Good afternoon and welcome to the Ultragenyx Pharmaceutical second quarter 2025 financial results conference call. At this time, all participants are in a listen-only mode. At the end of the prepared remarks, you will have an opportunity to ask questions during the Q&A portion of the call. It is now my pleasure to turn the call to Joshua Higa, Vice President of Investor Relations. Thank you. We've issued a press release detailing our financial results, which you can find on our website at Ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Eric Harris, Chief Commercial Officer, Howard Horn, Chief Financial Officer, and Eric Crombez, Chief Medical Officer. I'd like to remind everyone that during today's call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil. Thanks, Josh, and good afternoon, everyone. In April 2025, we marked our 15-year anniversary as a company. Over that time, we've taken four programs all the way through approval in multiple regions and added a fifth that we are commercializing outside of the U.S. At the same time, we've also refilled the clinical pipeline and now have five Phase III clinical programs fully enrolled or at the BLA submission stage. Over the last 15 years, Ultragenyx has been the most productive rare disease company in the industry across a broad range of modalities and therapeutic areas. Through the first half of 2025, continuous momentum with meaningful progress across our larger programs. I'll begin with UX143 (citrusimab), our fully human monoclonal antibody for the treatment of osteogenesis imperfecta. The ORPID and COSMIC studies are continuing to the final analyses that will occur around the end of the year. While I hoped the studies might have stopped early at the interim time point last month, we remain confident in completing a successful study. We're pleased the safety profile is as expected and that after looking at the data, the DMC recommends we continue to the final analysis. As we head to the final analysis, the continued treatment of phase III should further strengthen bones of the treated patients. The additional six months of treatment for the treated subjects, along with the larger P-value threshold at 0.04, will help power the final assessment. We look forward to unblinding the phase III data sets and sharing the results around the end of the year. Now, based on all the data we've seen in phase II, we're confident that UX143 will be a transformational treatment for pediatric and adult patients with osteogenesis imperfecta. The combination mechanism of building bone and reducing excess resorption at exactly the sites in their body where they need more bone will increase bone strength and reduce fractures, while at the same time improving overall bone health. In addition to reducing fractures, we're encouraged by the functional effect we're seeing on increasing physical activity and ability that speaks to the long-term potential for this treatment. Shifting now to GTX-102, our antisense oligonucleotide or ASO for the treatment of Angelman syndrome. GTX-102 received breakthrough therapy designation from the FDA in June. BTD aims to exercise development and review of drugs that are intended to treat serious or life-threatening diseases and whose preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies. Historically, it seems like there have been relatively few breakthrough therapy designations granted in the field of neurology because it can be challenging to demonstrate a meaningful potential clinical effect on neurologic disease symptoms. For GTX-102, we have been able to do that. The BTD designation was obtained based on our phase I-II study data in 74 patients with a full maternal UBE3A gene deletion that showed consistent developmental gains with rapid, sustained, and continued improvements across multiple symptom domains when patients have been on therapy for up to three years. For GTX-102, the magnitude and durability of our phase I-II data indicate our ASO is meaningfully improving the lives of patients who have this neurodevelopmental disorder. Last week, we also announced that GTX-102 phase III study ASPIRE completed enrollment ahead of plan with 129 patients in seven months. The interest from investigators and patients helped drive the rapid enrollment, and I also applaud our team for their efforts to expeditiously enroll this study. We're thankful for the support from the patient communities and investigators who helped us exceed our expectations. We're now on track to read out phase III data from this 48-week study in the second half of 2026. Now, switching to our commercial progress for the first half of 2025, our commercial teams continue their trend of delivering double-digit revenue growth. The $306 million in total revenue across the first two quarters represents 20% growth versus the prior year and keeps us on track to deliver $640 to $670 million of total revenue this year. Growth is continuing to grow in line with our expectations from royalty revenue in the U.S. and Canada and product revenue in Latin America and Turkey. DULJOVI, ASKESA, and MEPSEVII also continue to contribute to our top lines. Each of these launches are progressing well. I'll now hand it off to our Chief Commercial Officer, Eric Harris, to give us some additional details on his team's recent performance. Thank you, Emil, and good afternoon, everyone. As Emil mentioned, my team is continuing to successfully commercialize four products across the globe, starting with CRYSVITA in Latin America. In the second quarter, our team generated approximately 50 new start forms that led to approximately 50 patients on reimbursed therapy. We now have approximately 825 patients on commercial product in the region as the team continues to exceed our expectations for CRYSVITA. We continue to receive positive feedback from healthcare providers in the region who tell us how much better their patients feel when on CRYSVITA, which has led to an increasing number of doctors writing prescriptions for multiple patients. We expect growth in the region to continue following the successful negotiation of reimbursement from the Brazilian and Mexican authorities, the two largest payers in the region, and continued expansion in other Central and South American countries. I'll now shift to CRYSVITA in the United States and Canada, where our partner, Kyowa Kirin, has been leading commercialization for CRYSVITA since the transition in April 2023. Revenue in the second quarter of 2025 was supported by increasing new start forms and new patients on reimbursed therapy. We expect 2025 U.S. and Canada CRYSVITA revenue to continue growing as they work to identify new pediatric and adult patients with XLH and convert them to treatment. Moving on to DULJOVI in the United States, growth of new start forms in the second quarter continued to steadily increase, consistent with the patterns we have seen in prior quarters. Our team generated approximately 30 new start forms and added approximately 30 new patients to reimbursed therapy. This brings the total since launch in 2020 to approximately 600 patients on reimbursed therapy. The split between pediatric and adult patients continues to be approximately 65% peds and 35% adults. The total number of prescribers also continues to grow, with a total of approximately 270 unique prescribers at the end of the second quarter. For DULJOVI across the EMEA region, there are approximately 280 patients treated under named patient sales across the region. The majority of demand is from France, but we are seeing continuous growth across the EMEA region, including Kuwait, Saudi Arabia, and Greece. The demand for this product is quite strong across this region, especially given the fact that we are not actively marketing the therapy and simply responding to named patient requests. Before I close, I'll make a few comments on ASKESA, which we began commercializing in territories outside the U.S. with formal reimbursement approvals in just the last couple of years. In the EMEA region, we now have patients on reimbursed therapy from nearly all of the major countries, and we have added almost 100 patients since the beginning of the year, with a total of approximately 285 patients across 15 countries. We continue to successfully navigate the country-by-country pricing negotiations and respond to named patient treatment requests across the whole EMEA region. Our team in Japan continues to build on the launch momentum following the pricing and reimbursement approval that we received last year. In Canada, we are continuing pricing negotiations with government health authorities and recently added younger pediatric patients to the label. Over time, we expect ASKESA revenue to contribute more meaningfully to the total revenue as we continue to successfully launch this transformative product for HoFH patients with its high potency due to a novel mechanism of action, regardless of background therapy. As I have mentioned on previous earnings calls, we continue to expect some quarter-to-quarter variability in revenue, primarily due to uneven ordering patterns for CRYSVITA in Latin America. We remain confident in the growing underlying demand for all of our products around the world. With that, I'll turn the call to Howard to share more details on our financial results and guidance. Thanks, Eric, and good afternoon, everyone. I'll focus on second quarter 2025 financial results and guidance for the year. Starting with total revenue, in the second quarter of 2025, we reported $166 million, representing 13% growth over the second quarter of 2024 and 20% growth for the first half of 2025 over the first half of 2024. CRYSVITA contributed $120 million in the second quarter, including $79 million from North America, $35 million from Latin America and Turkey, and $7 million from Europe. DULJOVI contributed $23 million, consistent with its expected steady growth trajectory. ASKESA contributed $15 million as demand continues to build following launches in our territories outside of the United States. MEPSEVII contributed $8 million as we continue to treat patients in this ultra-rare indication. Total operating expenses for the quarter were $274 million, which included R&D expenses of $165 million, SG&A expenses of $87 million, and cost of sales of $23 million. Operating expenses included non-cash stock-based compensation of $39 million. For the quarter, net loss was $115 million, or $1.17 per share. As of June 30, we had $539 million in cash, cash equivalents, and marketable securities, which included $80 million of net proceeds raised through our ATM facility. For the three months ended June 30, 2025, net cash used in operations was $108 million, and in total, for the six months ended June 30, 2025, it was $275 million. We now expect 2025 net cash used in operations to modestly increase compared to 2024, primarily driven by timing delays associated with UX111, DTX-401, and UX143. We will remain on our path to GAAP profitability in 2027 and will continue to focus on growing revenues and rigorously prioritizing our spend, including stopping and delaying certain expenses prior to upcoming potential commercial launches. Shifting to revenue guidance for 2025, we are reaffirming the guidance we provided in February and May. Total revenue is expected to be between $640 and $670 million, which represents 14%- 20% growth over 2024. CRYSVITA revenue is expected to be between $460 and $480 million, which includes all regions and all forms of CRYSVITA revenue to Ultragenyx. This range represents 12%- 17% growth over 2024. DULJOVI revenue is expected to be between $90 and $100 million, which represents 2%- 14% growth over 2024. With that, I'll turn the call to our Chief Medical Officer, Eric Crombez, who will provide operational updates on the clinical programs. Thank you, Howard, and good afternoon, everyone. I'll start with GTX-102 for the treatment of Angelman syndrome. As Emil Kakkis mentioned, we completed enrollment in the phase III ASPIRE study ahead of initial expectations, enrolling 129 patients across six countries in a randomized controlled study in seven months is a remarkable accomplishment. This would not have been possible without the incredible dedication and support from the Angelman community, study site teams, and investigators. The accelerated enrollment of the phase III study underscores the urgent need and strong desire for an effective treatment for these patients. We will now shift our enrollment efforts to the Aurora study that will target younger and older patients and those with other genotypes. This study is open-label and intended to provide supportive information on safety and efficacy in this expanded patient population. The protocol has been finalized, and we expect to begin enrollment in the second half of this year. Data from this ongoing study will be included in approval filings after successful completion of the phase III ASPIRE study. Shifting to UX111 for the treatment of MPS3A or Sanfilippo syndrome type A, we received a complete response letter for our BLA filing last month, and we are actively working with the FDA to resolve the observations through a planned Type A meeting that should lead to an understanding of what is required for refiling of the BLA. Once resolution has been achieved, we expect to resubmit the BLA and anticipate an up-to-six-month review. I think it's important to note that the clinical review had been ongoing and that the FDA acknowledged at the late cycle review meeting that the neurodevelopmental outcome data is robust and that the biomarker data provided additional supportive evidence. The CRL did not note any review issues related to the clinical data package nor comment on the clinical inspection. There is a request for updated clinical data for specific clinical and biomarker endpoints and safety to be included in the resubmission. Next, DTX-401 for the treatment of Glycogen Storage Disease Type 1A, where we are now on track to submit a BLA in the fourth quarter of this year. We have been working on the BLA over the last couple of quarters, and the non-clinical and clinical sections are ready to submit. We want to proactively resolve any relevant CMC and facility questions that derive from the UX111 CRL that could possibly impact the DTX-401 submission before we finalize the CMC section of the BLA. We expect to resolve the observations over the next few months and then finalize the BLA submission. Finally, UX701 for the treatment of Wilson disease. Recall, we are in the dose-finding stage of the study, and in cohort four, we are evaluating a dose of 4E13. All patients in this cohort will receive immunomodulation therapy with rituximab and tacrolimus in addition to the prophylactic oral corticosteroid regimen patients in cohorts one through three received. Enrollment and dosing in cohort four is underway, and we expect to complete enrollment in the next month or two. I'll now turn the call back to Emil Kakkis to provide some closing remarks. Thank you, Eric. I'll quickly recap the milestones and catalysts over the second half of the year. For UX143 and osteogenesis imperfecta, we expect to have top-line data from the final analyses of the ORPID and COSMIC studies around the end of the year. For GTX-102 and Angelman syndrome, we'll continue treating patients in the 48-week ASPIRE study, and we'll begin enrollment in support of the Aurora study in the second half of 2025. For UX701 and Wilson, we'll complete enrollment of the fourth cohort in the next couple of months, and we expect to make a determination on the stage two dose in 2026. For UX111 and Sanfilippo syndrome, we are working toward a Type A meeting with the FDA to get agreement on our plan to resolve their observations, which we believe we can address. Following this, we would work through the agreements to resubmit the BLA, which would be followed by a review period that could take up to six months. Lastly, for DTX-401 and Glycogen Storage Disease Type 1A, the BLA submission is on track and should be submitted in the fourth quarter. These last 15 years at Ultragenyx have been incredibly fulfilling, and yet the best is still to come. While the news of last month did delay our approval for UX111 and did not accelerate the OI program, we're confident in the strong portfolio we have to build our future. Over the next six months, we expect to continue growing revenue, tightly manage expenses and cash burn, while we maintain our path to profitability in 2027. With that, let's move on to your questions, operator. Please provide the Q&A instruction. Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two to remove yourself from the queue. For participants using speaker equipment, it may be necessary to pick up the handset before pressing the star keys. We also ask all participants to limit themselves to only one question and one follow-up to allow ample time for others in the queue to ask their question. One moment, please, while we pull for questions. Our first question comes from the line of Joseph Schwartz with Leerink Partners LLC. Please proceed with your questions. Hey, guys. This is Will Devroe Soghikian for Joe. Thanks for taking our questions today. Congrats on the progress this quarter. One for us, considering the leadership at the agency has been rather fluid lately, could you provide a glimpse into any of your recent FDA interactions, especially at CBER? Are you noticing any meaningful changes in messaging and/or the folks that you're interacting with? Just trying to get a sense for how impactful these headlines we've all been seeing are on a day-to-day interaction basis for Ultragenyx. Thank you. I think our interactions since the CRL of late have been good. I think they are productive, and we're working toward getting our Type A meeting package sent in. We're pleased with how things are going. I know they've been under a lot of duress at the agency, a lot of turmoil and change, but things have been going well, and we're pleased with the progress so far. Great. Thank you. Thank you. Our next question comes from the line of Jun Lee with Truist Securities. Please proceed with your question. Hi. Thanks for taking our question. This is Mehdi on for June. Given GTX-102 and Rubinex both use LNA chemistry, could you please elaborate on non-target site dependent factors that drive very different dosing regimens that you both have for these drugs? The LNA chemistry we're using is primarily chosen because it is substantially more potent. It can have more toxicities, which is known, but its potency was dramatically better for the target on the order, at least one order of magnitude or more in our hands when we compare it to non-LNA chemistry. There is a reason for it. We think the potency gives us a dosing that's in the 5 mg-1 4 mg milligram range, which I think is a distinct advantage because the non-chemical or the chemical-based off-target effects will be less since we're operating at a relatively low chemical concentration. It's a little hard to compare all the different molecules. The Rubinex and the one from Roche is also an LNA. The one from Ionis is a different chemistry. Each of the chemistries has its upsides and downsides. We believe the LNA strategy in this case for this target gives us a much better potency and a better therapeutic window. I think that's why I think we're seeing, we think, better results in our program so far and why we've been given breakthrough therapy designation based on FDA's review of our data. Thank you. Thank you. Our next question comes from the line of Gina Wang with Barclays Bank PLC. Please proceed with your question. Thank you. I have a two-stats question. The first one is regarding COSMIC trial. Emil, maybe can you remind us what's the reason to run COSMIC trial, and then what is your assumption for bisphosphonate arm? If trial failed but ORPID is positive, how do you see the payer and the physician uptake of the drug? My second question, if I may, just also a very quick stats question regarding phase III ASPIRE. Your secondary endpoint, you allocate 10% of alpha. Just want to confirm, is that the 0.005? Why isn't it statistically hierarchy to have a full 0.05 alpha allocate for the secondary endpoint? Thank you. Of course, Gina, I would not expect anything more than detailed statistical questions. Thank you for that diving deep. The COSMIC study and the reason for it is to look at young patients who have severe disease who couldn't go in a placebo-controlled trial. In this case, they'd want to be on the drug that they're on, which they're on bisphosphonates. They all have been on bisphosphonates. We're simply randomizing some to go on our drug versus stay on bisphosphonates. We didn't assume a change in the fracture rate for those patients on bisphosphonates. We assumed that they continue to sustain. The question is, can we get a 50% improvement, which is what we were trying to power for? The one advantage of the study, although you would say a head-to-head may have less power, I'd also argue that the population is very narrow. They're all very young patients that have a very rapid response to the drug, a very rapid bone mineral density production response to the drug. We think that that will help power the results. For example, we believe the study has the power to succeed. If it perhaps just missed, for example, showed a difference, I think it still would provide supportive data in the age group and supportive data of what the head-to-head looks like. I actually think the study should hit, though, because I think of the consistent responsiveness of patients of that age and the fact that bisphosphonates have a relatively weak and variable bisphosphonate response. We feel good about the fact that the combination mechanism of action of our drug will overcome whatever you might see with bisphosphonates. Our read so far is that we're not worried about bisphosphonates as a competitor, but we want to have the data to prove to authorities, right, that UX143 is superior to bisphosphonates. With regard to ASPIRE, we allocate the primary to 90% of the power is to the Bailey and 10% to the MDRI, which you call it key secondary, but it's really the primary alpha split. The reason for that is the MDRI is a very powerful method, which we see very strong statistical significance. We didn't need to use much power to do that. The idea was if MDRI hits, it gives us a way of having a successful study no matter what happens to Bailey. If Bailey hits, we expect both to hit, then it's fine. Could be done sequential. You could do a sequential Bailey first, then MDRI, or MDRI first, then Bailey, and kept all 0.05. By doing them separately, it means that we're not dependent on Bailey. It doesn't have to hit in order to succeed in this design. You can still have a successful trial even if Bailey were not to hit. I think it just provides a more secure approach to statistics here. We appreciate sequential would be another way to do it, but we think what we've picked gives us the best chance and brings forth a new method. The MDRI method is a new method for the FDA, but it is a powerful method and we think will become the dominant superior way to look at complex multi-domain neurologic developmental disorders. Once we start showing this in this study, I think people will understand how much more powerful it is when you're talking about a very heterogeneous population of patients. We're excited that the FDA has given us a chance now to put that forth as one of the primary ways to assess our phase III study. Thank you. Our next question comes from the line of Tazeen Ahmad with BofA Securities. Please proceed with your question. Hi. Good evening. Thanks for taking my question. Emil, for the third and final read for ORPID, there is some debate among investors that if it is statistically significant at that final read at 18 months, that the level of clinical benefit will also matter more than it might have at 12 months because the argument is if it's taking that long to separate from bisphosphonates, how much better is it than bisphosphonates? I wanted to get your thoughts on what you think doctors would think about that particular argument. Does it matter as long as it's statistically significant? Does it matter how much separation it's getting at the 18-month time point? Thanks. Yeah, thanks, Tazeen. I think if you look at the treatment effect estimate, the difference between patients, I think you could have the same difference. Because of more variation, it just might take longer to separate the groups. The treatment effect size could very well be the same. We've had to try to caution people that if it's 60%, 67%, 40%, 50%, in this range, it is substantially better than what's currently observed. I don't think that that% number is going to have a dramatic impact exactly on what happens. I think any number in that range is a strong benefit to patients. What we can see from phase II, though, is that the effect on functional ability and other aspects of the patient health is substantial. That is what's going to drive the benefit. To give you the parallel, Tazeen, I always talk about XLH. You know the CRYSVITA story, we had an RSS score that was a primary endpoint. There's no patient looking at the RSS score change% telling us whether they're going to put the kid on drug or not. The truth is that proves that it does improve rickets. The reason it's so successful is the patients feel great, are more functional, more active, just like we're seeing with OI. That's what drives prescriptions. That's what drives patient demand. The numbers we have to hit, we will hit the numbers. I think the thing in utilization will come from the overall benefit. We think what we're seeing in phase II makes this drug at least as good as CRYSVITA in its effect on OI. That's why we're confident about where it goes. Thanks, Officer. Let's move to the next question. Thank you. Our next question comes from the line of Anupam Arama with JPMorgan Chase & Co. Please proceed with your question. Hey, guys. This is Billy on for Anupam. Thanks for taking our question. The person in the FDA acknowledged the neurodevelopmental outcomes data are robust and the biomarker data are supportive evidence. What additional clinical data is likely to be included in resubmission? Is this more kind of longer duration data we're thinking or additional biomarkers that we would be asked for? Thanks. Yeah, what they specifically asked for was an update on the clinical endpoint data and the biomarker data. Just because time will have passed, they just wanted the latest data we had, which we have data patients have been ongoing in the study. We'll collect their Bailey data and their Vineland data, the data that's sort of the developmental data they've seen, which they considered robust. We'll include whatever CSF biomarker data we have as well in that assessment as requested. It's pretty much an update on the ongoing data. It was more because time had passed, they just want to see that everything continued as we believe. We believe the patient is doing well. It'll be what I would call a routine update of the clinical data. Thank you. Thank you. Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald. Please proceed with your question. Hi. Good afternoon, everybody. For the ORPID study reading out later this year, I know you still have very high conviction in the trial being successful. I wanted to talk about a hypothetical scenario where maybe the fracture data falls slightly under what you were hoping for, but you see really strong benefits on pain. Do you still think that there's a strong case to make for the FDA here? Could you argue that this will drive higher adoption for patients since they deal with this on a daily basis over the fracture aspects? I think that your point is maybe there's a lot of some variation in fractures, and you just missed that, and you have other supportive data. I think the FDA will always look at the totality of the data in a rare disease program. We've had that many times in many programs. Our sense here is that we're seeing a fundamental mechanistic effect on bone mineral density. The effect it has on fracture, it depends on how many fractures that patient has, their particular condition. We have a lot more Type IIIs and Type IVs in the study. They have a lot of complex problems. I'm sure that the support of other data would help us in any situation, whatever the statistical or treatment size is. That's just generally been the case. We feel confident the fracture data will be what it is. We're seeing what's going on in phase II. We know that as time goes on, there's very few fractures among patients after they've gotten established on the treatment. We feel good we'll be able to do that. Hypothetically, I think the data will always be more than just fractures in this disease state. The body of data we have, we think will support its use however we come out with on fractures. Thank you. Our next question comes from the line of Yigal Dov Nochomovitz with Citigroup. Please proceed with your question. Hey, thank you. Hi, Emil and team. I just had a clarifying question firstly regarding Glycogen Storage Disease Type 1A in the filing. I think, Eric, you mentioned that you were making sure that you wanted to resolve any of the outstanding CMC issues on UX111 before submitting Glycogen Storage Disease Type 1A. Could you just clarify, is there a specific question that you're trying to answer on CMC related to Glycogen Storage Disease Type 1A by virtue of clarifying something on UX111, or is this simply just a matter of taking extra precaution to make sure that you've got everything right before filing the Glycogen Storage Disease Type 1A BLA? Eric, did you want to answer that or you'd like me to answer? I'll give it a shot and certainly happy for the follow-up. It's important to remember that the manufacturing facility up in Bedford is producing the gene therapy for MPS3A as well as for GSD-1A. Any findings related to that manufacturing facility would potentially pull through to GSD-1A. We just want to make sure we work through all of that and any pull-throughs to GSD-1A. Okay, thanks. On OI. Is that right? Hello, can you hear me? Yep. No, I think we're good. Go ahead. Okay. I was going to say on OI, you know, given the first two interims have passed and now we're looking at the final one, I'm just curious if you have any updated thoughts as far as what you believe the expected placebo AFR would be. Obviously, we've done some work and there are a number of epidemiologic studies out there, both in Scandinavia as well as the United States, which point to various ranges for AFR. I'm just wondering if you could comment on what you believe would be the most likely scenario at this point, as well as on some of the more specific aspects of the statistics, again, regarding this concept of variance or overdispersion, which, as we know, is a feature of this particular data set, given the way the fractures are distributed. Thank you. Yeah, so, yes, we're aware of the analyzed fracture rate available in the literature and looking at natural history the principal investigators have on hand. We really use a lot of the data coming on for pretreatment for baseline for both ORPID and COSMIC to do our modeling. We were really looking at those patients with a baseline AFR between 0.72 and 1 for our modeling to support both of the work for interim analysis and obviously the powering we did for the primary efficacy analysis period at 18 months. With the dispersion, yes, I mean, I think, while we did not change entry criteria for ORPID phase II going into ORPID phase III, on the strength of the phase II data, we had really what I consider to be a self-enrichment of patients with Types III and Types IV. I think they needed to see that strong safety and efficacy data to take the risk to come into clinic because remember, they really are at risk just from traveling into sites to sign consents and begin studying participation. I will say, we have a greater number of patients with Type III and Type IV OI in the phase III part of ORPID compared to phase II. Okay, thank you. Thank you. Our next question comes from the line of Salveen Richter with Goldman Sachs. Please proceed with your question. Hi, thanks for taking our question. This is Tommie on for Salveen. How are you thinking about the bar for the Angelman data next year, both from a regulatory and competitive standpoint? I am wondering if you've received any updated feedback about the use of Bayley IV as the primary endpoint. Thanks so much. Yeah, I mean, you know, again. All right, Eric, you want to do it? Go for it. Oh, sorry, Emil. I didn't know if you guys were back online or not. I'll give it a start and you can certainly jump in. The bar, I think, for Angelman, it hasn't moved for us. We had our interactions with the FDA. We do feel like we have full buy-in with the study there. We do work through our statistical analysis plans with them as well. We have been in communication with them. Again, falling back to the data we generated in phase II, and that was quite a few patients there who continue to see the attainment of new developmental skills over time. We are not seeing a plateau effect. We are seeing them continue to gain new abilities, and that's very important to them and their parents. We have a lot of confidence in our primary endpoint with Bailey cognition. Cognition is foundational to everything else you're looking at there, whether it be expressive language, receptive language, motor, or anything else there. It is foundational and we think an appropriate endpoint. We talked about using MDRI and really being an ideal tool for these types of indications because you're really looking at all of these aspects on a very straightforward, transparent scoring system to really look at the benefit in totality and also allowing some variability between individual patients. I think that rapid enrollment, and really, it's not just 129 patients over seven months. It's 129 patients in a very complex study. That really speaks to the enthusiasm with sites, with patients, and their families to really gain access to this therapy. Thank you. Our next question comes from the line of Maxwell Nathan Skor with Morgan Stanley. Please proceed with your question. Great. Thank you very much for taking my question. I was just wondering, can you elaborate a bit on how PRV proceeds are being factored into your path to 2027 GAAP profitability? Any insights into your relative confidence in receiving all three PRVs? Thank you. Obviously, PRV is an important part of it. I'll let Howard maybe talk through that, the PRVs and how we're working them into our cash plan. Yeah, we have PRVs from three of our programs, so UX111, DTX-401, and UX143 factored in. There has been a shift in timing on those, but we still think all of them come through. I think that's where I'd stop. Yeah, if it's reauthorized, it makes it easier for the OI one. If it's not, then the other two certainly will be done in time to achieve, and we'd expect their value to be higher. The net of whether it's three with reauthorization or two without, we think we're still up in the same place from a total cash. Great, thank you. Thank you. Our next question comes from the line of Yaron Werber with TD Cowen. Please proceed with your question. Hey, congrats. This is Gena on for your own. Congrats on the quarter and thanks for taking our question. You noticed that there's going to be more of a prioritization on controlling spend, including stopping and delaying certain expenses. Can you give us some more granularity about what this entails? Are you exploring any options in the event that responding to the CRL for UX111 takes longer than expected? Thank you so much. Yeah, thanks. I think a lot of this is practical stuff, you know, that we're focusing on. Maybe Howard can go through it with you. Our expectation on the CRL part is to get through. I mean, we've looked through the whole list. We actually had a lot of feedback already and have already done a lot of the changes and things. We don't really see there's anything in there that is undoable, very doable stuff. We're working through it. We're not really planning for us not to get it done. I think it'll be done. So far, we think the FDA has been responsive in our discussions since then. Maybe Howard, you could talk about how we're managing costs. Our goal has been and remains to be GAAP profitable, full-year GAAP profitable in 2027. How you get there, of course, is continuing to grow the top line, but also making sure that we are good stewards of our cash. With some of the delays that we've experienced this summer, we did the natural thing, which is to delay those expenses and make sure we're being prudent and making sure we're using our money's quality. Yeah, involve not hiring people that would have been hired for launches and managing other headcount. In addition to that, just really scrubbing through all the spend that might, that should be delayed as well and not just continue them ahead with momentum. We'll help that bridge us to the point in which we will get the cash and manage where we're at. I think it's just a prudent part of managing a company in these situations. We've been through this before. We're actually very facile at making the moves we have to make. Great, thank you so much. Thank you. Our next question comes from the line of Samantha Corwin with William Blair. Please proceed with your question. Hey, congrats on the progress and thanks for taking my questions. I had one on UX111 and then a broader question on your AAV platform. Do you think that the CBR leadership change will be helpful or kind of hinder the CRL resolution for UX111? Given the recent safety events with systemically administered AAV, are you thinking about modifying your immunosuppression regimens at all, or are there any additional precautions you've implemented to decrease the risk of AAV-related SAEs? Thank you. I think there's a lot of very good people at the FDA that are still there doing their jobs. Our sense is that they won't impact their ability to do their jobs. I think in some ways it might be simpler for the next period because the team that's head down in the work can do their work and work with us in solving these things. I think it'll stick to a very practical matter-of-fact, line-by-line resolution of issues raised. I think it's very doable without having high-level leadership for these kinds of things, these kinds of resolutions. Because the clinical data were felt to be robust and strong, there's a little less uncertainty in judgment because the safety was excellent. There's no real question marks there. It's just really more about getting the things, boxes checked on all the CMC pieces, which we think we can do. We're not so concerned about leadership for that particular aspect of it. With regard to the AAV platform, we're highly supportive of the AAV as a treatment strategy. We obviously have a lot of investment in it. For many of the liver-targeted ones, we're doing it at relatively lower doses compared to others. We have not seen substantial safety issues like you're talking about, either deaths or very serious liver complications. The lower doses we use, we think, are in a very safe range, and we feel very good on them. We are looking at enhancing immune modulation, but this is more about trying to alter or support more efficacy or managing anti-transgene responses. We are looking at that in our cohort four for UX111 to try to manage the immunological responses. The drug worth was just the simple steroids, fine. That's what we can get approved on. Our goal is always to continue to look to optimize. It's not a central thing trying to prevent a death. It's more about trying to optimize the outcomes. We will look at and be more facile looking at immune modulation where needed. So far, we don't have any programs that are of the high-dose type that have created more complexities. If you have a lethal disease, as Duchenne is or others, it is not inappropriate to have a situation where that would challenge a patient. I think parents should have the right to make their decisions about the risk-benefit. We think that a lot of these horrible diseases are a death sentence and a horrible death sentence for families. They should be given the opportunity to make their decision on what's the best healthcare for their kid. I think they are capable of making that decision with an approved product. Thank you. Thank you. Our next question comes from the line of Maury Raycroft with Jefferies. Please proceed with your question. Hi, this is Farzin on for Maury. I wanted to clarify for UX143 (citrusimab) if you can provide more granular timing on the split disclosure. Last patient visit should be end of October, so it sounds like there'll be no DMC review and you'll be unblinded to the data. Technically, it should be faster than two months than it took for IA2. Hi. You'd like what day and time the data are coming out? I'm sure we can print out that. The last patient I remember, there's this whole process of getting all the last data sets, the X-rays reviewed, finalized, cleaned, no issues. We have to look at blind data, make sure there's nothing wrong, no aberrations. It's a phase III study, so it's not something you want to rush through. It's the final assessment, so we want to make sure we do it carefully. We've been saying it's around the end of the year. Could it be before the end of the year? Could it be just after the end of the year? Somewhere in there. We don't want to nail it down because frankly, it's not possible to. We're not trying to be cagey here. It's just that we want to make sure we have a good time as a provider to get the study closed out absolutely perfectly. Every aspect of the study is perfect. We owe it to the patients and our investors to make sure that everything is perfectly correct when we go out and release data. Makes sense. For the Angelman, the demand is there clearly, and these are all deletion patients. Can you talk more about the patient baseline profile relative to your phase I-II enrolled patients? Should we expect more durability data from the phase I-II cohort of patients maybe this year? The patients in the phase II and now enrolled in the phase III are essentially the same. They're 4 year- 17year-old deletion-only patients. They're actually identical. The same criteria were used. They're really very comparable. Whatever we saw in phase II is probably pretty much what you should see in these phase III patients. With the Aurora study, we're going to look at younger patients or older patients with deletion. We'll also look at patients that have missense mutation or the ICD/UPD type. We're going to gain knowledge. The idea was to gain sufficient safety data to show that you can administer the drug and then show that their efficacy, even though in an open-label format, that the efficacy is comparable to the effect that we will demonstrate and prove as a cause and effect of the drug in the randomized control study. That's the idea on the approach we're taking. Did I answer your question? Should we see more follow-up data from the phase I-II this year? We hadn't planned right now. I mean, the team is working on two phase III programs right now. That is our focus. The last thing I want to do is put another item on their plate of running more. The patients continue to get drugged and are doing fine, and we're encouraged with it. We hadn't planned another cut of data yet. We got to get the phase III done and do them well. Got it. Thank you so much. Thank you. Our next question comes from the line of Jack Allen with Robert W. Baird. Please proceed with your question. Great. Thanks so much for taking the questions, and congrats on the progress. I wanted to ask a couple on the UX143 program. As it relates to ORPID, what kind of standard deviation are you seeing in any blinded data that you've seen? How confident are you in the existing statistical analysis plan that you have outlaid, and do you think there are any needs to update that SAP? I have a quick follow-up as well. Yeah, we haven't really talked through standard deviation. I know everyone is trying to calculate dispersion. You didn't say dispersion, though, but everyone's also saying dispersion just to show they're at the level of statisticians operating here. I know everyone's trying to do the math for us. We haven't put out the standard deviation, and I don't really even know it off the top of my head right now. There is a significant amount of variation because we've said about a third of the patients had a fracture rate at baseline from three or above and about two-thirds below. We also have an age range of five-year-olds up to 25. There's a bit of range in those things. Those are all factors in the standard deviation, both the standard deviation of the AFR, but also the bone BMD response, etc. We have comps in the SAP in the sense that the negative binomial model actually is the best way to look at this kind of fracture data. Frankly, today I actually did a little AI search, which you can do yourself, and look up negative binomial and fractures. It'll tell you actually this is the best method. You can do it yourself. It says among all the methods, there's some comparison papers. It's the best method. There are things and details to that, like what covariables, what are the items that contribute to variation that we can look at. Those are basically tweaks to the model that you can make. Usually in any stat plan, you offer some flexibility in what covariables you might use because you have to control for contributions of variation, which include the baseline AFR. It could include the type of OI. It could include the age, right? Those are three obvious ones that would be potentially included. Those are some of the tweaks you would do to a final analysis plan. The basic negative binomial model is set, and we're confident in it as a strategy. We just want to make sure we're using the right set of covariables to help control for baseline variation that's not related to actual treatment effect. That will help us ensure that we get the best result. Great, great. That's super helpful context. You did mention that the phase II seems to be demonstrating a very durable effect and even a deepening of response over time, or at least that's how I would characterize some of your earlier comments from UX143. I just wanted to ask if there are any plans to present updated data from the phase II cohort of 24 patients and when we may see that data set if there are plans. We don't have plans yet. The study is ongoing. The patients are doing really well, and we can consider doing that at some point, but we haven't made a specific plan yet to do it. Got it. Thanks so much. Congrats on the progress. Thank you. Our next question comes from the line of Hongye Wei with Guggenheim Securities. Please proceed with your question. Hi, this is Hannah for DEPGID. Thank you for taking our questions. We have a question regarding the OI program. Could you clarify which bisphosphonate therapy patients were on prior to entering the ORPID study, and roughly how many patients were on Reclast? Thank you. Yeah, we haven't disclosed which bisphosphonate is on, but we have said the vast majority, I think it's greater than 90%, have had bisphosphonates on board, like a large fraction. It's primarily because enrolling patients with a higher fracture rate, you know, the higher ones are in the study. The fraction had been on bisphosphonates was, I think, above 90%. We haven't said which ones. It's several different ones, so it wouldn't help you. Got it. Thank you. Thank you. Our next question comes from the line of Raghuram Selvaraju with H.C. Wainwright. Please proceed with your question. Good afternoon. This is Dan on for OM. Thanks for taking our questions. Congrats on the beat. Have you noticed or has Corinne mentioned anything notable about the U.S. or Canadian CRYSVITA markets? The royalties appeared kind of flat on a Q1 year-over-year basis, but increased over 17% Q2 year-over-year. Do you have any rationalization for that? How much of that increase do you expect to be sustainable in year-over-year quarter comparisons moving forward? Thank you. Yeah, I think there's always a little lumpiness in those regions because of how the ordering and buying. I haven't any particular explanation. I don't know, Eric, if there's something of insight that you have, but I think there's just a regional lumpiness in when the governments are managing what goes on. Yeah, no, we think the underlying demand has been pretty consistent and pull-through. As Emil Kakkis had mentioned, the ordering patterns have just been a little lumpy. Yeah, we're not making more than that for you. Thank you. Thanks, Officer. Let's move on. Thanks, Officer. Let's move on. Thank you. Our next question comes from the line of Luca Issi with RBC Capital Markets. Please proceed with your question. Oh, great. Hi, team. This is Shelby on for Luca, and thanks for taking our question. Emil, we have heard you in recent interviews noting that the FDA asked for things like more probes in your shipping validation for the Sansolipo CRL, as well as an inspector who was particularly stringent with his review. Can you expand on that, and then maybe bigger picture, can you share your opinion on whether you think the FDA is missing the forest for the trees here? Any color there, much appreciated. Thanks. I think one of the FDA's jobs is to actually check every tree in the forest. That's part of the rigor of the process. If there's a CRL that has a lot of bits and pieces because there are a lot of bits and pieces, I would say these are all things that need to get taken care of, and there are lots of parts and pieces to it. I think they're doing their job with regard to that detail. Should it be CRL or could we have done it in time? Those are questions you could ask, but we're going to do the work they asked for. The inspector and all that, I think it doesn't matter. At the end of the day, we have a CRL list of issues to do, and we're going to do them, and we're doing them. I think we'll be able to work that out with the agency and get it done. There are times when the FDA has to focus on certain details. It's part of the rigor they apply. We appreciate that, particularly the CMC rigor is essential, and there are reasons for a lot of things that relate to things that have happened. We are going to comply and improve what we can with everything we do. Thank you. Ladies and gentlemen, we have reached the end of the question and answer session. I'll now turn the call back over to Joshua Higa for closing remarks. Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at ir@ultragenyx.com. Thank you for joining.