Ladies and gentlemen, thank you for standing by. And welcome to the Ultragenyx First Quarter 2020 Financial Results Conference Call. At this time, all participants are in a listen-only mode. Please be advised that today's conference may be recorded. [Operator Instructions] I would now like to hand the call over to your speaker today, Ms. Danielle Keatley. Please go ahead.

Good afternoon. And welcome to the Ultragenyx Pharmaceutical financial results and corporate update conference call for the first quarter of 2020. 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. Joining me on this call are Emil Kakkis, Chief Executive Officer and President; Shalini Sharp, Chief Financial Officer; Camille Bedrosian, Chief Medical Officer; and Erik Harris, Chief Commercial Officer. I would like to remind investors 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 2019 annual report on Form 10-K that was filed on February 14, 2020, our quarterly report on Form 10-Q 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, and good afternoon, everyone, and thank you for joining us on today's call. Ultragenyx had a good first quarter despite everything going on. The impact of the COVID-19 pandemic has been felt by everyone at Ultragenyx, the patients we serve, their families, and their health care providers. This is a truly unique point in the history of our society when everyone's focus on their health has taken precedence over virtually everything else. When facing this pandemic, the need for a robust and effective biopharma industry has never been more clear. The biopharma industry has mobilized its expertise to develop assays, drugs, and vaccines in dramatic ways, and we are encouraged by the progress we are seeing. Although Ultragenyx is not directly working on a COVID vaccine, last year we invested in and supported our mRNA therapeutic partner Arcturus Therapeutics, who is developing an mRNA-based vaccine for COVID. They recently announced potentially important positive preclinical data for their mRNA COVID vaccine candidate showing that it is potent at inducing a COVID-19 virus-neutralizing immune response at a very low dose. The Arcturus mRNA vaccine is unusual because it uses self-replicating RNA technology that both amplifies bioreactor protein expression to induce an adaptive immune response and also stimulates the inhaling immune system better. We look forward to data from their clinical study, which is expected to initiate this summer. For our own products in the pandemic, we are continuing to do whatever is needed to support our patients. We've worked to ensure our patients treated with Crysvita and Mepsevii, as well as those participating in our clinical studies, continue to receive the treatments that they need during this challenging time. To date, only a relatively small fraction of our established commercial patients have had any issue with access. Fortunately, more than 8% of our Crysvita patients already receive their care at home via visiting nurses. This was established at the time to be convenient for patients and is lessening the potential impact of institutional closings now. A few patients that need help with the site of care are being helped by our team. One example of our efforts for the small number of patients that need our system is the work our teams are doing with payers and the temporary authorization to provide self-administration of Crysvita as an option where in-home nurse administration is not feasible. On the clinical development front, we are able to move our gene therapy programs forward, but there are some limitations on the data we can collect for those already treated. We paused the enrollment of the prophylactic steroid cohort and the DTX301 program for OTC due to institutional closings. That said, we are ready to go once they open and it is safe to resume enrollment. Our most recent gene therapy data were presented at the ASGCT Virtual Conference and include data from both our OTC and GSD1a program, as well as other presentations about earlier stage and technology programs. For the ASO clinical program to treat Angelman, our partner GeneTx has progressed to the clinic with GTX102 and enrolled two patients who continue to receive treatment. Further progress will depend on access at sites and our partner GeneTx is working to push the program forward in a safe manner. While COVID-19 has created a unique set of challenges, we are taking steps necessary to ensure our commercial patients continue receiving their therapy. Our discussions with the U.S. FDA remain on schedule, and our clinical and preclinical programs continue to generate data. With that, I'll turn the call to Erik, who will provide a commercial update highlighting the strength of our core business and what his team is doing to expand our global reach.

Thank you, Emil. During these extraordinary times, I am extremely grateful for the relentless work the commercial and medical teams do every day on behalf of patients. The commercial team is especially focused on ensuring the continuity of patient care. Since launching Crysvita in April 2018, we have grown the patient base significantly and our top priority is to ensure that these patients continue receiving the important clinical benefits of this therapy. During this COVID-19 period of social distancing, we are seeing a small number of patients who are not able to go to their site of care for treatment. Our team is working hard to find alternative solutions for these patients, which includes home health services by a nurse. As Emil mentioned, we are aware of a handful of instances where a specialty pharmacy has worked with the payer to allow for self-administration. These are exceptions that have been initiated by the patient and their healthcare provider in response to a specific concern about COVID-19 exposure. In North America, through the first part of this year, we have seen continued strong demand for Crysvita. More than 80% of patients received Crysvita through at-home nurse administration, which has helped to minimize any COVID-related disruptions. As one would expect, social distancing will present some challenges for new patients to receive a diagnosis and start Crysvita therapy. We are being respectful and understanding of the additional burdens this pandemic has put on healthcare providers, which has required our team to come up with new and innovative ways to safely educate these providers on our products. Our field teams are conducting virtual speaker programs to educate a national audience of patients and caregivers. We are also hosting national webinars for healthcare providers that will be led by prominent KOLs. Lastly, we have expanded our suite of digital tools and are using these resources to maintain close contact with our healthcare providers as they continue to actively manage their patients with XLH. We believe these types of efforts will support our initiatives around generating new start forms. Outside of North America, we continue to have meaningful discussions with regulatory and reimbursement agencies while also supporting this increasing demand for named-patient therapy. In Colombia and Argentina, we continue to receive positive feedback and see steady demand as the number of patients on reimbursed named-patient treatment continues to increase. In Brazil, we have seen a steady number of requests for Crysvita, with many of these patients filing legal injunctions to be able to receive the therapy. This has resulted in a growing number of patients who have been treated with Crysvita after successfully navigating the judicial review process. Earlier in the year, we had positive discussions with the Ministry of Health seeking to obtain full pricing and reimbursement approval. The COVID-19 situation forced the agency to shift its focus and put our discussions on hold, but they are still reviewing new patient requests, allowing patients with XLH to be treated with Crysvita. Based on these interactions and the increasing demand, we are confident that Brazil remains a significant opportunity for Crysvita in Latin America. Similarly, in Turkey, demand for Crysvita continues to grow as more patients are successfully being granted injunctions. Crysvita is an important part of therapy for patients with XLH, and we believe we will receive reimbursement approval for named-patient sales based on the strength of our clinical data and positive discussions we have had with Turkish officials in the first quarter of 2020. Shifting to UX007, we are continuing to prepare for a potential approval for this therapy for patients with long-chain fatty acid oxidation disorders by the PDUFA date of July 31, 2020. Based on the data from our clinical studies and feedback from physicians and patients, we believe UX007 fills a significant unmet need and that there are a substantial number of patients who can benefit from UX007 despite current treatment options. With the advent of newborn screening for LC-FAOD in the U.S., many of the 2,000 to 3,500 estimated patients are already diagnosed. The majority of patients are seen at approximately 160 of the major metabolic centers across the country. Our existing commercial efforts with Crysvita and Mepsevii have helped build strong relationships with these metabolic centers, which will be instrumental in the launch of UX007. Given the significant overlap with our current commercial activities, we will be able to leverage much of the current infrastructure and only modestly increase our existing field force. Looking forward, we have two potential approvals coming later this year. We expect there to be significant interest in UX007 LC-FAOD and Crysvita for TIO if they are approved. These launches will build steadily over time, all the while bringing important therapies to patients with few options. We are excited for what could be our third and fourth rare disease launches in less than three years, and we plan to utilize our collective experience to ensure our continued success. With that, I'd like to turn the call over to Shalini, who will walk you through the financial results for the quarter.

Thank you, Erik, and good afternoon, everyone. Earlier today, we issued a press release that included a financial update, which I will briefly summarize. Total revenue for the three months ending March 31, 2020, was $36.3 million. In the first quarter of 2020, total Crysvita revenue was $31.4 million. This includes $27.2 million in collaboration revenue in the North American profit share territory and net product sales and other regions of $1.6 million, or a total of $28.8 million in Ultragenyx territories. Non-cash royalty revenue related to the sales of Crysvita in the European territory was $2.6 million. Recall that the rates of the royalties in this region were sold to Royalty Pharma in December of 2019. Mepsevii product revenue for the first quarter of 2020 was $3.4 million, and UX007 named-patient revenue was $1.4 million. Our total operating expenses were $157 million for the first quarter of 2020. This includes $25 million, which was paid to GeneTx to maintain our option to acquire the company after their IND for GTX-102 was accepted by the U.S. FDA. This also includes $20.2 million of non-cash stock-based compensation. Our R&D costs were $113 million. We expect our R&D costs 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 Q1 were $47.5 million. We expect SG&A to increase moderately over time as we support our commercial programs and potential new product launches. Our cost of sales was a negative $3.5 million for the first quarter of 2020, which includes a credit of $4.6 million that was agreed to during the quarter with one of our manufacturers due to previously produced inventory batches of Mepsevii that did not meet our quality standards. As a reminder, the company had previously recorded a reserve of $5.7 million for these batches during the year ended December 31, 2019. We do not anticipate any supply interruptions or future reserves related to this particular issue at this time. Net loss for the quarter ended March 31, 2020, was $119 million or $2.05 per share basic and diluted, compared with a net loss of $96.8 million or $1.82 per share basic and diluted for the first quarter of 2019. The loss in the first quarter of 2020 includes a $7.7 million unrealized gain from the fair value adjustments on the investment in Arcturus equity securities and $8.1 million in non-cash interest expense on the liability related to the sale of future royalties. In the first quarter of 2020, cash used in operations was $95.2 million. We ended the quarter with $705 million in cash, cash equivalents, and available-for-sale investments. This includes $75 million from the Daiichi Sankyo common stock purchase which closed in March of 2020, but excludes the $125.6 million receivable from the Daiichi Sankyo strategic manufacturing partnership upfront payment. These funds were received in April of 2020. Moving to our guidance for 2020, we are currently maintaining the guidance range that we shared at the beginning of the year. Specifically, Crysvita revenue to Ultragenyx in our territories is expected to be between $125 million and $140 million. Those territories include North America, Latin America, and Turkey, and exclude the EU royalty as this was monetized in the transaction that was completed with Royalty Pharma that was announced in December of 2019. We also continue to expect the pace of our revenue growth to significantly exceed the pace of expense growth and therefore maintain our projection of a greater than 20% decrease in net cash burn, which includes net cash used in operations, as well as capital expenditures. As the COVID-19 pandemic evolves, we will continue to look at the potential impact on our business, including the guidance range, and we'll provide updates when or if they become material. With that, I'd like to turn this call over to Camille, who will provide an update on some of our recent regulatory interactions and clinical programs.

Thank you, Shalini. I too wish everyone a good afternoon. I will discuss our progress with our two programs currently under regulatory review and will provide an update on the Angelman Syndrome program. Starting with UX007 for long-chain fatty acid oxidation disorders or LC-FAOD, a devastating disease with significant morbidities despite newborn screening and current use of even-chain MCT oil. The FDA is currently reviewing the new drug application and has set a PDUFA date of July 31, 2020. The review process continues on track and we expect a review decision by the PDUFA date. Importantly, all of the anticipated clinical and manufacturing inspections for UX007 have been successfully completed. At this point, we do not believe that any additional inspections would be required for completion of FDA's review. In addition to the progress in the U.S., our marketing authorization application is under review by regulatory authorities in Brazil and we continue discussions with regulatory authorities in the EU and Canada. Based on our experience, we know that many patients with LC-FAOD are not doing well on current management with even-chain MCT oil and are seeking new treatment options. We have seen this interest through the significant number of requests for compassionate access and our named-patient program. Moving to Crysvita for tumor-induced osteomalacia or TIO, a rare debilitating disease for which approximately half of the patients have tumors that cannot be surgically removed, leaving them with no other current treatment options. Erik previously discussed our commercial progress with Crysvita and I am encouraged that we are moving closer to a second potential approval for this medicine for the treatment of patients with TIO. This would be the first FDA approved treatment for patients with this devastating disease in the setting of an unresectable tumor. The review of our supplemental BLA is on track for a decision by the PDUFA date of June 18, 2020. We continue conversations with the FDA and we do not anticipate that inspections would be required for completion of their review. I will now touch on our program with GeneTx Biotherapeutics to advance GTX-102, an antisense oligonucleotide 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. The disease is a neurodevelopmental disorder and not neurodegenerative. So there is potential to reverse many of the disease manifestations, which include speech and cognitive impairment, seizures, ataxia, and sleep dysfunction. We believe that the team at GeneTx has developed a very potent and specific differentiated antisense oligonucleotide approach that can directly target the disease. In addition, they have done a tremendous job of moving the program into the clinic rapidly and efficiently. The first cohort of the Phase I/II study has been enrolled and the two patients continue to dose escalation. Continued progress through the cohorts will depend on institutional status for continued safe study conduct. Earlier this month, GTX-102 was granted Fast Track designation by the FDA. This designation will help facilitate the expedited development and review of this potential therapy for patients with this devastating disease. While we continue to track the potential impact of the COVID-19 pandemic on site activation and data collection, the team is making good progress, and we expect preliminary data from this study in the first half of 2021. As you can see, we are making significant progress on the regulatory side and could have approvals for two new indications in the coming months, bringing important therapies to patients who are waiting and who do not have adequate treatment options today. Furthermore, the Angelman Syndrome program has moved into the clinic and the team continues to do a tremendous job advancing this program. With that, I will now turn it over to Emil.

Thank you, Camille. I will discuss our gene therapy programs and then we'll move to your questions. Starting with DTX-301, our gene therapy for the treatment of ornithine transcarbamylase deficiency or OTC. OTC deficiency is an excellent urea cycle disorder that limits the body's ability to detoxify ammonia and urea, and these patients can quickly deteriorate into full metabolic crisis, causing neurological deficits, hospitalizations, coma, and in some cases death. At the beginning of this year, 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, and we believe this higher dose has achieved a consistent response and adequate level of therapeutic effects. In total, up to six of the nine patients in the study have responded, and importantly, three patients have come off their ammonia scavenger medications and liberalized their diet. We consider these patients complete responders, and these patients appear to be metabolic cured. At next week's American Society of Gene and Cell Therapy Conference or ASGCT, we will present updated data from the first three cohorts of this study and plan to hold an investor conference call after the ASGCT presentation to discuss both the OTC and GSD1a data update. For the OTC program, we planned to enroll the fourth cohort at the same dose as cohort 3, but using prophylactic steroids rather than reactive steroids to potentially enhance the level of expression and provide more consistent expression. We’ve identified patients for this fourth cohort. Due to the COVID-19 pandemic, we are waiting to dose these patients through the closure institutions, as well as the potential risk to patients, especially those using steroids. At this point, we still expect data from this cohort in the second half of 2020, barring significant further delays related to COVID-19. We are also simultaneously planning our regulatory meetings and edge the Phase III study, and we expect to meet for an ANDA Phase III meeting with the FDA based on the first three cohorts alone. Based on our ongoing conversations with the FDA, we expect that ammonia will be a primary endpoint. The FDA considers ammonia a validated clinical endpoint, and they have approved other products based on ammonia. The Phase III study is currently expecting to begin enrolling in the first half of 2021. Moving to DTX401, our gene therapy for glycogen storage disease type 1a, these lead 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 complications. Patients or their parents live in fear of death if they miss a single cornstarch dose. Today, we've shown data from the first two cohorts with all six patients demonstrating a meaningful clinical response to the therapy at 2e12 and 6e12 gene copies per kilo dose levels, including a substantial decrease in the required dose of cornstarch. We specifically took over three patients at the same dose in December and are in planning discussions with FDA about the Phase III study. We will share the available data from the confirmatory cohort at the ASGCT meeting next week. While some of the later patient site visits at the cohort did not occur due to COVID-19, we expect to be able to share data from the sites that did take place, as well as cornstarch reduction data that we should not require site visits. In addition, continuous glucose monitoring was introduced into the protocol for this third confirmatory cohort, and we will be able to share insights from the available continuous glucose monitoring those conducted at home. Depending on these data and expected ANDA Phase II meeting with the FDA, we could be in a position to begin the Phase III study by the end of the year, depending on whether there are any further delays. At the end of March, we entered into a strategic partnership with Daiichi Sankyo and granted them a non-exclusive license for our gene therapy manufacturing technology, including our HeLa platform. Daiichi Sankyo is building their gene therapy program as a key part of their 2025 vision, and this new partnership shows the interest in our HeLa producer cell line platform in particular, that we believe is the most scalable mammalian AAV manufacturing system at the 2000 liters of suspension culture. Daiichi Sankyo made an upfront payment of $125 million in cash and a $75 million equity investment in Ultragenyx. In addition, Daiichi Sankyo will pay $25 million upon completion with the technology transfer of the HeLa PCL and HEK293 form, as well as single-digit royalties on net sales of products manufactured in either system. I will also point out that this is non-exclusive, and we look to build other collaborations around our AAV technology over time. I'll briefly recap our major milestones in the coming months that will continue to drive our progress, and then we can move to the Q&A. For Crysvita, we believe we're still on track to achieve revenue between $125 million to $140 million in North America, Latin America, and Turkey. This will be driven by continued good performance in both the U.S. and Canada and expansion of our reach in Latin America and Turkey over time. While we have seen minimal impact from COVID-19, so far the crisis does continue and could impact the business. We'll continue our special efforts to support established patients and new patients during this time. In addition, we're looking to expand procedures to treat TIO, a small patient population, but one with very urgent need for treatment. If approved in this indication, we believe Crysvita will be preferably adopted over phosphate therapy. For UX007, our NDA review is on track and we expect the decision by the PDUFA date of July 31, 2020. We are currently in launch preparation to be able to begin efforts immediately following approval. For the gene therapy programs, we've shown positive multi-responses for both our two programs in OTC and GSD1a. We will share data from both programs next week at the ASGCT Conference. Our program for rare disease also continues to progress, and an IND is expected by the end of 2020 provided the COVID-19 pandemic does not cause any delays in non-clinical or manufacturing activity. This program will be the second clinical program to utilize the company's HeLa manufacturing system in the clinic. GTX-102 ASO program for Angelman Syndrome also continues to advance in the first cohort dose, and additional cohorts are planned. We expect to provide preliminary data in the first half of 2021. As you can see, we continue to make significant progress on the commercial, clinical, and business development front, even during these challenging times. We've built a strong and resilient business leveraging traditional and non-traditional financing. While we will see the impact of COVID-19, we believe we are well-positioned to continue delivering important therapies to patients in need. I'll stop here. Let's move to your questions. Operator, can you please provide instructions for the Q&A portion of the call?

[Operator Instructions] Our first question comes from Yaron Werber of Cowen. Your line is open.

So Emil, just a couple of questions on OTC and GSD1a in terms of - it sounds like we're going to get updates in a week from now at the conference. How - are we looking to basically reconfirm the prior data or are you thinking that is it can the data potentially get better? And then, secondly on GSD1a, you won't be able to have all the data, as you mentioned, obviously, patients can get hospitalized now for the glucose monitoring. So what data can we expect at that meeting, and sure I might have a quick follow-up?

Sure, Yaron, obviously, I'm not going to pre-run the actual data. So, what I'll tell you is that the OTC that we're expecting is from the cohort that you've already seen. So it will be more data from that cohort. So that will just be further data on the existing cohort that we announced earlier in the year. The GSD1a Cohort 3 has not been presented before, so that's new data and a new cohort done at the same dose as Cohort 2. But it will be new three patients, and they will have a significant amount of data, though not all the data points because some of the later where we could not connect. But we think we have enough data to be able to present the story on Cohort 3 to the street. So that's what we're expecting, more of an extension for Cohort 2, but Cohort 3 should be some new data.

Okay. And then it sounds like you're going to talk to the FDA about the sort of the end of Phase II or the pre-Phase III meeting; at that point, you probably will not have the fourth cohort of three patients and prophylactic steroids in OTC, and it looks like you're going to have more follow-up in GSD1a, and hopefully by that point, you will get the glucose monitoring done as well. But I guess my questions are, as you sort of move into planning the Phase III, where in both programs you might still sort of enhance the dosing? Help us kind of think about, you don't want to hold the Phase III, but at the same time, you'll generate more data that can maybe even make the product even better suited for these patients. So, is the thought to move to Phase III and then potentially do a protocol change later on with the latest dosing, or are you thinking about additional lines? Thank you.

Yes, I understand, thank you Yaron. We would go with the Phase III program we prefer, and our expectation for OTC is that we will go with the prophylactic steroids arm design rather than reactive steroids. There has been enough data and enough programs to say that prophylactic steroids probably work better than reactive in general. We have enough safety information to suggest that. So our plan is to put forward the prophylactic steroids approach. We would like, though, to confirm that that works well by testing a few patients. But we can still begin the discussion with the regulatory authorities with the nine patient data we have in hand, and the difference we're talking about is what I would call a drug administration-related issue rather than design issue. The trial design, the randomized controlled design, the arm size, the size of the trial, the primary endpoint. All that can be talked through and worked through, the only toggle is the prophylactic steroids, and we think that the discussion we can have with the agency will help us. So we will go with prophylactic steroids; we've done before we actually start, but we can begin the process of regulatory conversation for OTC. For GSD1a, we are looking at these data. We will put it out, and while we'll call after the data come out, we can talk further about our next steps in the program. But in both cases, we're expecting to head to the agency with the nine-patient cohort information to make our call on the design and conduct a Phase III.

Our next question comes from Gena Wang of Barclays. Your line is open.

My name is David. I'm [indiscernible]. So, my first question is on COVID-19. Do you see any incremental impact on the manufacturing specifically?

Yes, so far, we have not seen a challenge for manufacturing; our supply chain appears to be intact. We also had substantial inventory on hand for all our products as we do for our rare disease program, which gives us a lot of cushion. But at this time, we're not seeing any impact on the manufacturing of the three products that are necessary to their commercial, and the third one would be the UX007 program. So far, all is good, and we're not having any issues with the supply chain.

The next question is on GSDIa, so I was wondering what are some initial thoughts on potential approval endpoints, for example, potential hypoglycemia and those potential trial designs for Phase III?

I can start with the last part first; the trial design that we have been discussing for both OTC and GSD1a is a randomized controlled design and probably around the 40-patient total, that's our expectation. We have not gotten an agreement on that with the HCS, the basic design. The primary endpoint for GSD1 is still being discussed with the FDA, but we have several options ahead of us, like hypoglycemia for certainly one of the original ideas that we would do and certainly is one that we can show, and it is important. We're also seeing that the reduction in cornstarch usage or requirement is another possibility, and continuous glucose monitoring opens up the door to looking at more of a real-world setting, what does their hypoglycemia look like, or how good is their glucose control. The good part about GSD1 is that glucose control is well understood by the agency and the medical community. So we can work through that story to develop a plan, not just primary, but secondary endpoints will characterize what we believe is an improved glucose metabolism situation where patients can reduce their cornstarch dramatically, achieve good control of their glucose, and have other metabolic benefits. So we think there are a lot of ways to go, but whatever the endpoint will be, we'll talk a little more about it after we present our Cohort 3 data.

Our next question comes from Maury Raycroft at Jefferies. Your line is open.

I had GSD1a one as well, just wondering if - for the expansion cohort, if you can say generally if the modified time to hypoglycemia challenge and reduce cornstarch, if that's had an impact in this cohort?

Well, we have done it and we will see that data. But I don't want to discuss it now. I think it's pretty natural, you've seen we gain less starch then get less glucose from it, that's pretty obvious. So we will be presenting that data shortly. But as you might expect, cornstarch quantity does impact how much glucose they get from it.

And then for the continuous glucose monitoring, I'm wondering if you were able to get data from the initial cohorts that could be compared with the expansion cohort, and should we expect some sort of a dose-response comparison in that update?

We will be putting glucose monitoring on the earlier patients but later in the course, we won't be able to look at before and after very well. So that will be one limitation. But we can look and see how their 24-hour fall looks, hypoglycemic events, how good their control is, how stable it is, and compare it to what we know is the common variability based on cornstarch treatment. So I think it will help confirm for us that the level of metabolic control glucose has improved in those patients, whether we can interpret the dose exactly. I think the dose determination would require more than just one test. I think we have to look at it from multiple parameters. There are only two doses in the program at this point 2e12 and 6e12. Our expectation is that we would assume that 6e12 is going to be a more potent dose based on the cohort data we already have. But between those two doses, I'm not sure CGM will provide the exact clarity. But I do think it will be one of the components that will help us confirm what we do going forward.

Our next question comes from Adam Walsh of Stifel. Your line is open.

This is [Edwin Zhang] on for Adam. A quick question on Crysvita for TIO, which I hope you will get the FDA approval very soon. First on tumors that of course TIO typically benign, is Crysvita mainly targeting those patients whose tumor cannot be surgically removed, and how many TIO patients are in this category based on your estimates? Thanks.

Sure, thank you. So, in general, the vast majority of the tumors are benign. There have been a few patients that had malignant tumors who do make FGF23 and do have the bone problems associated. But the majority of patients we are talking about have benign mesenchymal source tumors that are making a little bit of FGF23. We don't have good precise numbers on TIO in the United States, but we believe it's in the range of 1,000 to 2,000, and around half of them have non-resectable tumors that would be more likely candidates for treatment. Non-resectable first means you have to have found the tumor; sometimes it's hard to do, and secondly, it has to be a tumor in a place that you can remove without causing other harm. And so there are a lot of ways you can end up in a situation where Crysvita might be a better option whether immediately or in the long run. So I would assume it's about half of the total population at this point in time. So relative to XLH, it's much smaller, but the population in TIO is very severe in many cases and very devastating, and so there is a high urgency to treat, which is why we did a program before we got compassionate use requests for access.

Our next question comes from Laura Chico of Wedbush. Your line is open.

I guess maybe a couple on the instrument program with GTX-102; I know you dosed the first two patients already, and just wondering if you could remind us, are there certain regions of the brain that are going to be more important to achieve distribution, I believe in the marine model we saw Ub3a expression pretty consistent across the entirety of the brain. But just interested in your thoughts there. And then related to that, what proportion of Angelman patients are currently on anti-epileptic drugs?

So with regard to the first part, I don't know going into a very deep neural net discussion, probably on the conference call for work, but we can do a follow-up on that. I would say to you is the following; what we know from the data they have done in monkeys, because you all need to tie substantiated getting to a wide variety of brain regions and inducing transcription of the Ub3a gene. So we know the treatment effect growth is broad throughout the brain regions, and so we feel pretty comfortable whatever reasons need to get treated that there is regional distribution and uptake of the cell for action. We can go deeper separately, but I'd rather not go into all that. The second part you asked is a percent with seizures. I don't know if Camille has that knowledge; I know it's a significant fraction, but it's certainly not all of them. I don't remember the number off the top of my head, but it’s a substantial fraction. Camille, any thoughts?

Yes. Thank you, Emil. Thank you for the question. The exact proportion, I don't know either, but what I do know is that most if not all patients do have an abnormal EEG, which is quite pathognomonic of the disorder.

Our next question comes from Yigal Nochomovitz of Citi. Your line is open.

This is Samantha on for Yigal. Thanks very much for taking the questions. On the Daiichi manufacturing deal, it's so interesting and, in particular, it's non-exclusive, I wonder if you could first speak specifically what makes the manufacturing platform unique in terms of scalability versus others in the space. And also, can we expect you to be interested in doing similar deals with other companies in the future?

Well, I can answer the second part first, which is, yes, we are interested in doing other deals. We wouldn't do many because we do have to do tech transfer to support the partner with Daiichi, but we could do another deal or another two. The basic thing that's important that they're buying into is the fundamental reality; it's very hard to do triple transaction in very large scale. You can get 200, 400, 500 liters getting to the 1000, 2000 will be quite difficult to do reliably and to mix and create. Besides the fact that the plasma dose is not scaling, it is essentially linear at scaling, which means costs don't continue to go up. So the HeLa system is the reliable 2000-liter culture system, and because HeLa cells are very strong growers and they are growing suspension, we can basically take a clonal cell line which has the information to guide the production of AAV and grow it to a 2000-liter fully healthy fast-growing culture and then just add adenovirus in small amounts. So it is a very efficient infection for the entire culture, just like you would if you're doing vaccine manufacturing, and this creates trends the whole tank into an AAV production machine; the cells start growing and start making AAV. So the idea is we can grow the cells to large scale in a very healthy situation and then, in fact, the more efficiently. Just going to be way more efficient than doing triple transactions at large scale. And we are talking about 2000-liter scale, which is the largest main scale it's out there that's because that's disposable reactor size. We believe the HeLa system could potentially use for 10,000 liters if we create the right stable colon. We could even go larger, but it wouldn't be a single instant. After that, exact scale. That is just not going to be true for triple transaction; and the truth is that being able to do that without the material cost of plasmids and other reagents to simply grow these cells up in large scale and use very inexpensive anti-virus to induce AAV production. It's just going to be a substantially more efficient, more effective way to make AAV. The quality of the AAV vector made in that system, which is very similar to the natural biological situation right with nano helper with the adenovirus is the source of functions, provides a higher flow ratio of the product that's made in a better quality product out of the reaction to begin with. So you get larger scale, less cost material in a larger reaction, in a more effective quality of the product. So those are some of the factors I think that people are seeing, as we get more and more commercial AAV programs, especially ones needing higher doses. The scale, quantity, and cost of manufacturing can start to become a key factor because I don't think the world is going to take every gene therapy to $2 million or $3 million. So at some point, we have to think about all these diseases and how we're going to do this. And I think quality and scale of manufacturing is something we have, and I think the world is going to need it.

Thank you very much for all of the detail. And just on the tech transfer, can you speak about the typical timeline for completing that?

Well, it's over an 18-month period expected, although there is a period of continued support for a five-year period. But most of the tech transfer expected over about an 18-month period, and basically their people come to us, we will go to Japan, and of course, once we're all moving around, the idea is to teach them how to do all of it and to help them create their own PCL lines and do their own manufacturing in Japan. They have a plant that they're going to convert to that use.

And just one more if I could. With the prophylactic steroids cohort currently paused before you can dose the patients wind up, assuming this headwind continues a bit further into the second half. How many weeks on therapy will you need before you're confident that you can advance into the Phase III while using the prophylactic steroid dosing method?

Well, we will be advancing the Phase III plan in parallel with doing this. So this will allow us to kind of be able to before we do first patient in, we will have significant data. Obviously, we think probably gives enough to say whether patients are doing well, but it's more like 24 weeks to know how well UHS is, and they've got enough steroids. So that's kind of a timeframe. But what I'm saying to you is we can keep working the plan for Phase II up until the first patient in. What I said our plan would be to go with prophylactic steroids as our proposal and just getting that confirmation there is nothing unusual happening to reassure the FDA that this is and ourselves that there is no issue with doing it that way. As long as the first 12 weeks go well, we know it's safe, we know what the potency looks like in that timeframe; and we will collect data probably from 24 weeks to get a sense of whether we're getting better potency at least.

Our next question comes from Cory Kasimov of JPMorgan. Your line is open.

This is Turner on for Cory. Just on the Angelman study, I'm curious how frequently you are assessing functional endpoints and what's your confidence to be able to demonstrate an improvement in the 128-day timeframe? And just to that point, what the physicians are working with or interact with, what do they deem as meaningful improvements from the baseline of those functional endpoints? Thanks.

Very good, that's a very long detailed question. But I will – the Angelman program should be up on clinical trials, but I'll have Camille answer your question on the frequency in general; certainly at a high level. I don't know if we will answer all the changes in every endpoint at this point, but Camille go ahead.

Right, sure. Thank you. And thank you for the question also. Yes, patients are evaluated every month, and there are a large number of assessments across a number of domains because these patients experience developmental and debilitating abnormalities along the way. So there are a number of assessments. In terms of what is meaningful for the patients, as you can imagine sleep dysfunction, balance abnormalities, difficulty walking that leads to falling, seizures as was discussed previously, and most profoundly the inability to speak, and varying degrees of not being able to communicate as well. So right now, we're learning in this first in human study, and as we go forward, we'll be able to describe and discuss the abnormality in this study, but also what we're seeing in terms of what is meaningful.

I would add, as we get further along in the program, closer to actually having data, we will provide more depth to the endpoints and expectations of what meaningful. All the endpoints do have meaningful thresholds through what mean, but how precise that is, you're talking about a multi-system disorder like this, it's complex. So we need to still learn, as Camille has noted, and we look forward to providing more detail about the analysis and the interpretation of the data as we get closer to it. Thank you.

Our next question comes from Liisa Bayko of JMP Securities. Your line is open.

This is Jon Wolleben on for Liisa. Thanks for taking the question. Just on the 007 launch. You mentioned that there are about 160 metabolic centers that you're looking at. Can you discuss your launch strategy and how you're reaching those potentially, or what doctors you're targeting at first and how that might change over time?

Sure, I'll start and let Erik finish. We are very familiar with the 160 metabolic centers. We are already seeing them for MPS. We're seeing them for our OTC program, GSD1a program, GSD3 program. I've seen them for Cuvitru, Proterazyme, and Naglazyme. So, it's a group that we've seen a lot of triple product very well. We know these centers; we’ve been involved in a number of clinical trials with them, but simply there are key simulators. But there will be a segment among those, and maybe I'll let Erik talk about the strategy we are using to launch at metabolic centers.

Yes, thanks, Emil. As we stated, the majority of the patients are at those 160 metabolic centers across the country and where we already have a strong presence and strong relationships. And then there is also high awareness at those centers around UX007. So, our primary focus at launch is going to be transitioning those trial patients onto commercial therapy, and we expect those trials to also prescribe UX007 for some of the other patients that didn't end up in the trial. So we think we'll be able to leverage our current infrastructure with a small – relatively small and efficient team to support the launch, somewhere between five to 10 incremental hires.

Thank you. Our next question comes from Vincent Chen of Bernstein. Your line is open.

This is Brian on for Vincent. I guess one on the Wilson disease program. I was wondering if you could provide any color just on how you're thinking about what patients you might be going after. It's just, my understanding that largely speaking Wilson disease is pretty well controlled by chelation therapy, and this is also a very large indication. So I guess I'm just wondering how you're thinking about a target patient population there.

Yes, thank you. There will be some Wilson clinical data at ASGTC on the programs that you referenced. In Wilson, we submit for that data coming out there. The clinical strategy right now, if you look at patients that clearly have a significant disease; they are still on their drug. We clearly have significant symptoms. It is very, right now at early stage we want patients who are not acutely ill because we need to establish the safety. The design of the study will have patients first being studied that are relatively stable and then the patient population will expand later. We haven't really put out those details yet because we haven't discussed it with regulatory authorities. But clearly, when you look at the 50,000 plus Wilson patients, there are some who may be doing quite well on their chelators and may not need additional call, but the focus for gene therapy is on a substantial fraction that is still having progression of disease or still having symptoms despite chelation. So I think there is a significant fraction of patients in there, and ultimately the program will focus on those.

Thank you. I'm showing no further questions at this time. I'd like to turn the call back over to Danielle Keatley for any closing remarks.

Thank you and this concludes our call for today. A replay will be available soon, and if you have additional questions, please contact us by phone or at [email protected]. Thank you for joining us.

Thank you. Ladies and gentlemen, this concludes today's conference. Thank you for participating. You may all disconnect.