. Subsequent to the end of the quarter we closed on the first tranche of our common stock purchase agreement with Takeda whereby Takeda purchased 374,590 shares of our common stock for $40 million or an effective price of $106.78 per share. We believe that we are in a position to fund all of our current clinical programs through Phase 3 trial and potential launches. We do not have any debt outstanding.
With that, I will now turn the call back over to Emil.
Thank you, Shalini. As you heard we made progress with both our clinical and pre-clinical programs in the first half of 2017. We are on track to have five Phase 3 programs by the end of 2016 and other ongoing clinical studies and continue to move forward on the regulatory front as well with both conditional MAA filing and CHMP opinion expected later this year.
With that, let's move to your questions. Can the operator please provide the instructions for the Q&A portion of the call?
[Operator Instructions] And our first question comes from Eric Schmidt with Cowen.
Thanks for taking my questions and congrats on the continued progress. Emil, maybe you could just characterize the most recent EMA discussions you had around Ace-ER and then as a follow up, I was just hoping you could sort of outline what you hope to expect to see from UX007 and Glut1 deficiency, and specifically in the seizure study whether there is a bar that you need to achieve in order to get a broader label claims covering that subset indication?
Sure, Eric. Good talking with you. Thanks for calling in. So Ace-ER we haven't really discussed in detail our discussion with EMA. We have received questions, provided answers and prosecuting the process with them. And so we don't have any really more update to provide at this point. I think moving forward we just don't know if we're going to get a positive opinion. Remember we filed out Phase 2 data to press ahead and we think that there is some risk that that's not going to be enough but we don't know at this point how it's going to go. I think we've been working diligently to prosecute that but I would tell you having been through a lot of regulatory process at least you don't really know until you get toward further to the end. So right now that's where that stands. But I will say is that - and it’s from our plan from the beginning is we pressed ahead on Phase 3, we didn't sit back and wait for that and not move ahead. We moved ahead with Phase 3 the US as well. And so we haven't really lost any time by that filing. It just you know would be great if we could accelerate it, great for those patients. That’s Ace-ER.
On UX007, Glut1 here the question is what is a meaningful effect? I mean we're looking for a statistic significant reduction in seizures compared to the placebo, when compared to the baseline. In fact, the study is 3 to 1 randomized, so there’s not as many placebo patients in it. So we want to be able to show -- just if you look at the EMA, what they say is a 50% reduction in seizure than an individual who is considered clinically meaningful, right? And that's one of the secondary analyses we’re going to do. That doesn't mean the mean of all the patients is 50. I mean the individual to be considered a responder have to have a 50% reduction in seizures. So I think that’s the regional thing to say, that you have at least sufficient in a higher reduction in seizure in any individual but that's clinically meaningful. I wouldn't claim what the overall result is going to be because you may have some people that respond and some people that don't. And so you don’t have a blend of that when you look at the overall data. So we're looking at the top line analysis that says, are we seeing just statistical significant reduction in the seizure or not? And then we look at the individual responders and try to determine if that’s clinically meaningful by looking at that degree of response. So that's where we are right now on that. We did close screening which is good and there may be a few some more people out of screening that enrol, they have to have a certain level of seizures that they find to enrol, that’s why we can’t give you an exact number yet. So those are your questions. Thanks Eric.
Thank you. And our next question comes from Gena Wang [Jefferies].
Thank you for taking my question. So I have two questions regarding KRN23. For the first one I know you have reported growth velocity measurement. Just could you please share with us your measurement methodology and what would be your ideal outcome? And I have one follow up.
Yes. So for KRN23 the change in growth velocity means you have to have an estimate of the velocity before, not just where they are on the growth curve but how fast are they growing. So we're collecting historical data on these patients in the period before they enrol which will give us an estimate of the pre-treatment rate. So we’re going to look at the pre-treatment rate compared to the post-treatment rate of growth and look for whether there is a significant improvement in the rate of growth. But we do know looking at the baseline and we've mentioned this in December was that there's definitely some patients have more growth impairment than others. So there's a spectrum of growth impairment in the population. So it's probably also more important to look at the growth velocity in people who are impaired as opposed to if you were not as impaired. And that's just the heterogeneity in the disease.
What's been published before on the oral phosphate treatment is that growth in velocity is not really improved by oral phosphate treatment. And so we're going to look at patients who are having growth -- whose growth velocity is impaired compared and looking to see if we're seeing an improvement or not. We haven't set a percent change and I will caution you from thinking about like achondroplasia or some other disease. They are all very different diseases, achondroplasia is a very severe growth impairment for example. So I think these are all going to be a little bit different but what we’ll make sure to do is to provide a clinical context to the growth velocity data, so it can be interpretable to you and what it means.
Follow up question is for the Phase 3 pediatric trial design, you mentioned you will include standard of care as a reference. Are you looking for superiority versus standard care, any feedback from the FDA regarding trial design?
So the trial design is randomized controlled, it’s not blinded because you can’t blind the standard of the current treatment standard which is oral phosphate is impossible to create a blind or a double dummy type design. So it is randomized controlled but not blinded and FDA was completely accepting of that. And RGI-C is the primary endpoint accepted. We have decided to make it a superiority trial just because based on the data we have to date as patients who have been on standard of care all but one in the Phase 2 data we've shown you already had significant rickets and we're looking at the ability to improve their rickets and we think we've seen a substantial improvement.
We also think from a value standpoint showing superiority over the current treatment I think is important and we think the data we have so far gives us confidence is, that’s something we can do. So it will be a superiority design compared to standard of care.
Our next question comes from Joseph Schwartz with Leerink Partners.
I was wondering first of all if you could give us an update on how you're doing settling on a prototype for the design of Phase 3 for trihep in FAOD. I think you said that you wanted that to have a hospitalization component and when we attended the INFORM meeting on FAOD we were struck by the improvements in cardiac parameters but not rhabdomyolysis relative to MCP1.
Yes, very good. So we're still continuing to work on the Phase 3 plan and part of the issue is, how many patients out there have what burden of illness for FAOD because we want to make sure designing a Phase 3 that treats a common phenotype and there's not that much really known about phenotype. So we're collecting data on the burden of illness across patients. We're also then testing various instruments for a patient reported outcome which, we saw in our own data was maybe more compelling a result because perhaps some of the symptoms are just not just muscle, they’re fatigue, they’re other fatty acids of change which suggested a really significant improvement in the SF-12 if you remember when we presented that data. So I think we want to verify why is the SF-12 better to understand it because usually vague PROs are not as acceptable as primary endpoint if you're going to use that type of endpoint. So we’re trying to understand the basis for that phenotype.
The rhabdo effect you're talking about, I think that – if you look back at the old -- Dr Rowe literature from 2002-2008, rhabdomyolysis effect is more modest compared to the impact on other aspects of the FAOD phenotype. So I think what you were seeing there was something we had already seen. Clearly the rhabdomyolysis effect is complicated. It may be an inflammatory response, has some secondary things that are not just energy deficiency, there are probably some inflammatory components to the disease. Rhabdo itself is not really the basis for the exercise and tolerance type endpoint, rhabdo is part of it but the fatigue and lack of energy short of having actual rhabdomyolysis is probably a bigger factor in the change in exercise tolerance and a change in the PRO. That makes sense. So even if you're not changing rhabdo events you can be changing how the muscle functions day to day even if you're not affecting inflammatory reaction.
So to summarize all that we are continuing to work on gaining information to design an effective study and ensuring ourselves that the burden of illness in that particular sub-population, because it's a disease no one has ever treated before. It's not a single study that’s in a drug program, we're having to kind of create from scratch that information that will allow us to understand what to do and taking a little bit of time. In the meantime we're focusing on the Glut1 Phase 3 movement disorder where we had very substantial effect, and we think that that’s something we can push ahead more quickly on.
And just if I could follow up on that, I'm just curious -- thank you -- I'm curious because I noticed that as I mentioned – or as you were just saying, the FAOD study is probably going to be – vis-a-vis the MCT oil but the Glut1 DS work you're doing is versus placebo but ketogenic diet is is popular at some major centers. So I'm wondering why is that and where does trihep sit in in the grand scheme of things as a result do you think?
Sure. So in FAOD, it’s pretty well established that MCT oil and other treatment oil that even chain as standard of care is internally used to current treatment. And so it's hard to run a study where you don't use that as a control, it’s just not felt to be right since most patients, many patients are taking it and not all. So that's kind of the basis for the choice there is really felt to be not as ethical to do. In the case of ketogenic diet, if we ran a study – if we run a study with just us compared to placebo we can actually do a really high quality controlled study. If you throw ketogenic diet into mix, then it's impossible to blind the study because you can't blind ketogenic diet. So then you lose a lot of things by doing that. So ketogenic diet is somewhat a choice the patients may take or not take. They may decide to try to do it. Others may not. We think that there's still a significant population among the movement disorder patients who are older that really can't do ketogenic diet, therefore we don't have to compare to it because they’ve already opted not to do it. That makes sense.
So in that situation that while it may be standard care they've already opted against it. They've opted out. So it's a little easier to do a placebo controlled study in that setting. That does make things simpler, I think active controlled studies are always more difficult than placebo controlled.
Thank you. Our next question comes from Adam Walsh with Stifel.
My first one is on the trihep for the Phase 3 movement disorder study in the Glut1 patients. Emil, could you just elaborate a little bit on the line in the press release that talks about the company working on further substantiating the clinical meaningfulness of Glut1 movement disorder events? What does that mean and can you elaborate a little bit on what is clinically meaningful in this condition? That's the first one. Thank you.
Sure. So based on the investigator study that was conducted and we released on before there were six patients that had a 90% reduction in these events as reported by a diary. The diary just recorded a whole series of things that were happening to them and to turn that into an endpoint, you have to recognize that no agency FDA or EMA has ever seen the diary for this particular disease before. So it's never been used as an endpoint. So when looking at those diary entries, while in neurologic disorders they are familiar with diaries, like migraines, like regular features. They are less familiar with what it means to these various events that relate to movement disorders. And the movement disorders is relatively heterogeneous, there's eye problem, tongue problem and breathing, fatigue, physical movement dyskinesia, dystonia. So each patient has a common set of patterns that they're having, that are happening at intervals and I think what the agency queried was whether these were clinically meaningful, where all of the ones being reported in the diaries were meaningful and how it could be substantially tested. They've never really seen this disease before. That’s the situation where we needed to have enough data substantially, that these events are disabling, that they're not just annoying but they're actually disabling.
Our belief from these is that these are disabling, their effect to profound movement, they’re episodic, they last for an average in the studies around 45 minutes. And patients usually are not doing other things while these events are happening. So I would say from a physical effect standpoint is it’s almost like having a seizure, because they’re being disabled, every other day for 45 minutes and usually when they're doing something that's either emotional or physically active, so it's not when you're sitting on a couch, it's when you're -- something's going on down. So it's like the worst moment, basically problem. But we don't -- we don't have enough quantitative data on that. So what we're basically doing is collecting data to say how disabling are these things and interviewing patients to cut the burden of illness information which allows us to see, these are disabling and understanding when we're collecting a diary, how are we substantiating that this event that they're reporting is a disabling event. And so that means honing the diary to make that case. We’re making these responses -- these changes in response to queries from the FDA and we're just trying to substantiate clinical meaningfulness of these events. We feel they are clinically meaningful, we just didn't have enough data to say to provide support for that. This is a part of what I would say happens whenever you're doing a brand new program from scratch and we're learning a lot doing some additional data but I think we feel pretty comfortable that we will be able to move forward with a diary but we will have some improvements to the diary to help substantiate that they are disabling, or clinically meaningful events that we’re scoring.
That's great. Thanks. If I could just a quick question on the adult XLH on the key secondary endpoint of pain. What is the baseline level of pain in these patients and can you remind us of the PRO measures that were used in the Phase 1/II trial? And then finally you mentioned something that paint meds might be allowed in the study, which ones would those be and how you’d control for that? Thank you.
So the question is, in the KRN23 adult study, randomized controlled study, what are we looking at in terms of pain? Let me back to history, in the Phase I/II study, IN202 [ph] that was done before, there was pain as part of the WOMAC pain score which is a rheumatoid arthritis score but it was pain score from that score and then there was the stiffness score as well in the WOMAC, we used both of those and showed improvements we observed by study conducted by KRN. We subsequently did a burden of illness study which we did announce also. In the burden of illness we also asked now the BPI, brief pain index questions, a long list of WOMAC, so we can kind of calibrate how patients score, and show that they both behave very similarly as instruments so we have that data from P.P.I.. Question three is how much was the worst pain you had in the last twenty four hours, so the brief pain index has a number of other questions as well but the one that the FDA has requested us to look at the brief pain index is the question 3 specifically for that endpoint, we will be looking at the other questions.
So based on that data we also are conducting -- we plan to include then the BPI question 3 which we believe is reflected well by the WOMAC study, WOMAC pain score that they respond very similarly, so we felt pretty comfortable with that in the burden of illness study. While the pain can be complicated and we're fully aware of that and we are tracking and monitoring pain medications patients are taking which can be a confounder. I think the two or three main points about that, one, we will track them. We haven't told people to stop taking pain meds. Because we think that's difficult to do. So we haven't said you can take this or you can’t take this one. What we said is, where we want you to be have stable pain medication you have to have a significant BPI question 3 score baseline in order to enrol and get past screening. You’re going to ask me what that number is, that number already has posted – actually I don’t remember the number off the top of my head, is it a 4 or something but there's a score number we can get that to the group. But there's a particular score number that you have to have at baseline on your current regimen of pain medication, then going forward we're going to monitor your pain medication to assure that they haven't changed them. But what we decided to do in order to improve the precision of the test is instead of just measuring it at one time that they find one time week 12, one time at the end. What we said is we’re actually measuring it several -- a series of days in a row which will give us a score that will average and that allowed us to be more confident, it’s just not a one day random thing that’s changing the score, that something is so persistent and consistent kind of effect. So that's what we're doing with BPI question three.
We will also have scores of stiffness in the assessment and I think those stiffness scores are probably just as important as pain scores. We focus in pain based on our FDA discussions but I think stiffness is equally important. Who want to point out there are more than just the one pain endpoint, there's other secondary endpoints which you think are important both stiffness and functional scores as well.
Our next question comes from Heather Behanna with Wedbush Securities.
Just a quick question. Most of my questions have been answered -- on the XLH study in adults, the open label bone biopsy, you commented that this study has been increased to 14 patients. I was just curious if that's a demand or if you just want a little bit more power with the study, or if you could just give us some color on that.
Well we originally said 10 because we felt like getting 10 people to submit to multiple bone biopsies is already hard, but we actually had a lot of demand. So we were able to enroll 14. So it wasn't because we had a power issue. We don’t think there is a power issue at all. But it's just -- there were enough people showed up and so instead of turning them away we just included them. So that's the only basis for it.
And should we expect the data to read out from both studies at around the same time?
So the bone study is a 48-week endpoint because we're going to give the bone enough time to heal the osteomalacia, we’re going to score the osteomalacia on past pathology assessments. So we're going to give full the 49 weeks. Whereas the pain stiffness phosphate stuff is being scored at 24 weeks in the other study.
Thank you. And our next question comes from Yigal Nochomovitz with Citigroup.
Just a question on the Glut1 DS trial design, did you at all consider the following design trihep plus ketogenic versus ketogenic, does that make any sense and would you consider that maybe for a future trial? And if not, why not?
Well we've considered it and actually have supported them investigator studies to look at it. The trick with adding trihep to ketogenic diet is complicated from metabolic standpoint, how you would account for triheptanoin in the mix but we know in our seizure study enrollment, one of the challenges we had in enrollment was that there were people who were prescribing ketogenic diet, were still having seizures, wanted to be in our study but they didn't want to stop taking what they tried with ketogenic diet, even if incompletely ineffective in how they were doing it. And so that made it challenging. So if you're going to do the ketogenic diet add-on study you also then need to figure out what is it you're adding on to, right, you can't have like a random array of implementation of ketogenic diet also. So it adds another level of complexity. We do think however and you're right, it's an important study to look at, we've decided to support some pilot patients through investigator study just to get a little more experience to understand how to use the combination. We currently believe there is a role for triheptanoin as an add-on key ketogenic diet that it wouldn’t necessarily be a complete prohibition but it may be required some complexity in how you manage it and how you manage diet in the context. But to try to do the first randomized controlled study that way I think is tricky to do because it's just complicated because, remember the placebo we're using is not really for -- in the context of a ketogenic diet it's not a placebo, that is the safflower oil, long chain oil is part of the ketogenic – maybe to be part of ketogenic diet. So it's actually relatively inactive in that situation right here.
It's a complicated story, I guess, for everyone there. We thought about it. We're looking at investigator studies we may do in the future but we decided to work on the seizure and the movement disorder in the placebo controlled setting is the first line approach. And then we'll look at how to use it in add-on mode.
And just a question on clarifying, Shalini, you mentioned about 17000 for the named patient sales, is that just basically reimbursement at costs? I guess I would have assumed a higher number even for one patient given where you expect to price that drug?
Right, so for named patient sales, we are currently recognizing revenue upon receipt. So this reflects the receipt of payment from one of our sites. The dosing of the drug also depends upon the size of the patient, it is weight based dosing and the patient happens to be an infant. So the pricing is a dependent a little bit on the number of kilograms per patient. So it would be very hard to interpret what the $17000 means if you don't know what period of treatment is covered or what the weight of the patient is et cetera. So I can’t provide a lot more detail on that, we haven't disclosed what our per kilogram pricing is for named patient sales but it's not done at cost and it is highly dependent on the weight of the patient.
Thank you. And our next question comes from Arlinda Lee with Canaccord.
Maybe to follow up on the named patient sales and I know you can't disclose pricing. But is the named patient sales pricing along the lines of the pricing that we would see in the commercial setting?
Well the pricing that you see in the commercial setting obviously depends on the molecule and the average weight of the patient and things like that. But it is certainly within the ballpark of what you would see for other enzyme replacement therapies for MPS disorders.
And then on the KRN23 Phase 3 pediatric study initiation, what are the gating factors? We're going to see some additional 40-week data and 64-week data later this year, doesn't sound like that's going to be part of the -- something that will restrict the start of the Phase 3 but I guess I'm kind of curious what is there left to be done in terms of trial design or anything else?
Well, right now the trial design is completed in the program. It's been filed the site and is in progress. So there's something -- we're not waiting for any data and we think we had enough data so far and the piece of program designed it with the RGI-C, our current treatment controlled arm and all that. So we're just going in execution mode right now and there's nothing really dependent on any data that would alter what we do.
And I guess lastly, as you think about building your pipeline early stage and so on, I guess I'm kind of curious, on the Takeda deal, what kind of led you to that collaboration over others, how do you see collaborations in building your pipeline going forward?
Well we talked with a number of parties but the group at Takeda has really put a big effort into externalizing innovation there and that they had a pretty substantial catalogue of compounds and rare disease opportunities that they just were not able to do on their own, they wanted to find an expert partner. And I think for us the deal which brought us a partner with cash, with the med-chem type products which were things we wouldn't be able to develop on our own, made for reasonable synergy in terms of creating value. We knew the rare disease space and how to approach development in an efficient way and they had molecules which they had spent considerable effort on developing which we can turn into something of value. And I think that's a good partnership when both sides are contributing something important to the deal. We didn't really go out looking for these things, we’ve had a number of people come talk to us. I think they just had a deal for us and made a lot of sense providing us both cash, buying additional shares of stock as well and multiple products that we can pick up on our own option. There was an anchor product area which we're very interested in which we haven't really talked about yet but it was the core of why we do a deal like there’s got to be some value driving product that is the core of the deal like that. Otherwise it's hard to get something going us all on really alone.
So with that product in hand, that gave it the deal more value to us in the short term and we think they are certainly a great company, have done a lot of great partnerships in the past. So we're hopeful that we can get something -- creat something great for the rare disease patients with them.
Our next question comes from Cory Kasimov with JP Morgan.
Hi this is Brittany in for Cory and thanks for taking the questions. Most of them have been asked but just one on the commercial side. Can you provide any updates on where you are with building out your commercial infrastructure and launch preps?
I will let Shalini answer that one.
Sure. So we're currently focusing on just a small number of key hires and they are focused firstly on Germany where reimbursement does take place on approval, if approval is obtained, and also in France where they have named patient programs and also on patient diagnosis which is something that we need to do across all of the programs, and it’s something you want to do pre-commercial as well as post commercial. So the way that we're focusing on the commercial infrastructure is in a very staged and measured way until we know whether or not or when we would have an approved therapy in Europe. But generally speaking our commercial infrastructure requirement should be relatively limited compared to larger market indications, that’s certainly core to our strategy around how to build that out.
And our next question comes from Kennan MacKay with Credit Suisse.
So Emil, in the press release it states that you will be filing KRN23 for conditional authorization in the EU for the treatment of XLH. Could that be regardless of age or -- and include adult patients or will that just be restricted to the pediatric setting?
Well, Kennan, we think we have data both on adults and pediatric in terms of control of phosphate and bringing phosphate in the normal rate for both. That would look at the rickets data as evidence of that change in phosphate done by the spectrin is sufficient to alter bone health. And so our general plan is to apply for not just ped but the whole indication. Of course regulatory authorities may have different views but that is what our approach is. I’d point out that our Phase 3 adult data is coming very soon, in fact, would likely arrive in the middle of the review period. So we potentially have the opportunity to enter that data into the review process as well. So the top line answer would be our goal would be to get approval for across the indication but we'll have to of course negotiate with authorities in EMEA regarding what label they would provide.
Just a follow up, regarding the Phase 2 trial in peds stage one through four. Can you talk a little bit about what you think that could add to sort of the data package that you will have there?
So the very youngest patient study?
Well, I think what you have to understand is a little bit of the diagnostic pathway -- diagnostic treatment pathway for children XLH. For patients that are sporadically diagnosed, there is a new mutation ped’s family history or the adult family history, they usually get discovered at age 2, one and half when they start walking and the legs are falling and they end up with the orthopedic evaluation or meta-genetic evaluation for bone disease. So for that patient two, three years old, they would have to -- if we don't have a label for under five they would end up starting on oral phosphate for some years before they would get access to KRN23, which we think would be a terrible mistake if we believe our data that would suggest treatment early in life is probably going to be beneficial, that is of treating rickets early before it gets advanced, would probably be beneficial. So in order to assure that we don't end up in that situation we've set up -- and this is not only true for KRN23, but the other programs to do under five study, not after marketing but as soon as we can help provide some safety information after seeing this case of phosphate control and we’ll look at rickets as well in patients under five when they are normally first diagnosed to help assure that our label tries to press for early include patients as young as one is when they're normally diagnosed. Even in families that have XLH in them that are known they still don't start on treatment until they start walking here, usually waiting.
So the whole goal here is that when a patient – if we’re approved, we want to be able to get approved when a patient is diagnosed XLH, that we're first line and we don't become second line of oral phosphate and then get switched later. Hopefully that makes sense and I think some under five safety data, efficacy data provides the support for us in the regulatory process to help reduce the risk that our label would get restricted, doesn't eliminate the risk but it reduces the risk that your label would get restricted.
Thank you. Our next question comes from Edward Nash with SunTrust.
This is Mike Guo on for Edward. Thanks for taking my questions. So regarding the Phase 2 KRN study, what are the next steps for its indication especially on the timing for the pivotal study? The second question is, what are the indications can potentially be addressed by KRN23, other than XLH and TIOs?
So maybe I hope I understood. You said the Phase 3 XLH study is adult one is fully enrolled and the peds one getting started. So those you assume, definitely what else would we be doing for XLH, we have the under five study, we're certainly doing right now and currently that’s the spectrum in the ongoing Phase 2 extension. That's the spectrum of studies that we have ongoing for KRN23 in XLH at this point. We are doing the work in tumor induced osteomalacia which is ongoing. There should be more data on that later in the year as well, bone data on the first group of patients I think coming later in the year. Go ahead, maybe you can explain your question a lot more if I did not get.
Yeah, sure. And so my question is about the TIO indication. So after the Phase 2 data, at the end of this year, eight patients, what are you thinking regarding this indication, what are the steps for this indication to move forward please?
Oh, I see, you really want to know about how we're going forward with TIO indication. I am sorry. Didn’t quite get that. All right, so in the TIO indication, the first, you want to see what they looked like, the first two patients, bone data was very encouraging and we're encouraged by it. We look at the TIO as a follow on indication rather than a separate indication. But our expectation is, we don't have actually defined and verified plan that we've discussed with regular authorities. We have added some additional patients in that plan, we're getting a lot of requests for that treatment right now in those patients. I think we're still working through what the reg strategy, ultimate pivotal filing strategy would be. Our expectation for KRN23 is for XLH, it’s in the lead and we’d file with that. So we've been looking at this one as potentially a supplemental filing. The question is what do we need in order to do that, we don't have enough regulatory feedback at this point to know. And I think we want to wait and see what the data look like. The two options would be potentially having more patients than just doing more Phase 2 data, if it's very compelling and completely without question then potentially that's something that could be pursued whether that’s a filing path or not. Alternatively we could do -- have to do a controlled study which is a more typical request of the regulatory authorities. So I think it depends on what the data look like and how well -- how compelling it is for regulatory authorities.
So the other question from me is about additional indication can potentially be targeted by KRN23, other than the two indications you are doing, XLH and TIO, so what other indications can you address?
Well, two of the other hypophosphatemic rickets disorders, is other is a dominant, the autosomal dominant, the autosomal recessive type, they’re relatively uncommon and we have not yet planned programs for those two indication, however we expect there will be a need to look at them at some point. And if we get requests for studies or investigator studies, we may look at in that manner. But right now we don't have an active plan on developing it for those two relatively less common versions of hypophosphatemic rickets. There are potentially other uses for anti-FGF23. We haven't really talked about those publicly. I think we need to develop – we’ll get a little deeper and further along before we talk about what other uses we might want to work on. Does that answer your question?
Yes, thanks a lot for answering my questions.
Thank you. Our next question comes from Carol Werther with H.C. Wainwright.
Oh thanks for taking my question. So I have a couple of questions about the pre-clinical programs. Are you going to take UX004 forward, or are you waiting to sort out the partnership with Takeda, and take one of those programs forward? And if you mentioned it, could you mention it again? Thanks.
Thanks. Great to hear from you. Carol. We're planning to bring the UX004 program to [indiscernible] into the clinic. We're just timing it with -- we have a lot of things on our plate obviously, we have six clinical programs, two more filings to conduct. And so we're just trying to manage the flow of activity but our expectation is that would follow an idea in that program is currently in what we call the pre-idea or stage zero stage where we're doing the manufacturing scale of production and planning the toxicology program, regulatory and discussions et cetera for 004. So we're in that phase. I would expect us to file next year. I don't look at that one as having an impact on where we go with the first Takeda program. But we will -- we have a number of other programs in place so we have to think throughout our stage and manage it. We have -- we want to continue to invest, but we also have to manage our burn and our cash position as well. So we have to be thoughtful about our choices and timing. And the growth of the company.
I think we want to make sure we don't get ahead of ourselves, while at the same time continuing to grow value. So 004 is still moving ahead and so we have product from the Takeda deal, there are several others that are in our preclinical pipeline, we haven't discussed specifically that we might consider at some point in the next two three year period. So there will be a little more time before we say anything but at this point 004 is moving ahead.
And I noticed that you're supporting a symposium at ASBMR, the Bone Society meeting --
Yes, and I was wondering if you could just discuss if you have any data presentations through the end of the year?
We haven't really laid out of which meetings and presentations. ASBMR has been a big meeting for bone – rare regenerative bone disease. So in the past we have presented data at that meeting, we haven't yet announced when and what meetings we're presenting what. But we will provide you ahead of time. There are a number of different meetings going on, so it’d be hard on the call right now to kind of outline them but we will give analysts a heads-up as where things are coming out and when we can.
And our final question comes from Matthew Harrison with Morgan Stanley.
This is [Cyrus] on for Matt. Thanks for taking the question. So for KRN23, how do you expect uptake to be different between adults and pediatrics, and then in Europe, how do you expect the initial reimbursement decisions to develop, given the different timelines of potential approvals?
Well, the adults, peds uptake, obviously if you take the feedback from Tom Carpenter at our R&A Day I think that’s probably the best, I mean his feeling was that, that he would expect that all pediatric patients, assuming the drug is approved and found safe and effective by regulatory authorities, that he would expect to put all these patients who are currently getting oral phosphate, are nearly all of them are treating, we expect to treat them. With adult patients he thought that maybe 60% of his patients and I've heard that number 50%, 60% of patients with adults are being actually treated, that is a disease that’s so severe that they can't just stay off the treatment sometimes. So his feeling was that these were -- that made them candidates for treatment for KRN23. So sort of the overall percentage.
The uptake, I think people’s assumption is that peds is so devastating bone disease, so bad and that they will rapidly take off and we would expect that assuming we have our data are what it needs to be. I personally think that maybe we're under appreciating how bad the adult disease is and how much patients we’d want to get on treatment. The only data point we have for that now is the fact that when the patients were taken off care of KRN23 that were adults, from the INTO2 study there were 22 patients who came off – taken off the drug, we enrolled 20 of the 22 back on drugs again, 20 of the 22 who want to go back on injections and writing letters, I think so. Our view is that there is a medical need in adults that’s not trivial that’s substantial. And we think that as our data hopefully come out, and present that we will be able to make that forward. But I think the Phase 3 data will be really critically important to make that case. So that’s a little hard to say what the adult peds uptick will be. I think you’re talking about a commercial setting after we've managed to get past regulatory authorities and get approved.
So sorry what the second question was – I lost it.
For Europe, how do you expect the initial reimbursement decisions to be developed given the different timelines of potential approvals?
Different timelines for adult versus peds?
And why our goal would not to be different, but I would say our planning is to come up with a single pricing strategy, that we prosecute and that we -- I would say you have heard this many times, you'll suggest one pricing strategy and then another indication, you change the pricing strategy. But honestly it becomes quite incredible an ordeal to manage, changing the pricing I just don't think that's a very valid and very valid way to approach it. We think there's probably an adult and a pediatric indication, we're going to develop the data that support that. I think we will come through pricing with a reasonable strategy to make sense from both indications upfront rather than thinking about a strategy for one of the others.
I would point out to you that there is -- it appears to be some difference in the dose requirements for peds and adults and the pediatric patients are heading more toward 0.8 mg per kilo twice a month whereas the adults at 1 mg per kilo, once a month. So there is a differential also which will have some impact on the question of cost versus value. Which is a factor. So right now we would -- we try to come out with one worldwide price approach to this that makes sense and that accommodates the adults and the pediatric situation intelligently. And we've made it very clear in the past that our goal is to penetrate all the patients that they would benefit from treatment and not create a pricing value that results in the narrowing of acceptance of the product into a very small segment rather than the whole population. The adult population is very significant number of the kilogram of the patients that it needs out there because they're obviously larger, and this is weight based dosing. So I think you have to think through that whole commercial strategy and our goal is to maximize the revenue curve which is not necessarily maximized through price itself if you will. So that will be the work that Jason who's not here on the call and his team will be working on how to triangulate and come up with the best approach to pricing and reimbursement in Europe. Of course, working with Kirin, who of course owns the rights to KRN23.
End of Q&A
I'm not showing any further questions in queue. I would now like to turn the call back over to Ryan Martins.
Thanks. This is all the time we have for questions today. With no additional questions, this concludes the call. The replay of the call will be available shortly. If there are any additional questions please contact us at 844-758-7273 or IR at Ultragenyx.com. Thanks.
Ladies and gentlemen thank you for participating in today's conference. This does conclude today's program. You may all disconnect. Everyone have a great day.
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