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Ultragenyx Pharmaceutical Inc
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Ladies and gentlemen, thank you for standing by. Welcome to the Ultragenyx Fourth Quarter and Full Year 2019 Financial Results Conference Call. At this time, all participant lines are in listen-only mode. After the speaker presentation, there will be a question-and-answer session. [Operator Instructions]
I would now like to hand the conference to your speaker today, Danielle Keatley. Please go ahead.
Thank you. Good afternoon and welcome to the Ultragenyx Pharmaceutical financial results and corporate update conference call for the fourth quarter and full year 2019. We've issued a press release detailing our financial results, which you can find on our website at ultragenyx.com.
I'm Danielle Keatley, Senior Director of Investor Relations and with me today are Emil Kakkis, Chief Executive Officer and President; and Shalini Sharp, Chief Financial Officer.
I'd like to remind investors that this call will include 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, the types of statements identified as forward-looking in our quarterly report on Form 10-Q that was filed on November 6th, 2019, our annual report on Form 10-K that will be filed soon; and our subsequent periodic reports filed with the SEC, which will all be available on our website in the Investors section.
These forward-looking statements represent our views only as of the date of this call and involve substantial risks and uncertainties, including many that are beyond our control. Please note that actual results could differ materially from those projected in any forward-looking statement.
For a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward-looking statements as well as risks relating to our business, see our periodic reports filed with the SEC.
I'll now turn the call over to Emil.
Thank you, Danielle. I'll start with our commercial performance in the fourth quarter of 2019. Shalini will then summarize our financial results for the quarter and the year. I'll come back at the end to discuss the progress across our clinical and preclinical programs and our outlook for the rest of the year.
Starting with Crysvita, which has been the main focus of our commercial efforts and the primary driver of revenue in 2019. Performance in the fourth quarter built on the momentum in the first five quarters of launch; this was reflected by continued increase in completed start forms and the number of patients on reimbursed therapy.
In the U.S., we ended the year with approximately 1,590 completed start forms, 160 more than the third quarter. We also ended the year with approximately 1,330 patients on reimbursed therapy, a 200-patient increase versus the end of the third quarter. As the commercial team continues to work to penetrate the adult market, we believe Crysvita will continue to be one of the most successful rare disease program launched.
Our 2020 Crysvita revenue guidance of $125 million to $140 million further reflects the confidence we have in Crysvita and our commercial team's ability to execute. Now that the early launch period is over, going forward, we do not plan on providing specific launch metrics, but we'll focus on revenue for Crysvita.
To put our launch progress in perspective, we mapped out the top rare disease launches through their first six quarters over the last 15 years. We found that Crysvita is one of the top rare disease launches based on topline total product sales. We've also generated a substantial revenue of setting a price and substantially lower than any of the other top rare disease drugs.
As a result, we have successfully ensured that payers view our pricing as responsible, allowing us to reach more patients, especially adults and achieve a positive financial outcome for the company. This approach corridor philosophy about improving access and total revenue by moderating rare disease pricing.
Turning to Canada, we are seeing continued prescribing interest from physicians and the number of reimbursed patients with private insurance has exceeded our expectations. More than half of Canadians have supplemental private insurance today and the number of pediatric that adult patients who are receiving Crysvita through their private insurance drug plans continues to grow. We also continue to pursue public reimbursement in Canada, which will take more time.
Moving to Latin America. In Argentina and Colombia, the number of patients are reimbursed name patient treatment continues to increase, and the feedback has been very positive.
In Brazil, the demand has been strong, with a significant number of patients successfully navigating the cumbersome legal process and a few receiving reimbursed treatment to-date. We're also seeking pricing and full reimbursement approval by the Ministry of Health to enable more rapid access for patients in Brazil. Ultimately, we believe there is significant potential for Crysvita in Latin America, with growing demand in multiple countries for the product.
Briefly turning to Mepsevii. The therapy is approved in the United States, Europe and Brazil, and demand continues to build gradually as typical for enzyme replacement therapies. We are also continuing reimbursement discussions with various government health authorities throughout the world.
With that, I'll turn the call over to Shalini, who will provide a financial update.
Thank you, Emil and good afternoon, everyone. Earlier today, we issued a press release that included a financial update, which I will briefly summarize. Ultragenyx's total net revenue for the 12-month period ending December 31st, 2019 was $103.7 million. And for the fourth quarter of 2019 was $35.6 million. The following is a product-by-product breakdown of these figures.
For Crysvita, during the year ended December 31st, 2019, we recognized total revenue of $87.3 million. This includes $74.9 million in collaboration revenue in the U.S. profit share territory in Canada and $8.1 million in royalty revenue in the European territory from our collaboration and license agreement with our partner, Kyowa Kirin or KKC.
Net product sales for Crysvita in other regions totaled $4.3 million. Total Crysvita revenue recognized Ultragenyx for the three months ended December 31st, 2019 was $29.9 million. This includes $26.1 million in collaboration revenue in the North American profit share territory, $2.2 million in royalty revenue on KKC sales in the European territory and $1.6 million in net product revenue in other regions.
Recall, there is a significant order that was placed on the last day of the third quarter of 2019, which was recognized in the fourth quarter due to shipping terms. Depending on ordering patterns, we continue to expect fluctuations in our quarter-to-quarter revenue recognition from time-to-time.
In Latin America, full reimbursement takes place on a country-by-country basis and can take some time, which can be further complicated by economic and political instability. Total 2019 Crysvita sales in North America, Europe and Latin America, which are shared with KKC were approximately $104 million for the fourth quarter and approximately $316 million for the full year 2019. Mepsevii product revenue for the fourth quarter of 2019 was $4.4 million and was $12.6 million for the year. Due to the rarity of MPS 7, we expect revenues for this product to be somewhat irregular from quarter-to-quarter and to build very gradually as is typical for enzyme replacement therapies.
UX007 named patient revenue in the fourth quarter was $1.2 million and was $3.3 million for the year. We also recognized $0.1 million in revenue this quarter and $0.5 million for the year from our research agreement with Bayer. As we have stated previously, we continue to expect revenue from this agreement to be minimal going forward.
Our total operating expenses were $130 million for the fourth quarter of 2019. For the past several quarters, up to 20% of our operating expenses, excluding expenses related to business development transactions like genetics and Arcturus has consisted of non-cash items.
Our research and development costs were $83.1 million. We expect our R&D cost to increase moderately over time as we continue advancing product candidates from early preclinical development into early and pivotal clinical studies.
Our SG&A costs in Q4 were $41.9 million. We expect SG&A to increase moderately over time as we support our commercial programs simultaneously launching across multiple geographies. Our cost of sales were $5.1 million for the fourth quarter of 2019. This includes a $3.8 million reserve on Mepsevii inventory that did not meet our quality standards.
Recalling the third quarter of 2019, there was a $1.9 million reserve for a similar issue. We expect that a majority of these reserves will be recovered from our supplier, and we do not currently anticipate any supply interruptions or future reserves related to this issue.
Net loss for the fourth quarter of 2019 was $93.8 million or $1.62 per share, basic and diluted compared with a net loss of $87.8 million or $1.73 per share basic and diluted for the fourth quarter of 2018. For the year ended December 31, 2019, net loss was $402.7 million or $7.12 per share, basic and diluted, compared with a net loss for the same period in 2018 of $197.6 million or $3.97 per share basic and diluted.
The net loss for the fourth quarter of 2019 and for the year ended December 31, 2019, includes unrealized gains of $1.4 million and $13.4 million, respectively from their fair value adjustment on the investment in Arcturus equity securities. The net loss for the full year ended 2018 was reduced by $170.3 million, due to sales of priority review factors.
For the year ended December 31, 2019, cash used in operations was $345.4 million. This includes $20 million for the genetics upfront payment in the third quarter of 2019, $15.6 million for the amended Arcturus license rates in the second quarter of 2019, as well as adjustments for significant non-cash charges, including stock-based compensation expense of $82 million.
We ended the fourth quarter of 2019 with $760.4 million in cash, cash equivalents and available for sale investments. This includes proceeds of $320 million we received from the sale of the company's royalty interest in Crysvita in the European territory.
Moving to our guidance for 2020. We continue to expect the Crysvita revenue to Ultragenyx in our territories to be between $125 million and $140 million. Those territories include North America, Latin America and Turkey and exclude the EU royalty, and this was monetized in the transaction that was completed with royalty Pharma that was announced in December 2019.
We expect the pace of our revenue growth to significantly exceed the pace of expense growth. And therefore, we are projecting a greater than 20% decrease in net cash burn, which includes net cash used in operations as well as capital expenditures.
Thank you, Shalini. I'll spend a few minutes on our clinical and preclinical programs before turning to the upcoming catalysts. I'll start with Crysvita for Tumor-Induced Osteomalacia, a rare disease for which approximately half of patients have tumors that cannot be surgically removed and leaning them with no other current treatment options.
In December of last year, we submitted a supplemental biologic license application ahead of our anticipated timing, we expect to hear back from FDA on submission acceptance and redesignation later this month.
Turning to UX007 for LC-FAOD. A devastating set of diseases with a high mortality rate despite newborn screening and current use of MCT oil. The FDA is currently reviewing the new drug application and set a PDUFA date for July 31, 2020. As we've discussed before, the FDA does not currently plan to hold an advisory committee meeting to discuss the application. The review process continues on track, and we expect our review decision by the PDUFA date.
In addition to the progress in the U.S., we've also submitted a marketing authorization application to regulatory authorities in Brazil, and we continue to stretch with other regulatory authorities in the EU and Canada. Based on our experiences, we know that there are a lot of patients with LC-FAOD, who are not doing well on current treatment of MCT oil and are seeking new treatment options.
In France alone, for example, there were originally only a few doctors requesting UX007 via the ATU named patient program. Now there are approximately 20 physicians treating 34 patients with LC-FAOD, who are using UX007 through that name patient program. We expect there to be significant interest in the product, if approved, but as with many inborn air products, we believe, will build steadily and will take time. In the developed world, there are approximately 8,000 to 14,000 patients with LC-FAOD and we own the worldwide rights to the product.
Moving to DTX301, our gene therapy program for ornithine transcarbamylase deficiency or OTC deficiency. OTC deficiency is an X-linked urea cycle disorder that limits the body's ability to toxify ammonia into urea. These patients can quickly deteriorate into full metabolic crisis, causing neurologic deficits, hospitalization, coma, in some cases death.
In January, we reported positive data from dose Cohort 3 and longer-term data from the first two Cohorts of our OTC study. In Cohort 3, we are seeing responses from all three patients. Two of the patients are confirmed responders. And the third patient appears to be responder as well, but we will wait until we have longer-term data to confirm this.
In total, up to six of the nine patients have responded. Importantly, three patients have come off their ammonia scavenger medications and liberalize their diet. We consider these patients complete responders and these patients appear to be metabolically cured. Based on these days and the favorable safety profile, we believe the Cohort 2 1e13 GC per kilogram dose is the appropriate dose level we're seeing a more consistent response across patients, and we believe this higher dose has achieved the adequate level of therapeutic effect.
From here, we will enroll a fourth cohort at the same dose of Cohort 3, this time using prophylactic steroids rather than reactive steroids. We believe this will enhance the level of expression, also provide more consistent expression. We expect data in the second half of 2020 from this cohort. Deposit will proceed to dose three more patients and simultaneously discuss the design of the Phase 3 study and in points with regulators. Based on our ongoing conversations with FDA, we expect that ammonia will be a primary endpoint. The FDA considered ammonia validated clinical endpoint, and they've approved other products based on ammonia.
Switching to DTX401, our gene therapy program in glycostasis ease Type Ia, a disease that leads to severe and sometimes life-threatening hypoglycemia. Patients with GSDIa today have to take cornstarch every three to four hours, which can keep glucose levels up. But it does not address the disease and its long term consequences. While Cornstarch therapy has same lives and improved health is not a normal life by any measure in patients or their parents live in fear of death, they miss a single dose of Cornstarch.
Today, we've shown data from the first two Cohorts and all six patients demonstrating a meaningful clinical response to the therapy at the 2e12 and 6 to 12 dose levels. This includes improvement in glucose control, shown by time to hypoglycemia reductions in Cornstarch requirements for all patients.
The second dose cohort, all patients showed a meaningful reduction in Glycogen Storage and improvements in metabolism, these data indicate the core two dose is showing greater transgene expression and our view that these patients have greatly improved glucose control. They are weighing down their start requirements, and we think we have a treatment that could change the future of GSDIa patients.
We've now moved to a confirmed Cohort of three patients at the same dose and are simultaneously having to schedule with the FDA about the Phase 3 study. We expect to have data from the confirmatory Cohort in the first half of 2020. And we could be in a position then to begin Phase 3 in the second half of 2020.
I will also touch on our agreement with the gene genetics Biotherapeutics to advance GTX-102, an antisense all genocide for the treatment of Angelman syndrome. Angelman is a devastating neurologic disease that affects approximately 60,000 patients worldwide, and there are no approved treatment options today. Disease is not neurodegenerative. So there is potential to reverse some disease symptoms, which include speech, cognitive impairment, seizures, ataxin, and sleep dysfunction.
As a result, we think Angelman's one of the disease in neurology that could benefit most from a treatment. The disease mechanism is well understood, and as are well valued class that can target the disease directly. We believe that the team at genetics has developed a very potent and specific differentiated antisense oligonucleotide. We are excited to partner with this group.
The IND for this firm is now active, and GeneTx has received IRB or Institutional Review Board approval for the first study site. We expect enrollment in the Phase 1/2 study to begin in the coming months. Following, the acceptance of IND, we paid the $25 million milestone to obtain the option to maintain the option to acquire the company until the earlier of 30 months after the first patient's dose or 90 days after the results are available from the Phase 1/2 study.
The last one, I'll discuss is DTX201 for hemophilia A, a program is partnered with IR and use the material from our proprietary HeLa manufacturing platform. At the European Association of hemophilia and Allied Disorders meeting last week, Bayer presented data on first two low dose Cohorts of the Phase 1/2 study. All four patients showed a response with three of the four patients showing clinically meaningful increase in Factor VIII levels. One patient Cohort 1 achieved clinically meaningful Factor VIII levels and has experienced only four bleeds post-treatment compared to 99 bleeds the prior year. Both patients in dose Cohort 2 achieved clinically meaningful Factor VIII levels out to 24 and 30 weeks.
Patient four on Cohort 2 has been bleed free in treatment-free for up to seven months of the data cutoff, the same patient had a mild ALT/AST elevations that were managed with a short tapering course of steroids. And the other patients have not required steroids at all. A third high-dose Cohort has been dosed and we expect to see additional updates this year. Bayer is responsible for the clinical execution of this program, we are pleased to see that our HeLa manufacturing platform validated and look forward to continued progress with the program. As a reminder, we are eligible to see milestones and royalty payments from Bayer for this program.
I'll spend a few minutes now discussing a number of important milestones in the coming months that will continue to drive our progress, and then we can move to Q&A.
For Crysvita, in 2020, we expect revenue between $125 million to $140 million across North America, Latin America and Turkey, representing a 58% to 77% increase versus 2019 in the same territories. This will be driven by continued strong performance in the U.S. and expansion of our reach in Latin America through name patient sales and pending regulatory decisions as well as growth in Canada.
With our rare transmission for Crysvita for the treatment of TIO, we are looking to expand procedures in this additional patient population, while there are fewer patients with TIO there's often a very urgent need for treatment. If approved in this indication, we believe Crysvita therapy will be adopted over phosphate therapy.
For UX007, we will continue to work with the FDA to view our NDA, working towards the PDUFA date of July 31, 2020. The review is progressing well, and we look forward to being able to provide this treatment to many more patients with LC-FAOD.
For the gene therapy programs, we have shown strong data for our two programs in GSDIa and OTC. And they both says, we believe we have found the appropriate dose. The GSDIa program will have a data readout confirmatory cohort in the first half, and the OTC program will readout in the second half. We are simultaneously having discussion with FDA about the Phase 3 studies for both programs.
The Bayer Hemophilia A program is riding us first clinical data using material from our proprietary HeLa platform, our Wilson disease program will use the HeLa manufacturing system what enters the clinic, and we are targeting an IND for this program by the end of 2020. We'll also provide more updates on the GTX102 ASO program for Angelman as the program begins to enroll patients.
To summarize briefly, our commercial team continues to execute at an extremely high level, making Crysvita one of the top rare disease launches. The continued efforts with Crysvita and MPS VII, as well as two more potential launches this year set us up to grow -- substantially grow our commercial business.
In 2019, we had annual revenue exceeding $100 million for the first time with substantial growth expected in 2020. We're now well-capitalized with $750 million in cash equivalents, where you can combine them with the financial discipline we are applying and expect to reduce net cash burn in 2020. This puts us in good position to drive our clinical programs forward.
Our gene therapy programs are advancing through a confirmed two dose cohorts through Phase 3 studies and the agent in Wilson disease programs are both large indication opportunities that are nearing clinic with diverse set of early-stage product candidates to follow.
We have become a diversified rare disease company, we will continue to grow. We're constantly innovating, adapting rare disease drug development strategies, trial designs and endpoints, working with regulators to establish a more efficient model for rare disease drug development as well as evolving the way we commercialize product in these indications and efficiently manage the cost structure. These are just some of the things we do each day, and they have the foundation while we built an exceptional rare disease company.
With that, let's move to your questions. Operator, can you please provide the instructions for the Q&A portion of the call.
Yes, sir. [Operator Instructions] And our first question will come from the line of Gena Wang from Barclays. You may begin.
Thank you for taking my questions. I wanted to congratulate you on the great quarter. I have two questions. The first one is regarding the Crysvita 2020 revenue guidance. Just wondering the 58% to 77% growth is mainly driven by U.S. growth or geographic expansion? How much growth assumption was building for Latin America?
My second question is regarding the Angelman syndrome. Could you walk through the Phase 1 trial design in terms of initial dose? And how would you dose escalate and what kind of data will lead your decision to acquire GeneTx?
Great. So on the Crysvita launch growth. Shalini, do you want to answer that particular one about the numbers.
Sure. Yeah. No, thanks for the question, Gena. And as has been the case so far, North America is the vast majority of our revenue expectations. And that continues to be the case during 2020, although we expect the other territories to start to become more and more significant over time.
Good. So on the Angelman program, I don't think I can go through the entire clinical protocol on the call today, just would take too much time. But what I can describe to you is that the design basically will take children up to four to 17. And basically, they're going to start at a low dose and then be able to titrate each patient up quickly to therapeutic dose levels within just a few doses.
And as the first cohort gets through, looks safe and the next court will start at a higher dose, then the next quarter higher dose, it will be about 20 patients in these dose cohorts, but all the patients will probably end up on one or two therapeutic dose levels, and we'll be able to evaluate them both therapy efficacy as well as safety at those two therapeutic dose levels.
So it will be a very -- more rapid adaptive design, which is certainly our preference and, frankly, was supported and requested to some degree by the FDA as well. The GeneTx team has done an excellent job of putting that plan together. And we're excited to see the site open and things beginning.
Thank you.
Thank you. And our next question comes from the line of Yaron Werber from Cowen. You may begin.
Hi, thanks for taking the question. Maybe I have a couple. Shalini, maybe just for you, just so we know we get the models right. So it looks like the European royalty will still be recorded, but as a non-revenue -- I'm sorry, noncash revenue. So is it still contributing to earnings in that point? And would you then show us a GAAP to non-GAAP adjustment? And then I have a follow-up as well.
Sure. So that's correct. It is considered a non-cash revenue item going forward. It will -- technically part of our net income, net loss, EPS, all of those calculations, but it is a non-cash item.
Our guidance for 2020 did not include the EU royalty because it's a non-cash item. So because we're not actually receiving cash-based revenues for it, we're no longer providing that as part of the guidance going forward. So hopefully that's helpful.
In terms of our plans, in terms of how to make this more clear going forward, we are planning to segregate the non-cash interest and non-cash revenue on the income statement, so that would be very obvious to you where those items are coming from. And as we go forward throughout the year, we will evaluate whether it makes sense to provide more different kinds of key performance metrics that might be helpful to the street.
Okay, got it. And then, Emil, for you, I mean, the guidance does include TIO? And maybe give us a little bit of a sense how many TIO patients are currently diagnosed in the U.S. So we have an assessment of how big that market could be?
Well, I'll tell you the exact number of TIO's hard to say. But we've talked about it being 1,000, 2,000 and perhaps half of them being sizable. But I would say to you, those are soft numbers and the true exact number, it's hard to know. All I can say is we have been getting a lot of interest and inquiries about TIO. And so we think -- but I would just put it clear that the size of the market, clearly, relatively small fraction of what you see with Crysvita.
On the plus side, the patients often are really sick. And so the urgency to treat will be higher, so hopefully that gives you a rough idea, but I would say our confidence around the exact number is less, but it's in that ballpark.
Okay. And maybe just a final question on Angelman now that program is in the clinic. And this is really a super interesting program that's preclinical data looks really good. And so the question is, in terms of the clinical assessment, and this is obviously a Phase 1/2, but what's the latest thinking about how to put together some kind of is there a composite or a disease based metric or sort of a multi-scale domain assessment for Angelman?
Well, I agree with you, the Angelman is an incredible opportunity. And I think the science has been really solid. And so when you look across what happens in the Angelman patients that covers really five different domains of function. And so the strategy is how would you figure out when you have a variable set of domains for this disease. And we've certainly pioneered the use of multi-domain responder disease is one way to do that, that would involve looking at five different endpoints, let's say, fleet speech, cognition, gait, seizures. As each individual domain, the patients respond in the domain, they score a win or if they get worse, and they score a decline you basically add up the wins across the patients.
We've shown, the strategy can allow you to look at heterogeneous diseases and gain substantially more power. So it may be approach we would use. We're still talking with our generic colleagues about the exact strategy for a pivotal study. I think the first thing we need to learn from Phase I/II is, is the drug safe? Does it help patients in a fundamental way? As we learn from that, we'll be able to go forward. But we think it's important to treat as many or all of the major manifestation. And -- but at this point, we can't be sure what will happen until we get some more data. But we're excited to see it happening. And the prospect of change in future Angelman syndrome being part of that is very exciting to all of us here at Ultragenyx.
Thank you.
Thank you. And our next question will come from the line of Joseph Schwartz from SVB Leerink. You may begin.
Hi. I'm Joori Park dialing in for Joseph Schwartz. Thank you for taking our questions. Our first question has to do with your operating expense. It's encouraging that you are able to -- you're expecting to reduce your operating expense this year compared to last year. Could you provide any color to help us understand how you'll be able to achieve this while you expand your development and marketing initiatives in a variety of territories?
Thank you. It is amazing, isn't it. But let's be clear, we're -- we talked about net cash flow. I'll let Shalini speak to it different. But I would point out to you, there are some fundamental things we do that are unique to us. So I'll just touch on that. For example, there are whole post-marketing programs based on a single study called the disease monitoring program. The reason that's important is both Crysvita and Mepsevii, R&D costs are falling precipitously, falling the approval of the program because the cost of the DMP is more modest, but importantly and well spent, but we've eliminated the need for multiple other programs. Because most companies have rising R&D expenses for a product after approval that ends up causing a problem in how you manage OpEx. By that falling, it allows us to reallocate resource than to manage our burn. But I'll let Shalini then explain a little more of what we said about OpEx versus cash net usage.
Right. So we have not said that operating expenses are expected to decrease in 2020. What we have said is that they are expected to increase modestly in 2020, but that the pace of revenue growth will far exceed the pace of OpEx growth. And therefore, the net cash burn expected for 2020 should be more than 20% lower than in 2019. So we have not said that OpEx will be decreasing this year. And I think what Emil described to you is on a per program basis, for commercial programs, we are able to reduce the operating expenses, particularly on the R&D side. And as a result of that, we're able to absorb more new R&D programs without increasing operating expense in total. But in total, across all of our programs and across R&D and SG&A, we do expect modest increases during 2020 in operating expense.
Okay, great. Thank you. That's very helpful. And then my follow-up question has to do with DTX401. Is there a standardized protocol to decrease cornstarch in Cohort 3. We ask because it seems like cornstarch reduction is mainly up to the discretion of the trial site physician. And so we were just wondering if there will be a more standardized protocol to decrease cornstarch to have a more consistent results across all sites?
Thank you. I think it's important to understand that the cornstarch reduction is a new thing. And by the way, when the trial was started, they weren't necessarily expecting that would decrease, they thought they were just going to help the patients have more steady glucose, but it's pretty clear they can reduce their cornstarch. And so far, there is not a defined protocol that we view. We let each investigator titrate each patient on a case-by-case basis. And it's a little hard to have a protocol, because these patient has on different amounts of starch, taking in different ways and has various other aspects to how they do it. So it actually is very -- would be challenging to have a single protocol.
But your point is well taken. I think as we look through our Phase II data, we will look at when to start titrating starch and to try to create some parameters around that progression and particularly what target glucose would you want to hit before titrating. I think that's one thing we can kind of try to standardize so the progression toward reduction in starch is consistent across patients and groups. What I can say that we're pleased with as least the earliest cohorts have titrated down, and we're pleased with the fact that we're able to greatly reduce cornstarch usage and still retain euglycemia for patients. But Joori it's a good point. We're continuing to look at that, but we don't -- we've not regimented it currently in the Phase II study.
Okay, great. Thank you very much.
And our next question comes from the line of Tazeen Ahmad from Bank of America. You may begin.
Hi, good afternoon. Thanks for taking my questions. Emil, I just wanted to get a little bit more color. You mentioned in your prepared remarks about pursuing Wilson disease as part of your collaboration. Can you just give us a little bit more color on when that study will start? And if we should expect to see any data on that in 2020? And then I have a follow-up.
Yes, the Wilson program is not a collaboration, though, it is our wholly owned program. And the gene -- the program is currently in the manufacturing scale-up stage in order to prepare the product using the HeLa cell system, and we would expect to hit the IND through the end of this year and start the clinical program. So that's kind of the general time line and we're in complete control of that program is our fully. And at this point, we're looking to try to manage the development program.
We'll be meeting with the agency, and we're trying to figure out the optimal combination of endpoints, but we will be looking for a streamlined development path. And that's something the agency has indicated they would support. And that will – something we'll have to talk through as we work through the year, but we're excited about the potential to treat Wilson disease, particularly because it's such a large indication.
Okay. I thought that was part of your license agreement with REGENX. Maybe I was just mistaken about that?
The REGENX. Do you mean the capsid?
Yeah.
Well, they're – they license the capsid to us, yes, but it's not really a – I thought you were talking about the partnership, like the buyer, what he may think. We do have REGENX license to the capsids for all of REGENX capsids for Wilson disease. So we have all of them, based on the original dimension license that we exercised.
Okay. And then, as it relates to the 301 program in OTC. Can you just talk about where you were with recruitment for the prophylactic steroid cohort? What's the gaining factor in recruiting these patients?
Well, we – from the – toward the end of last year, we're actually lining up patients for recruitment in the next cohort. But we do have to get through the DMC review and FDA review. And so, those are some regulatory steps that are ongoing. But we have lined up patients, and we believe the recruitment will go faster this time.
We had a slow period last year recruiting Cohort 3. And we've ramped up the forces in our patient diagnosis program to tee up a lot more OTC patients earlier on. So, I feel we'll be able to handle that enrollment when the protocol is approved and ready to run.
Okay. Thanks. And then a quick last one, if I may. For FAOD, how should we be thinking about the size of the sales force? And do you plan to expand beyond which you already have right now? How many sales people do you currently have?
Well, our Crysvita team will be staying dedicated to Crysvita. They won't be spending a long time. This will be a separate team that will involve a small sales team and likely a small coordinator team, which would be dietitian type group.
Because the number of targets for FAOD are more in the range of 160 metabolic centers versus more than 1,000 for Crysvita, we think the scale of the field team could be scaled similarly. So we expect it to be a relatively small incremental step for us, from a sales team standpoint.
And from an infrastructure standpoint, like the UltraCare team that handles reimbursement, all that, that we'll be able to leverage our investment in that and the supply chain and other things that we've already created. So I think it will be a reasonably efficient addition to our portfolio and would not be an entirely new set of people for all aspects of commercialization.
And you've not said how big your current sales force is, have you?
Well, the current field force is around 36, but there have been a few extras, because we've added some special – four more, so it's probably closer to 40 now. And that's the current UCL team. But there's also a patient diagnosis team in the medical affairs side, which is around 30 people. And then we have MSLs as well, which we haven't really talked much about, but the UCL, we normally think of as a field team of 36 for Crysvita, or 40.
Okay. That’s helpful. Thank you.
And our next question will come from the line of Maury Raycroft from Jefferies. You may begin.
Hi. This is [Indiscernible] filling in for Maury. So for the Hemophilia A program, can you contextualize how your program differentiates from other Hem-A program? And how do you view this strategic opportunity? For instance, like the median could be the first-in-class support.
So the question is, how does our Hem-A program differentiates itself from the others? Yes, our program is better, that's why. So I think the thing we're – that's different about ours is, the AV that's being used is an a AVA [ph] clad E [ph] variant. And it has a relatively efficient capsid for delivery to the liver. And we think we're seeing therapeutic levels achieved at 5e12 and e13, right, which is substantially lower than what you're seeing with the BioMarin AV5 capsid, which is known not to be as an efficient a capsid.
The Spark program is running at 2e12, 1e12 lower, but it's had more inflammation. So the one differentiator I would see right now is that we're having at moderate titers, clinically meaningful factor VIII produced with actually only one out of four patients needing steroids, so without inflammation.
So we think there is some differentiation in terms of the combination of safety and dose that we're seeing. And I think it puts it in a position to be an incredible opportunity, that notwithstanding BioMarin and their program is certainly well ahead of this program.
But we think Factor VIII in hemophilia is a very large opportunity. We also think that it will take time that patients will not immediately jump to do gene therapy and that there'll be plenty of time for an entrant with an excellent safety and efficacy profile to be competitive in the space.
Thanks. That's helpful. And provided the UX007 is approved. So what would be the sales force and commercialization effort look like? A little bit a similar, multi-pronged approach at Crysvita?
Well, yes. So there are some assets that will be the same for FAOD. We will have a – the patient diagnosis program will operate. However, because it's a more narrow set of target sites that manage newborn screening in serious patients, the MSLs may take some of the load of patient diagnosis and so the PDLs that are out in the field could also find patients as they're out doing their work.
So we will have a little bit of the PDLs helping. The MSLs will be doing a lot of the patient diagnose work as well. So that part is somewhat similar to Crysvita. The field team will be significantly smaller, because it doesn't need to be as large, scaled more properly in number of targets.
But I think the overall structure of those teams of our UltraCare guides, which are the people that handle reimbursement and do the personalized care for both patients and physicians that will be the same, and the quality of that team, I think is extremely important at taking care of patients at their most fragile moment when they've got a bad disease and are trying to get treated.
So we think a lot of it, it will leverage our expertise that we've put together. And it's one of the great things and Crysvita to first it allowed us to build out a lot of these efforts and create a situation in which we can begin to leverage our experience and infrastructure for launching the FAOD product.
The other thing advantage was that FAOD and Mepsevii are actually the same doctors as well. And those are the same doctors as treat GSDIa as well as OTC. So with four programs now in the same doctor pool, we're going to start gaining a lot of leverage in our patient diagnosis, the MSL functions as well as the sales functions going forward. And I think that will be a valuable part of creating an accretive business prospects with the -- each additional approval comes through.
Thank you very much.
And our next question comes from the line of Adam Walsh from Stifel. You may begin.
Hi. This is Edwin Zhang for Adam. Congrats on the successful year of 2019. I have two questions on UX007. We know you have a PDUFA date in July with FDA. My first question is, what is your plan for UX007 registration in EU. I know you have patients from U.K. in the trial. But just wondering if you need to do additional studies to support filing in EU, then I have a follow-up.
We're currently exploring with the EU authorities individual countries as well as the EMA itself regarding the strategy for filing. So we've had discussions in a number of areas on that topic, and we're trying to explore ways to do it. We also have to develop a pediatric investigational plan that's accepted which would also be important in allowing us to file in Europe.
So that process is still ongoing. We expect we should be able to file. However, there is a process we have to go through and whether a study would be required, something we'd have to look at over time. I would also point out that if the U.S. approval occurs with the U.S. approval, we could take that as we have to Brazil, Canada and many other territories for pressing ahead of a launch globally for the product. So Europe is an important territory, but there's many other territories that will leverage the U.S. approval and drive forward.
We believe the product is addressing a very profound need in the FAOD population and that delaying anything for another study is not really appropriate. The FDA agreed with us on that. And we think we should be able to get the EMA to under -- to appreciate that as well, allow us to move forward. But we're still in talks on that topic.
Great. Thanks. A second question also UX007. Have you studied any discussions with peers, what is the initial feedback on, for example, pricing? I believe you have done market research. What is your expectation on the market uptake of UX007 after the potential U.S. approval? Thanks.
Well, we have done some initial work with payers as well as physicians. And I think what we've been hearing is that the reduction in major clinical events is considered an important and meaningful benefit to patients who go on triheptanoin. I think we've gotten universal agree that that's important and a big effect in their mind.
So we believe that there is good support from payers for covering the product. We haven't put out what our pricing is at this point. I know the street in general is talking about a price point around $100,000 per year per patient on average. We've guided people do not use the typical type of pricing for this product. I think the key thing to understand about pricing and uptake is the fact that there is a relatively cheaper oil for MCT out there that has an established usage, but certainly, there's a lot of shortcomings, we think. But that product is often out-of-pocket for patients, whereas UX007 would be a pharmacy benefit product, out of pocket, the period of pocket product.
So we think those are some benefits and we'll continue to do our analysis of this. But we caution on the whole inborn error thing is that all the inborn error products we developed usually had steady -- slow, steady kind of growth and adoption. We don't expect to be precipitous large crossover to the drug immediately, particularly in context of another existing established treatment, but we do believe the product will do well over time. But just it will be a steady growth product for us.
Thank you.
Thank you. And our next question comes from the line of Laura Chico from Wedbush Securities.
Hi. This is Kenneth on for Laura Chico. And we just had a question. One of the objectives that you've talked about is remaining active on the business development front. I guess I'd be curious to explore if you see the potential in your pipeline, given you're looking to advance multiple INDs in 2020? And if there's a need to explore externally at this stage, given the breadth of treatment modality you’ve accrued? Thanks.
Yes. So we like to stay acted on BD because unfortunately opportunities show up not when you're ready for them, but when they're ready, when they’re ready to show up. So I think it's very important to open your eyes what's there and do it. I would point out to you that you all like the Crysvita product. But at that time, we had four products or three to four products in play, we were very busy, but it showed up, and we could get the deal.
We did the deal, even though it seemed like an ad, because it was a great opportunity for us and, of course, turned out to be quite important. We always keep our minds open to be ready for opportunities when they show up. Similar to the acquisition of Dimension, we weren't planning on an acquisition, but the moment arrived. And I think it's extremely important for a company to be dynamic and nimble and take the shot.
So we actively look at products. There are things out there. There are also technology we have that might be leverage as well. So there's a lot of ways to do business development to help us. But we're going to be cost-conscious and we're going to make -- try to make smart moves, and we're not a company that's going to go throwing a lot of money into an auction that goes crazy and approach BD that it'll be judicious, prudent, smart and I think find undervalued things that we have a special skill at making -- improving.
So we are open for looking at things, but they have to be high value. We're looking for things that are not gene therapy, since we've got a lot of investment in gene therapy and we don't want to be all gene therapy. And so, we'll keep our eyes open, and we'll do great deals. I think Angelman was one example. I think it was a deal, we should do when it shows up. And we're excited about the prospect of treating that disease given the size of that opportunity.
Thank you.
Thank you. And our next question comes from the line Salveen Richter from Goldman Sachs. You may begin.
Hey, thanks for taking my question. This is Andrea on for Salveen. Maybe a question on your manufacturing for gene therapy, could you talk a little bit more about the processes in place to transition your GSDIa program to the HeLa production? And then as a follow-up to that, what the transition process might look like as you move to your in-house manufacturing facility and what the associated timelines would be? Thank you.
Yes. So just to remind people, the OTC program and the GSDIa are both using triple transaction, 293 strategy using suspension, transaction type strategy. So those are -- both will be that when they get to commercial that is what we're planning.
With GSD1a, we've already created a HeLa system for production of it, have run it and so we know that it works and can be done. What we've decided to do is transition that to HeLa after approval in post-marketing because we didn't want to introduce another delay in the process of getting approved. So we'll go-to-market with the triple transaction program, assuming we do the Phase III successful and then we would transition to HeLa sometime after approval.
Now the timeline for the plant that we are developing, it's -- there's two parts of the plant. One is, the quad control analytical part, which we've already set up and built the lab in our operating -- our own analytical laboratory for the GMP test release of gene therapy products, which we think was a very important investment and that's operating already in the Woburn area. That part of it. That will help shorten the time to drug -- product release and put those critical aspects of product quality in our own hands and our excellent tech ops and quality teams.
With regard to the plant itself, we are working on citing and putting in play. We'd expect it to take -- be a several year process to identify, build. At that point in time, we will shift our products as necessary into the plant. But I would also say, it doesn't mean we wouldn't use contractors. I think we would be using contractors plus our plant.
With time though, the plant would take on larger and larger load of our commercial and clinical development needs and the speed with which we can put a new clinical development program into the clinic should increase as we will have the flexibility then to put our programs into manufacturing.
And our expectations that plant would run the HeLa and potentially 293 triple transaction though with time we were try to get all of our programs to shift to the HeLa platform. Being -- that it's larger scale, better cost structure, no use of plasmids. And so far, at least with the HeLa that we have to date, looking very good from a safety and efficacy perspective.
Got it. Thanks so much for the color.
And our next question will be from the line Yigal Nochomovitz from Citi.
Hi, this is Samantha on for Yigal. Thanks very much for taking our question. On DTX301 for the ammonia being used as the Phase III endpoint, I'm curious if you could elaborate what assay are you planning to use to measure ammonia? And will it be the same assay and protocol be used at all trial sites? I know that there's some variability with emotion measurements. I'm curious on what you've seen on technical venerability there?
Well, ammonia is variable, but less about the assay than it is about the sample collection and transport. So the problem with money is, the sample patient prep, sample collection, sample transport and care is where ammonia can go variable. And that's why it's important to what we are doing is a 24-hour area under the curve of money.
What that means is the patients in the hospital, not as an outpatient in the hospital and they're therefore 24 hours in blood tests are taking every few hours, usually through a catheter rather than through a needle stick. The catheter allows you then to have free flowing blood from the vein, allow you to get more accurate venous blood ammonia levels, and those in our assays in a traditional way, but the samples are able to be managed, set up and sent to the proper lab in a prompt timeframe.
By doing it that, we've gotten relatively consistent ammonia on visits and that's the approach we're taking for using it in the clinical program. Does that answer your question?
Yes, it does. Thanks for the color. And just switching gears a bit for TIO. I'm curious, would you leverage the similar path -- regulatory path that you stated for FAD in terms of utilizing a potential U.S. approval for Canada and Brazil? And how are you thinking -- would you bother regoing into the EU, given the royalties have been outlined or sold to royalty pharma?
Well, we sold the royalty, but remember, our partner still has the right to Europe. So they're probably still going to want to sell it in Europe. I'm assuming. So the TIO, will put that product into all of our territories, for sure. We think we can leverage the data because it is - builds upon the XLH data in terms of phosphate control, bone fractures and osteomalacia, which are verified at a pathologic and using bone scans in the TIO population.
It has already been approved in Japan, by the way, by our partner has gotten approved in Japan already. So we think with the U.S. approval, we'll certainly be able to leverage that and file that elsewhere as well. And I expect there'll be patients globally that will benefit from the TIO from treatment in to.
Got it. And then just on UX007, how many formulations are you planning to bring to market. I think I remember in the past, you mentioned you may have had a powder formulation at one point?
Yes. So there are possible ways to make the oil into a powder. The current formulation will be a bottle that patients can measure their quantity out. It's around, let's say, total per day is around 70 CCs, something like that. And they're usually doing it in four times a day.
There is a potential to make a powder, the one power we try didn't work out. We could look at other powders or sashes and other variations in the product presentation. And we want to do that actually to make it convenient easy for patients to take this with them to work or to school and other for settings.
So we're starting with the bottle, a 500 ml bottle that they measure and mix with their food or drink, and we'll probably work on having some other variations over time, but we don't have a powder currently ready to go.
Understood. And just one quick one for Shalini. How quick do you expect OpEx to flatten? Should we be using the moderate growth based on 4Q numbers?
Well, the – it's not going to be sort of a precipitous drop from one quarter to the next. It's going to be gradually slowing down, but still increasing. So the rate of increase will be slowing down over time.
Got it. Thanks very much. Thanks very much for taking the question.
Thank you. And our next question comes from the line of Joon Lee from SunTrust. You may begin.
Hi. Thanks for taking my question. If I recall correctly, you mentioned before that you need an order of magnitude less vector to get the same effect in hemophilia as compared to BioMarin's hemophilia gene therapy product. So is the vector you generate using the new HeLa platform different in quality or just different in terms of improved quantity of production and if it's different in quality, what are your strategy to bridge from the old to the new GSDIa vector post approval? Thank you.
Sure. Thank you. There are several factors that make it different. One is that it is AAV. The AAV8 variant and so AAV8 itself is a more efficient capsid than AV5 in terms of delivery to the liver side is one feature of the improvement, but that's not related to the platform, but just the choice of capsid.
The platform itself allows us to produce the AAV in using the normal biology and using adenovirus recovery, and that allows the biology means we get it really acts as it normally would in nature and the vector being made has a higher fill rate right off the column, right off the production, and that allows us to create a better consistent AAV that way.
So there is a quality benefit in doing it with HeLa system, and I think that could translate into a cleaner product that might have less issues. We know with plasmid transfection system. There can be plasmid and managing pre DNA as a factor. And so that's one thing we think the HeLa system would also reduce so we think there is both the quality effect. And there's also the choice of cats that are probably going to contribute to the effect of the Hema A program on hemophilia.
So if it's different in quality, does that complicate the bridging on a post-approval basis, would you need an extensive new study? Or can you help us understand what the process is?
You mean, if you're talking about bridging and Glyco Storage Type 1 if we're going to bridge crossing over?
No, no. Your – does it change the quality of the vector that you're using to transduce? And if so, does it change sort of the PK/PD or biology of how the drug works as a product?
Yes. Well, the actual product, remember gets purified the full versions get purified. And so at the end of the day, you end up with something closer. But remember, if you start with the better quality product write-off, the reactor then purifying it is easier. And you get a get a higher yield. So I don't think that we do not expect, and we looked at HeLa versus 293, we haven't seen a significant difference in distribution PK/PD of the product what we're saying is the manufacturability, how much you can make, how much you can get is easier to achieve. And so we think it will be potentially safer. We would expect going from 293 to HeLa, truly the drug, which is the D&A is the same. So the cash is the same. So it's really the process. So we would expect that we could do the same kind of traditional non-clinical work. As well as some limited human bridging work in order to demonstrate similar safety and efficacy in order to move that forward.
We would still need to talk with the regulatory authorities about that. But we don't think it's a fundamental change in the vector and if anything, the quality could be better, not worse, and I don't think that entails more – it doesn't entail more work generally.
Thank you. And I just have one follow-up, sorry. It's rather naive question, but for the 301 program, can you remind us why prophylactic steroids should lead to improved transaction and improved expression? Is information of a function of how much vector you put into the patient? Or is it more of a function of how much actually gets transduced and lead to productive expression of the gene product?
And I'm asking this partly because it seems like based on your most recent data from the OTC program, women were just as well transduced as male. So just curious what your latest thinking is there? Thank you.
Yes. Well, look, capsid quantity or dose does have an effect inflammation as the higher dose, we've gotten more inflammation of just normal and expected. But inflammation is a little bit of downstream of the problem with the steroids and prophylaxis as we hope is actually the suppress and need immunity, which reduces the transduction efficiency of the vector, which we think would improve efficacy is what we're trying to improve the efficacy.
That is the number of liver cells that are expressing your transgene by suppressing, we expect more of those cells to be to overcome their name immunity on a cell by cell basis and get more cells expressing, which we think will result in more robust treatment.
We base that – based on some our own non-clinical work and some clinical work of others that it appears that suppressing the immune through prophylactic steroids does have a significant benefit on expression. That will have the effect of reducing downstream inflammation, but it's really about preventing the silencing of gene copies, which is a common problem you see in non-human primates in adults, but not so often seen in mice. And that's probably why humans and non-human primates are harder to treat with AAV gene therapy than mice are.
Thank you so much.
Thank you. And our next question comes from the line of Vincent Chen from Bernstein. You may begin.
Great. Thank you for taking the questions. Couple on Crysvita, if I may. I was wondering if you could provide us with a little more color on where Crysvita patient growth in North America is coming from. What -- well, maybe in the U.S. specifically, what's your sense for the balance between adult and pediatric patients? And within the adult portion, what portion of folks who are newly diagnosed compared to folks who are previously known in clinics? And how is this mix trending over time?
Very good. Good to talk to you, Vincent. So, in Crysvita, we've been seeing some steady shift toward adults with the most recent ratios, 45% adults and 55% kids and we'd expect that to steadily shift further as we continue to find adults that are been lost to follow-up.
I don't have a breakdown for you on how many are newly diagnosed, and you have to define what newly diagnosed means. There's a lot of patients who were diagnosed clinically 20 years ago and told they have a disease and they know they have a disease, but then we then get them genetically tested and confirm, it's XLH. So, which who diagnosed them. The guy that said you have a bone disease or us that gave you a genetic, so there's a number of patients in that kind of group that were diagnosed, but they were diagnosed at a time when no one knew what the gene was, right?
And so we're doing a lot of work on free genetic testing to take those patients diagnosed with rickets that have ongoing problems that are turned out in a pretty high fraction to be XLH patients.
So, that is something that's happening now and finding what I would call those patients I would say to you that those patients were diagnosed. They have the bone disease, and they know of it. It's just they weren't confirmed as being excalation. I think that's a lot of the effort we're doing. But it's harder to know is how many adults there had some disease that weren't really figured out correctly. They're truly undiagnosed as having rickets as a child. I don't know what that number is for sure. What we can say so far, though, is we're pretty confident that our 12,000 patient number for all XLH is probably about right, and that the 9,000 adults.
We still have a significant fraction of those adults to work on getting the therapy. And our target is to get at least half of those adults on therapy over time, not next year, but over time as we find them. So, it's a little less about -- I think it's more about finding the patients who have the medical problems and know they have rickets, but are no longer going the centers that would normally treat it. And that's going to those secondary specialties and that's what the PDL team is actually out there doing right now, the teams out there calling on those doctors out and about, who appear to be treating someone with rickets disease or bone disease and helping them finalize that diagnosis.
I see. And if you think about this population, which I guess is the -- maybe none of disease, but newly confirmed. I was wondering if you could give us some sense for how that the number of patients that fall into that bucket sort of the maybe no newly confirmed, how is that number trending in terms of like the quarterly clip over time. Is that something -- would you say that's been responsible for driving the last couple of quarters of growth and is sort of proceeding at a similar clip? Or would you say that's sort of trending one way or the other?
Well, it's a fraction of the growth. I think there's been a lot of patients that we have diagnosed at centers that we still are been driving the growth the first six quarters, ones that were already there are known. That are doing it. And over time, those patients are going to be an increasing part of the story, it's finding more and more of those rather than ones are already kind of known to the clinic. But obviously, you try to focus the launch on the low-hanging fruit that are already in hand. And the PDLs are starting to look -- claim the branches for the other fruit, but in this process.
Is there much more room to run on that sort of low-hanging fruit and nonclinical? Your six months or six quarters rather into the launch, which is usually when things start to peter out, but it sounds like there's actually still more room to run from your comments just now.
There are still more patients out there. There are definitely more patients that we know about that are already in those centers. But there are some centers that have actually written prescriptions for almost every single patient they have. So, some of our top prescribers have written 40, 50 scripts or more. So that's a lot of patients. So there's definitely some that have already prescribed everything they have, which I think is actually a testament to their commitment, like their experience commitment that they're going to put every single patient they have on it. But there are some that haven't. And one of the questions is, well, some people think maybe oral phosphate is okay for their kids.
Well, in October we got a label update that says oral phosphate proceeds way better. And we think that's something we can take out to exhaust me at some pace. Or they think of doing a panel phosphate and maybe change your mind about the value of switching.
And then we have to look at the question for some adults -- some doctors who didn't treat adult for safety reasons and gotten them in the mode of thinking maybe adults don't need to be treated. And that is where using speaker programs and patient ambassador programs are helping people understand that those adults that may not be complaining that much, but are not doing well. And once they get treated, they realized how much better they could be, and we’re seeing a lot of good stories like that. And that communication is important to get out of the mindset that not treating adults is the right thing when they often have a very significant disease.
So that piece, the other part where they know the patients are there is now getting people to understand why, really, they should put all their patients on or a majority of their adults on drug and that's another part of the story that we're working on.
So far, we're impressed that once doctors are prescribing, they then start prescribing more because the feedback is always really strong and positive and that that seem to continue moving forward with putting their patients on Crysvita.
Great. Thank you so much for all the color.
Thank you.
Thank you. And our next question will come from line of Jeff Hung from Morgan Stanley. You may begin.
Thanks for taking the question. For US701, you mentioned that it's in the manufacturing scale stage. Can you talk about what else remain outstanding before you file the IND?
Well, we've done our preliminary talks work, but generally you want to use the scale at materials of the final talk to access some piece. So we've done our preliminary, so we understand that comfort with -- detox profile looks excellent. So we'll have to do that as well and we're also working toward our pre-IND and our discussion on the design of a trial that would be a more streamlined design that allows to move quickly ahead. That requires both understanding the trial design, the patient population and the endpoint. Now, there are established endpoints for Wilson disease, including free serum copper, as well as liver copper by imaging. And while those are established and valid, the question on the gene therapies, how do we -- what do we do to help substantiate the cost and price of gene therapy for a life changing treatment.
That requires also capturing aspects of quality of life, serologic function, liver injury and other aspects of disease and making sure that we build a trial that captures the breath of the efficacy of the treatment and creates the case required the transformative and also verify for us if that’s true that the drug is transformative?
We think it can be and so we want to make sure we trial the design of the endpoints and we're doing a lot of work and survey studies and other things to help develop our clinical study plan. That part is ongoing right now as well.
The manufacturing is really controlling the timeline, non-clinical -- clinical study plan, meetings regulators, and that puts us some timeline toward the end of the year to get IND filed and be ready to go.
Okay. Thanks.
Thank you. And I am not showing any further questions. I’d like to turn the call back to Danielle Keatley for any closing remarks.
Thank you for joining us today. This will conclude our call, and a replay will be available soon. If you have any questions please give us a call, or you can reach us at ir@ultragenyx.com. Thanks for joining.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.