Ultragenyx Pharmaceutical Q1 2026 Earnings Call Transcript

Ultragenyx Pharmaceutical (NASDAQ:RARE) reported first-quarter financial results on Tuesday. The transcript from the company's first-quarter earnings call has been provided below. This transcript is brought to you by Benzinga APIs. For real-time access to our entire catalog, please visit https://www.benzinga.com/apis/ for a consultation. View the webcast at https://event.choruscall.com/mediaframe/webcast.html?webcastid=p8c3kTVK Summary Ultragenyx Pharmaceutical reported Q1 2026 revenue of $136 million, with key contributions from Crysvita ($93 million), De Joby ($18 million), Evkiza ($18 million), and Mepsebi ($7 million). The company incurred total operating expenses of $305 million, including $30 million in cost of sales and $275 million in combined R&D and SG&A expenses, resulting in a net loss of $185 million. Ultragenyx Pharmaceutical reaffirmed its 2026 revenue guidance of $730 to $760 million, indicating an 8-13% growth over 2025, and aims for profitability by 2027. The company continues its strategic focus on advancing its clinical pipeline, including GTX102 for Angelman Syndrome and upcoming regulatory milestones for DTX401 and UX111. Management expressed confidence in the long-term potential of its developmental programs and outlined plans for potential gene therapy product launches in the second half of the year. Full Transcript Howard Focus on our first quarter financial results and guidance for the year Starting with revenue Total revenue for the first quarter of 2026 was 136 million. Crysvita contributed 93 million, including 39 million from North America, 46 million from Latin America and Turkey, and 8 million from Europe, which were consistent with the anticipated quarterly timing and trends. Eric just mentioned. Crysvita contributed 18 million, consistent with our expectation for steady demand growth. Evkeeza also contributed 18 million, representing 64% growth over the first quarter of 2025 as demand continues to build following launches in our territories outside of the USA. Lastly, Mepsevii contributed 7 million as we continue to treat patients in this ultra rare indication. Total operating expenses for the quarter were 305 million, which included cost of sales of 30 million and combined R&D and SG&A expenses of 275 million. Total operating expenses included $30 million of noncash stock based compensation and $30 million of expenses related to the restructuring announced last quarter. For the quarter, net loss was 185 million, or $1.84 per share. As of March 31, we had $534 million in cash, cash equivalents and marketable securities. Net cash used in operations for the quarter was $197 million. Recall in the first quarter of the year, we typically use more operating cash than in each of the subsequent three quarters because it includes items like the payment of annual bonuses. In addition, the first quarter of 2026 included 38 million in payments related to UX143 manufacturing activities as well as 5 million related to severance and other payments from our recent reduction in force. Net cash used in operations are expected to decrease in the remaining quarters of this year as we continue on our pathway. Profitability in 2027 Shifting now to guidance for 2026, we are reaffirming the revenue guidance we provided in February. Total revenue in 2026 is expected to be between 730 and 760 million, which represents 8 to 13% growth over 2025 and excludes potential revenue from new product launches. Crysvita revenue is expected to be between 500 and 520 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx Pharmaceutical. This range reflects growing underlying global demand, partially offset by expected timing of ordering patterns in Brazil that we anticipate will normalize in 2027. The Crysvita revenue is expected to be between 100 and 110 million. We are also reaffirming the R and D and SGA guidance we provided on our last call. Specifically, we expect 2026 combined R& D and SGA expenses to to be flat to down low single digits versus 2025. We also continue to expect 2027 combined R& D and SGA expenses to decrease at least 15% in 2027 versus 2025. With that, I'll turn the call to our Chief Medical Officer, Eric Krombas. Eric Krombas (Chief Medical Officer) Thank you Howard and good afternoon everyone. As Emil mentioned in the opening I'll focus on the clinically meaningful Phase 1/2 data that we have generated with GTX102, our antisense oligonucleotide for the treatment of Angelman Syndrome. This data is from our Phase 1/2 open label single arm studies which informed the Design of the Phase 3 double blind sham controlled Aspire study. Given the differences in study design, these phase 12 results are not necessarily predictive of phase 3 outcomes. In our press release earlier today, we highlighted that a total of 74 patients have been treated with GTX102 as part of our phase 12 program. This is one of our largest phase 12 studies we have conducted and was designed to inform the dose, dose, regimen and endpoints for our phase 3 studies. There are now 66 patients in long term extension study with patients generally receiving the 14 milligram quarterly intrathecal maintenance dose. These patients have now been on continuous therapy for an average of three years and some patients are now in their fifth year of treatment. These patients continue to demonstrate improvement across multiple developmental domains with no new cases of transient lower extremity weakness. We took a cut of this data in March of this year to be able to highlight the long term safety and efficacy of GTX102 in a forthcoming manuscript and I wanted to share a high level summary today. Starting with the Bayley-IV cognitive raw score, there are 53 patients in the phase 12 study with a Bayley-IV cognitive raw score. Among 12 at this time point they were approaching a mean change from baseline of 10 points exceeding the meaningful score difference of 6 points, and with longer term follow up we see continuing and improving benefits in cognition. Turning to the Multi Domain Responder Index or MDRI that uses clinically meaningful score differences consistent with FDA guidance as opposed to statistically driven changes to determine a positive or negative response across five different developmental domains in the phase 12 data set, we now have MDRI data at month 12, 24 and 36 that evaluates response across cognition, communication, behavior, sleep and gross motor. When comparing response to baseline, the P value across all three time points is less than 0.0001. Not only is this a very powerful statistical assessment of five different measures, it is consistent with doctors and families broader view of neurologic diseases like Angelman's. It is the intersection of all of these developmental changes that reflect how individual patients truly respond to a treatment in a holistic way. In the 48 week Aspire Phase 3 study we had primary statistical alpha split between the Bayley-IV cognitive raw score and the MDRI. This is not a hierarchical evaluation meaning that both of these endpoints will be tested in parallel. If the Bayley cognition hits less than 0.04 or if MDRI hits less than 0.01, we will have a statistically successful phase 3 study. We also took a look at expressive communication in our phase 12 study assessed by the Bayley IV. Similar to cognition, we saw meaningful improvements in expressive communication that continued and improved in longer term follow up. Based on the totality of data generated in our Phase 1/2 program, I remain confident that the developmental progress and continued learning of new skills in these patients supports a meaningful benefit of using this ASO to provide UBE3A from the paternal allele. I'm looking forward to seeing the results from our Phase three studies and the potential to replicate these results in larger controlled studies. I'll now turn the call back to Emil to provide a reminder of our catalyst for 2026 and some closing remarks. Emil Thank you Eric. I'll close with a few of the catalysts we have later this year. A full list can be seen in the corporate deck posted to our Website Starting with DTX401 for the treatment of glycogen storage disease type 1a. We continue to work well with the FDA and look forward to our PDUFA action date of August 23rd. The FDA has also informed us and ADCOM is not planned next for UX111 for the treatment of Sanfilippo Syndrome. The BLA that was resubmitted earlier this year is being reviewed with the PDUFA action date of September 19th. Lastly, GTX112 for the treatment of Angel Syndrome is on track to read out the top line phase 3 data from the EXPINE study in the second half of the year. Ultragenyx Pharmaceutical has been one of the most productive companies in rare disease companies in the industry and taking programs from early research to approved therapies for patients who have no other options. We've done it across multiple modalities, multiple therapeutic areas and we look forward to bringing the next set of first ever treatments to the patients need them. The surge in late stage programs the last two years has challenged us like it would anyone. But the benefit is once we turn the corner of these programs into approved products, we have the potential for a significant acceleration in our growth. That will be a special moment in the history of Ultragenyx Pharmaceutical. With that, let's move on to your questions. Operator Operator. Please provide the Q and A instructions. Thank you. At this time, we'll be conducting a question and answer session. If you'd like to ask a question, please press star one on your telephone keypad. Confirmation tone will indicate your line is in the question queue. You may press star 2 if you'd like to remove your question from the queue. As a reminder, we ask you please limit to one question and one follow up. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment please. While we poll for questions, our first question comes from Tazeen Ahmad with Bank of America. Your line is now live. Daniel Hey guys, this is Daniel on Fort Tazeen. Thank you for asking your question. I was just wondering if you could comment on the new update for Angelman Syndrome. Like what level of consistency are you seeing for patients improving on the Bayley-IV and the MDRI and kind of how we should think about variability between the two endpoints for the phase three. Thank you. I'll touch on it. Maybe Eric can add some more. I think the Bayley that we're conducting is being done with primarily with an outside firm that's coming and doing the test at the site. So this is a. We're running a very high quality operation in terms of how we'll measure the test to help reduce variability. I think the consistency is something we can't comment on at this point in a phase 3 study, but we can talk about what how it's looked in phase two. I think it should be expected to be similar to what we've seen before. And I think the MDRI has been a very robust and consistent measure just in its nature because it has multiple domains that we've seen strong results and I think Eric just talked about them. So Eric, what do you think about the Bayley-IV consistency? Eric Krombas (Chief Medical Officer) Yeah, so I think, you know, looking at the results from phase one two and very much applied to how we designed phase three, the most important thing we did was include patients with full gene deletion. This means they're expressing no UBE3A and gives you a very consistent patient population driving those consistent results. We saw in phase two and. And what we think will be replicated there. And then again as a reminder, bringing patients with other mutations that add variability into our second phase three study, Aurora. Emil Yeah, that's a very good point, Eric. Yeah, consistent genetic type will definitely help us get consistency, particularly consistency in what the placebo or the untreated sham will do. Because without treatment, patients with Angelman Syndrome do not gain on the Bayley-IV significantly. Move on to the next question. Our next question comes from Joseph Schwartz with Larynx Partners. Your line is now live. Great. Thanks very much. So, a couple questions on GTX-102. In Aspire, are you stratifying randomization or pre specifying subgroups by any baseline factors? It seems like in rare pediatric trials, even modest imbalances and baseline severity could be important. And there's some literature in Angelman that this could influence variability. I'm just wondering how confident you are that Aspire is protected against any potential baseline imbalances. Well, thanks, Joe. I'll let Eric ask. In specific, in general, for all of our programs, we are very aware of this whole skewing issue on the randomization. So we will always, for primary endpoints, will. We'll stratify our primary endpoint to do our best we can. However, nothing is perfect. So what are we doing for Angelman Syndrome? Eric Krombas (Chief Medical Officer) Yeah. So specifically for Aspire, we stratify both by age and cognitive raw score. That being our primary endpoint, we want to make sure we have consistent balance there. Okay. Emil And then we noticed that you haven't narrowed the timing for Aspire top line data yet. Do you have any sense when during second half of 26, you might report the data is late third quarter? A good assumption since you finished enrollment in late July last year. It's fun, isn't it? Keeping you in the dark about exactly when it's happening? Yes, I think you probably can guess based on the timing of things. The question is that when you close out an international study, a lot of endpoints, you do want to do it carefully, and so we're not being precise on that only because we want to give ourselves time to get everything straight before we do unblinding. We've said the second half, but you can tell by when last patient in was, you know, roughly when the trial should have the last patient out. But the timing it takes to finish up a study with Sham, there's electroencephalograms, there's a lot of things in there that will take a little time. So we give it a Phase three program. We're going to take the time to make sure. We're being a little unfortunate nonspecific now, but it's all on track. Thank you. Maury Raycroft (Equity Analyst) Our next question comes from Maury Raycroft with Jefferies. Your line is now live. Hi. Thanks for taking my questions and congrats on the progress. The phase 12 longer term commentary is helpful. Just clarifying, could we see the detailed Phase 12 data ahead of the Phase 3 top line? And it seems like you're seeing a clearer stat seg signal on MDRI in the phase 1 2? And based on the point improvement you mentioned for cognition, I'm wondering if you're seeing a statsig p value for cognition versus the natural history study data set. Emil Well, I think we've commented on the primary endpoint natural history comparison before is our powering analysis. I think we've said that, that we would, we would be well powered. So I think that that's already sort of an analysis. MDRI is just extremely powerful method. I think it's the way forward for neurological diseases. Your question asks, will you see the detailed data? Probably not. I think we haven't set which science meeting the data will come out yet. I would assume be later in the year. We have often presented things at the FAST conference, but we haven't set at this point a plan for the phase two data. But it's not necessarily ahead of phase three at this point. But we wanted to put out a little bit of data now just to give people confidence about what's going on and just give you a sense of the magnitude and outcome and the fact that we're confident about how the drug looks and that it continues to show good safety and the kind of cognitive benefit, MDRI benefit that gives us confidence in the design and what we're conducting in phase three. That's helpful. Maybe one other question. Just wondering if, prior to the database lock in stats plan, do you have to have any discussions with FDA on magnitude of improvement on the primary endpoints or is it just showing a stat signal benefit? Is that sufficient? Yeah, there's no regulatory step between us and unblinding at this point. We're all agreed and there is no defined required minimally change for the, for the Bayley-IV. I think that is something that we don't need in the design. It's a continuous variable. However, we will always have what is known as a clinically important important change of five points. We'll always look at data that way. But the powering of the primary endpoint for Bayley-IV cognition is based on a continuous analysis, which is really the appropriate thing to do. But if you look at the numbers we just told you 10, that is almost twice the minimally important difference already. So I think we're at a pretty good place. Joy Fun Got it. Thanks for taking my questions. Our next question comes from Nupam Rama with JP Morgan. Your line is now live. Hey guys, this is Joy Fun for Onupalm. Thanks for taking your question. Maybe just one of the two upcoming gene therapy launches, DTX-401 and UX111 in the back half of the year. Could you just discuss where you are in terms of commercial manufacturing and product scale up and just your overall readiness from a launch perspective. From a chemistry, manufacturing, and controls (CMC) launch perspective. Thanks so much. Emil Yeah, no, good question. I think we've been manufacturing actually since last year and for GTX 401, the active pharmaceutical ingredient (API). Drug product, both meet at the plant and in Bedford facility. And then for UX111, we have a contract manufacturer that's making active pharmaceutical ingredient (API) in Ohio. And we're making, we're finishing the full finish in our Bedford facility plant. We've been running runs last year and this year and that's part of our expenses that we're spending money on is actually building inventory. And that's been going well and we're building inventory and feel like we should be in a reasonable position at the time of launch at this point. So I think we're ready. I think the launch teams have been working on their work. I think the two PDUFA dates are quite close to each other, but the doctors we're going to are actually the same doctors. And there's certain synergy that will happen by having the same quality. Most of the centers will be doing both products. Some may do one or the other, but the qualified treatment centers are getting set up, contracts in place and I think the synergies with having two of them will be real and we're excited about the possibility. Of course, we still need to get approval at this point from both manufacturing and commercial standpoint. We're set up and moving forward and excited about the prospects of launching two gene therapy products. Great. Thank you. Ellie Merrill (Equity Analyst) Our next question is from Ellie Merrill with Barclays Bank. Your line is now live. Hey guys, thanks so much for taking the question. Just can you give us any more color on how we should think about the timelines for getting data from the Aurora study? And if the data are positive in the Phase three Aspire trial, how are you thinking about what your base case will be for the ages in A potential Angelman label and if this will include adults. Thanks so much. Emil Thank you. So Aurora study is how we're going to expand the label to other indication type genotypes and ages. So the mean Aspire studies 4 to 17 all deletion. And so we have a younger group, the older group and the other genotypes included in Aurora study. The study is still continuing to enroll and enrolling well, but it's also an international study and we'll continue to collect data. So we'll have some data at that time. We haven't really said through anything about how we'd approach our filing launch at this point in time. We're going to wait and see what the data look like and our put together our plans. The study with Laura though is still more enrollment to do. Stephen Great, thanks. Our next question comes from Yaron Warber with TD Securities. Your line is now live. Hi everyone, this is Stephen on for your own. Thanks for taking my question and really appreciate the color on angelman. You mentioned the 14 mig was generally the maintenance dose being used. Can you give us some color on, you know, whether there might be more than one dose being used, why that might be happening and whether there could be more than one maintenance dose in the label. And secondly, in terms of profitability projections given that PRVs are selling for, you know, substantially over 100 million at this point, any color on what you're modeling in terms of PRV monetization and whether we can expect that full year 27 profitability to be sustainable. Emil Thanks. Okay, well, I'll touch on the dose at high level. I don't know if Eric has anything more to add, but then I'll let Howard deal with the erv. The profitability question. So the vast majority of patients are 14 and from the main trial they the protocol actually in the spar brings them to 14 in terms of how it's done, there are some patients that certainly been on drug for a longer period of time in various regimens. So I don't know if there's anything else to add. I think it's a very high fraction around 14. Eric Krombas (Chief Medical Officer) Yeah. And that is what we expect to label on. So we expect, you know, our maintenance dose of 14 milligrams every three months. You know, once we get into commercialized setting, we have our dnp, we can explore, you know, potentially different dosing. You know, maybe some patients would benefit from every two months. Some could benefit from a higher dose there too. But our plan is to, you know, prior after discussions with the FDA with a 14 milligram maintenance dose. Howard That's really the main source of what you're going to see. So Howard, so with regard to the prv, we watch this with interest to see how, how they've been selling. As part of our plans, we have two PRVs we plan to monetize one for 111 and one for 401. You know, we, I think we've stated in the past that we, we've baked it into our model at a little over 100 million each. So anything above that would be upside. Of course, there's also an opportunity for a PRV with 102, which would also be upside to our model. So that's how we're thinking about monetization. And I think you'd also asked the question about sustainability of profitability post 27. You know, our plan is to not just hang out at the razor's edge, but to continue to grow profitability. And depending on the launches we have and their success, we'll figure out how much we can reinvest back into the pipeline versus drop to the bottom line. But that'll be a fun conversation to have in due course. Salvine Richter (Equity Analyst) Sounds like it. Thanks very much. Our next question comes from Salvine Richter with Goldman Sachs. Your line is now live. Good afternoon. Thanks for taking my question ahead of the phase 3 Angelins data in the second half. Eric Krombas (Chief Medical Officer) Can you speak to the path forward in the event that MDRI hits but Bayley4 doesn't? Thank you. I think, as Eric noted today in the script, that we still consider that a positive study. That is we have essentially two ways to succeed. The Bayley cognition can succeed and the MDRI provides maybe a more robust option. We negotiate this position with fda. I think while their tendency is to stick with single primary endpoints as their approach, we think the MDRI is actually a smarter and better way to go for neurological disease and it's an opportunity to move in that direction. Our expectation is, as Eric had said, that a missed Bayley four, but a positive MDRI is still a, a demonstration of efficacy in the program. Obviously that would assume that let's say Bailey cognition just missed and then MBRI hit. You know, that would be one potential scenario. We would not expect, for example Bayley cognition to go negative and then have an MDRI positive have that work out. So the question really be could Bailey miss for some reason? And MDRI provides an insurance policy and support for efficacy in the product that's broader than just cognition. So we feel like there's ways, two ways to win for the program and we're actually expecting both to hit. But as you know, we can always miss our best intentions in a randomized controlled trial. But I think the combination of both gives us a higher chance of being positive regardless of what happens in the patients. Kristin Klusta (Equity Analyst) Thanks. Let's move on to the next question. Our next question is from Kristin Klusta with Kantor Fitzgerald. Your line is now live. Emil Hi, good afternoon. For this latest Angelman cut that you looked at for the phase 12 data, can you tell us how the one year plus data is stacking for cohorts A and B relative to what you saw across different measures for Cohorts 4 and Z and whether that's further strengthen your position of the dosing regimen and techniques you took Forward in phase 30? Okay. Yes. So we've shown the cohort A and B before. I think the card A and B is continuing to behave and I would say remember that's the most of the patients. C and D is relatively few patients. It's really mostly A and B. So I think what we're talking about is cohort A and B extending now through the full year. And that's the data we're talking about. So it's really driven off of A and B. That A and B is we think is pretty comparable to what you're seeing in the phase three because the A and B was in all the international sites. So that included the seven or eight countries that were also doing studies including a high overlap with these sites that we're actually using. So I think that the A and B cohort, which is the primary driver of the data you heard about today, is very replicable with regard to what we're doing in phase three, both from the sites, countries and patient time. So I think it is a good model. I think the data should be in line with what we expect in phase three. Selena Let's move on to the next question. Our next question comes from Maxwell Score with Morgan Stanley. Your line is now live. Hello, this is Selena on for Max on Angelman. Could you describe the contribution of caregiver input to Bayley-IV cognition in the phase 12 and how that changes over time with the longer follow up data? Thank you. Emil Well, thank you for that very technical, detailed question. I'm not sure everyone knew about caregiver input, but just to be clear, in the raw scores that we're using for the Bayley-IV, the FDA does not want us to include caregiver input. All right. So all the analysis has to be done by the psychologist tester. And so we are not including any caregiver input in the Bayley-IV primary endpoint per FDA request. Now, out of the. I'm getting the number. Is it 20 or 30 items or something? There's like a couple items where caregiver input can two or three that can have an effect. So when we look at raw scores or with or without caregiver, we don't think for Bayley4 cognition, there's significant issue. If you're doing the expressive Bayley, there's actually a lot more caregiver input potential, and so it might have more effect on the receptor, I'm sorry, expressive communication than on cognition. So it's only a couple, two or three things. We haven't seen it have an impact, but we are doing it without caregiver input. In the phase three trial, Eric Krombas (Chief Medical Officer) Emil and Eric, I think the question was maybe more around the phase 12 data that we've talked about, if we were able to look at that without the caregiver input. And I don't think that's how the phase 12 was run. Yes, that's correct. For Phase 1/2, we did use caregiver, but. And it was, you know, part of the conversation designing Phase three that the FDA made that request. We actually performed the test both ways in phase three, but the primary endpoint does not use caregiver, and that's important to eliminate bias. And that's true for both. You're actively treated in your control group, so it's a reasonable request. Emil So we can analyze without those items, and they will not have a meaningful impact. Also, I said that if we drop them out, they're not impacted because there's only a couple items out of a very large number where it might be impact them. Right. Okay. So the situation is there's two or three items that the caregiver says that they think they're developing, but the doctor to see it, they've got a soft child see it, they could score a point or two. But we're saying if you drop those out, it's still. It's fine in cognition. So our point would be that we see in phase 12 is. Would be consistent with, with or without cog in caregiver input. Right. Does that answer the question? Josh? We're good. All right, boy. We're getting deep on cognitive on coas, so let's go on to the next question. Jack Allen Our next question is from Jack Allen with Baird. Your line is now live taking the questions. And congrats on the progress. So I wanted to ask about what your expectations are as it relates to the sham performance in the Aspire study. Emil I know there was a limited data set from Angelman, but are there any other surrogate neurodevelopmental indications that you've looked at as it relates to sham performance? And then my other follow up was on the profitability. Any comments you can make as it relates to what you need as it relates to success from the gene therapy programs and Angelman, that's baked in for assumptions for profitability. Do you account for those in the profitability guidance or is it just the current base business? Howard Well, let's Howard, deal with the probability question, but let me deal with the sham performance. Well, obviously we would not expect sham to have an effect and we haven't looked at all possible studies, but certainly in our own control studies we've seen, we haven't seen much change. I would say to you that when you're talking about the performance of development, these kids are not going to have a placebo effect. Exactly right. Because they're not thinking, hey, I'm getting a treatment, I should be better. They're not going to think this way. They're not developmentally changing by not having caregiver input. Which is maybe why the FDA doesn't want allows there to be a more objective assessment of what's happening. So we're really saying could they get better on their own without anything happening? What we're saying is that the deletion patients just don't. So we're pretty comfortable the sham forms will not be important. I don't know that there's other developmental disorders that are comparable, maybe Rett syndrome or other types like that. But at this point we don't feel that the sham should be any different from an Afro history. And the deletion patients are pretty stable in terms of their Bayley cognition scoring. They do not change much and we're talking about less than a point a year. So whether it's a randomized trial or even an Afro history, so at this point we're comfortable with it. But I understand the point right now where you seem comfortable with it and we have adequate power. Even if there was higher background signal, we should have added power to overcome that with the treatment effect we expect. Jack, regarding profitability and launch success assumptions, right now, what we've said for Topline is that we assume continued double digit growth from our current products plus contribution from upcoming launches, which could include 111, 401, 102. We haven't said much more than that. But maybe what I can say is that it certainly doesn't require all of them to be successful for us to get to profitability. And we have different levers we can pull to make sure we can live up to our promise of 2027 path of profitability. Ben Burnett Great. Thanks so much for the caller. Our next question comes from Ben Burnett with Wells Fargo. Your line is now live. Emil Great, thanks very much. I wanted to ask about the GTX 102 program and great to hear about the long term, long term data. I think you mentioned there are 66 patients in the long term extension. Could you comment on sort of the reasons for discontinuations and then I have a follow up? Sure, yeah, we can do that. It's actually been a little bit here, a little there, but it's mostly often in the beginning. Maybe you can comment on that, Eric, for them. Eric Krombas (Chief Medical Officer) Yeah, so very consistently it was all due to burden of study participation. I mean we do need to remember that some of these patients live very far away from treatment sites and it does become a burden for these families. So that was across the board the reason for those discontinuation study burden. Emil It sometimes happened kind of early too because some people realized they just couldn't do it. But yeah, so it wasn't, it wasn't safety related. Ben Burnett Okay. Okay, thank you. And then the other question I just want to ask is just around Crysvita. So I appreciate kind of the commentary you gave on the call just around some of the variability around ordering patterns. But I guess the question is what visibility do you have kind of going forward through the next couple of months and sort of what gives you sort of the confidence and kind of the yearly guidance number for Crispita? Emil Yeah, well, I'll let Eric comment a little bit because Eric's very close to the team at Kieran on what's going on. But I think one other element of this is that every year we're going to have one other factor which is the way the royalty is in the first part of the year. It's a little bit lower than it crosses the threshold and it goes up. So whatever revenue is coming, our percentage goes up as the year goes on. And that's why the quarterly revenue goes up as well. So it's just an ordering pattern thing. And there's going to be this continuous ramp up of our percent in the royalty stream. So it's just going to reset every year and crawl back up. Eric, what gives you confidence in Crysvita going forward in the North American territory? Eric Krombas (Chief Medical Officer) Yeah, no, it's quite simple. We're very confident in the underlying demand that we continue to see with finding patients and patients wanting to get treated across our regions, which is why we reaffirmed our guidance. And consistent with prior years, we expect the same sawtooth pattern that we've seen previously with, you know, lower Q1 and a rebound in Q2 and softer Q3 and a strong Q4. Emil We expect, you know, as we have in previous years, to continuing to deliver on our commitment to the street. Yeah, I think the thing that we would see in Q1 though is like the star forms. What's the start? That's the demand you talked about. And so and continuations and so forth. So demand is strong. Crys Vita, it's a great product. People stay on it when they get on it and they continue to grow it. And we're here to support them and do our own work where we're commercializing. But we Crysvita continues to grow and do well. And we just have to understand there's always this quarterly pattern. It's going to happen almost the same every year. So we feel comfortable how the year will go. Miguel Nachomosis Okay, thank you for the color. Our next question comes from Miguel Nachomosis with Citigroup. Please. Your line is now live. Hi, great. Thanks for taking the question. I was curious about the long term extension data and you mentioned that you've seen the positive improvements in multiple domains and patients are continuing to improve developmentally. I'm just wondering how you assess those metrics with respect to sufficient powering on the endpoint for the Aspire trial for the Bayley 4 cognition. Do those observations in the long term extension study on development improvement give you confidence that the powering on the Bayley 4 is sufficient for for the Aspire trial? And what would be the clinically meaningful delta that you'd want to see on Daily 4? Yes, Nigel, thanks for the question. I think, look, we, I think Eric just talked about hitting around 10 points, let's say in the one year timeframe. So that's the part of the A and B cohort and the others together that have, you know, gotten to the one year mark. Emil So some people are at the three to five year mark. What we're saying is that one year they're hitting a number which is pretty close to what we've been expecting the whole time. And that size gives us shows that we're radically powered and it's well above the mid at one year. So we're feeling comfortable at that size. And by the way, most people that know that just that test are shocked at how much change there is because it usually doesn't move at all. For most people are expert, including Kim Goodsby, who's our physician, who's a developmental specialist. You just don't see this thing move. So 10 points is a big number. What we are saying and where it put forth is that when you continue to follow these kids over the longer haul, they continue to go up in Baylor cognition. And so that kind of tells us that the patients are having a sustained benefit of the ASL on their function in their brain as they're continuing to gain ground. That to me is really important and that's what the long term is telling you. I think you phase three of course is very important for getting filed approval. But what is the commercial potential of a product? I think the long term safety and chronic treatment and continue to gain ground tells you this is the treatment that has the ability to help kids over long periods of time in the post market setting. And so with phase three in hand being able to get to a commercial setting, I think this gives us more confidence of the potential of the drug to be a long term benefit for patients with ancient syndrome. Okay, thanks. And then one on UX111 since the resubmission, have you had any other requests for information since the acceptance in April or any other inspection requirements post acceptance of the bla? Yeah, well we're having what I would call routine discussion with agency. We normally don't discuss the details of those. We've had what I would call routine discussions on the BLA and those continue and at this point we feel that business is normal moving forward and we won't really comment in detail about it until something a decision gets made. We're excited about the potential of that program and are planning for a launch assuming we get approval. Thanks. Gavin Clark (Equity Analyst) Our next question comes from Gavin Clark with Evercore. Your line is now live. Hello, this is easy on for Gavin. Thanks for taking our question so two from us. One is for Angelman MDRI endpoint. So just for clarification for the stat analysis. So what is the delta versus sham control is actually defined? It's a difference in the medium net response between the two arms or the difference in the proportion of the patients that are treating a net response in at least one domain. And secondly we have question about 106 in GNE myopsy which we saw recently got IND clearance. So wondering what is the key difference between this new molecule versus previous one that looks like also run through the same indication but failed in the phase three. So what are Some key takeaways we can learn from that history study to inform the current trial design. Thank you. Emil Sure. Thanks. So, for the mdri, what you're looking at is Net Domain Improvement. So each patient will have a number of domains that they hit. Right. And we look at Net Domain Improvement, comparing the distribution curve of the treated patients to the distribution curve of the control patients. Right. So it's a Net Domain Improvement. How many positive wins per patient do you see? And we've shown before that we had often two domains or more on average per patient, around that, in that range. But those domains can be variable, that can be various combinations. There are some patients that had as many as four or five domains of improvement. So we'll look at those distribution curves for the net domains per patient. All right. That's the statistical comparison for GNE myopathy. I've been involved in that program from the very beginning. It's a horrible muscle disease. We think maybe around 10,000 patients out there, and we think it's very chronic and terrible disease. The original molecule, sialic acid replacement, didn't work as well because the sialic acid just didn't penetrate. What? The new drug is a pro drug, one that we designed that has enhanced hydrobicity, that helps target uptake into muscle and gets released and transported by the sialic acid transporter. So it allows it to get taken up into the lysome and cleared across the lysomal membrane into the muscle. And that improved hydrophilicity mechanism will allow us to, in the animals or in dogs, to deliver large amounts of sialic acid to the cells, substantially better than the other molecules, like many, many fold better. So we think the potency is just dramatically better. And that puts us in a better position to actually achieve the replacement therapy that's required. And we know from the prior work and particular biopsy work that these patients have an 85% depletion of falic acid in their muscle. This drug should take us back to complete replacement, if not above replacement levels of sialic acid. So we have greater hope this can be an effective drug for genealopathy. It's a program, I should point out, is funded through a venture philanthropy agreement with the patient group and who are very interested in the product moving forward. And we were able to do that even under our financial constraints with the fact that they were funding it. So they're funding us through the phase two proof of concept, which is allowing this program to move forward at this point in time. Thank you. Our next question comes from Luca Izzi with RBC Capital Markets, your line is now live. Oh, great. Yeah, thanks so much for taking my question. Congrats on the progress. Maybe Emil and Eric, circling back on a couple part questions. What is your relative level of conviction on Bayley's 4 cognition versus MDRI? It feels to me that during the call you came across as incrementally more positive on MDRI versus Bailey soar cognition? One, would that be fair? And two, if so, can you still amend the protocol to potentially reallocate more alpha to the MDRI versus the Bailey store cognition? Again, any call there. Much appreciated. And then maybe super quickly on oi, I did not see anything in the press release or in fair remarks. So should we assume that you have discontinued that program? Ahmed Faram Thanks so much. Have we discontinued a lot? Oh, I see. Missed it. So the MWRI is a more powerful measure. It has five endpoints in it. They gain power from all those endpoints. It is a very powerful way. We've been promoting it. We used it in our MIP Sevy program. It's just new for regulators. And so at this point in our agreement with regulators, we put 80% of the power into the daily four, which is actually where you need the power because it's, there's a sort of smaller magnitude effect. The MDRI hits very strong statistical significance. So you don't really need more alpha sign MDRI even if you have higher confidence in it because it's tremendous amount of power. And so I think what we've done is the appropriate proportion and we don't really need to shift it more. The oi. We continue to do evaluations and discussion. We put a little bit in the release on this. We'll, we'll inform the street when we have a decision what we're doing. But we did not discontinue the program. It continues at the moment until we complete and get answers to key questions and make a determination. Got it. Thanks so much. Our last question comes from Raghuram Silvashi with HC Wainwright. Your line is now live. Emil Thank you for taking a question. This is Ahmed Faram. Just have a question about the PDUFA dates coming up in the second half, 2026. Can you frame the cadence of the commercial rollout and when to expect a meaningful revenue from both UX111 and DTX401? And then the second question is on the GTX 1 or 2 in Angelman you mentioned discontinuation rates due to non safety burden. Are you preparing in any way to reduce discontinuation rates in a commercial setting or do you not foresee that being an issue? Thank you. Sure. So obviously launch of gene therapy is complicated, the reimbursement part of it and so forth. We're not guiding on any revenue, what the revenue would be for this year, but we're certainly planning to move forward on getting launched together. I'm sure Eric could go through this in great detail. I'll just summarize for you, Eric, please, that there'll be obviously various policies at launch we'll have to manage. But eventually we were talking to payers and appropriate meetings now to help lay pipe floor the planning process for that. But the reimbursement will be some of the process and then we'll have to work through and get patients treated. So our expectation is that there will be some time from Purdue to date to be able to get things going. We're trying to work as hard to get it going within a few weeks and to see how we can get it going. We expect to have product available and it's more a question of getting the commercial process going. But I think the team's been working aggressively on getting all the pieces in place it would take and I've been participating with them on some of the payer meetings that look at what the plan is, what the policies were and how to navigate the process to get the best outcome for patients. For discontinuation rates, we actually find the discation rates very limited. Actually it's really small to handle. And usually the treatment effect that patients start seeing is so meaningful that, you know, that's something that patients been looking for their whole patient families are looking for their whole lives. So we don't expect a big discontinuation rate, but as we move forward in it, we will clearly need to manage the accessibility and convenience. And this may involve, you know, bringing in a device to help make lumbar puncture is easier. But we're going to do our best to make sure this is as burdenless as possible. And I would say too that a randomized trial or any kind of clinical trial has way more burden than getting something clinically in terms of what you have to do. So I think the amount of tests and stuff is a lot and I think for an ageman family, that was probably more of a factor. So at this point, based on what we've seen, and we're not expecting discontinuation to be a big deal, but we are also going to do our best to take care of patients before there's an issue and give them the best patient experience we can in terms of convenience for a treatment that involves an intrathecal delivery of an asl. Joshua Higa Thank you. We have reached the end of the question and answer session. I would now like to turn the call back to Joshua Higa for closing remarks. Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or email at ir@ultragenyx.com. Thank you for joining us. Disclaimer: This transcript is provided for informational purposes only. While we strive for accuracy, there may be errors or omissions in this automated transcription. For official company statements and financial information, please refer to the company's SEC filings and official press releases. Corporate participants' and analysts' statements reflect their views as of the date of this call and are subject to change without notice.