Ultragenyx Pharmaceutical Inc. ($RARE)

Good afternoon, and welcome to Ultragenyx First Quarter 2026 Financial Results Conference Call. [Operator Instructions] It is now my pleasure to introduce your host, Joshua Higa, Vice President of Investor Relations.

Thank you. We have 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; Erik 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. We are now in our 16th year since our founding, and this year is expected to be transformative with growing revenue and multiple new drug approvals. We're on track to well exceed $700 million in revenue from our global commercial business with a consistent track record of double-digit annual revenue growth. We have a PDUFA date for two gene therapies that would bring first-floor [ treatments ] to patients and families with no other disease-modifying options. Also, we will unwind our Phase III ASPIRE study, evaluating GTX-102 in patients with Angelman syndrome in the second half of this year. We're continuing to execute global clinical trials across the largest late-stage pipeline in rare diseases. We're also manufacturing our gene therapy products in our new facility in [ deferred ], Massachusetts. I'll start with GTX-102 Angelman syndromes. The first patients enrolled in the Phase III ASPIRE study have reached their day 338 visit and have transitioned to open-label extension study. The rest of the patients will be completing the blinded portion of the study in the next few months at [ crossing ] our open label extension. With the AURORA study, we are expanding GTX-102 treatment to other [ ag ] and [ ggenictyabanes ] and syndrome and enrollment of study continues to go well. We prefer to evolve the first-ever treatments for diseases that have not had significant breakthroughs in the past. And so do not simply work in disease areas where there are other competitor programs at similar stages of development. In the case of Angelman syndrome, we made an exception given the size indication and the excellent work genetics had done with the scientist [ Scott Dindot ] to develop a [ HodenASO ] that worked in a large animal model rather than just might, which often do not predict human biology. The precode research, Scott conduct in his lab at Texas A&M is a tour to [ formable ] Cogenex. He is able to identify and target a separate and distinct region of the Andersons message those led to more efficient transcript knockdown and greater potency in the clinic. This was a superior science that led us to study Angelman syndrome. Later in the call, Dr. Crombez will walk through the longer-term [ fac ] durability and safety data from the Phase II study in his section. But I want to highlight now that we have 66 patients on therapy for an average of 3 years and was the longest approaching 5 years. with continuing and improving benefits across multiple domains and with a favorable safety profile. Based on this longer-term data, we believe GTX-102 can deliver clinically meaningful treatment effects and can be safely administering product dosing. What we see in the Phase II data we believe GTX-102 is making an important difference in a [ lot ] of these patients and their families. Shifting now to our global commercial efforts. Our commercial business continues to deliver. We're now getting revenue in more than 35 countries a result of strategically investing in high-quality teams who can efficiently navigate complex approval and reimbursement process around the world. This reflects a disciplined country-by-country execution, our teams deliver every quarter. This base business is not only generating meaningful and growing revenue, it is the engine that will power our next phase of growth. Our team is currently commercializing Globe and MEPSEVI are poised to add DTX401 and UX111 to their responsibilities as we look forward to approvals for these two products later this year. Our established global commercial business is bringing first-ever treatment to patients who need them, paving the path to profitability in 2027. I'll now turn the call over to our Chief Commercial Officer, Erik Harris, who will provide details on his team's efforts in the first quarter.

Thank you, and good afternoon, everyone. As Emil mentioned, the underlying business remains strong, and we are well positioned to capitalize on the potential upcoming launches. Howard will share details, but we remain fully confident in our 2026 revenue guidance. Throughout the first quarter, the commercial and field teams have continued to meet the growing demand for our products across the globe. I'll start with Crysvita and want to put the first court revenue in the right context. The revenue in North America, Latin America was consistent with our expectations and the ordering patterns we have seen in prior years. This is a business we know well. We see continued strength in the underlying demand across all of our regions, including in markets like Brazil, where bulk orders by the mystery of health can result in quarter-to-quarter variability. In Latin America, approximately 30 patients began commercial therapy in the first quarter, bringing the total number of patients on Crysvita to more than 950 in the region. We remain fully confident in the fundamentals and strength of the business and along with our partner, KKC in North America. Our ability to continue to find and treat patients with XLH and [ TIO ]. Shifting now to DOJOLVI with the trend of our steady growth years post approval. In the first quarter, our North American team generated more than 30 start forms, far exceeding their target for the quarter. In North America, we now have more than 675 patients on reimbursed therapy. And in Europe, there are approximately 300 being treated through named patient or early access programs. The next stage of growth is likely to come from Japan where DOJOLVI was granted conditional approval last year, and we look forward to the full approval and launch of the product this quarter. I'll close with EVKEEZA, which is another example of our experienced team's ability to successfully commercialize rare disease products. In our region outside of the United States, we are seeing exceptional growth from this program as our international commercial teams navigate the country-by-country reimbursement process and respond to requests for early access from patients and their physicians. In total, there are approximately 370 patients across 18 countries who are receiving EVKEEZA. We expect this will continue to be an important and growing contributor to our revenue base. Beyond the individual product performance, I want to step back and highlight what I believe is the true strength of this business, the scale and reach of our global commercial infrastructure. That depth of market presence across rare disease markets that require significant expertise, patient-finding capability and reimbursement navigation is a genuine advantage. It is what enables us to efficiently bring first-ever treatment to our disease patients. And critically, this infrastructure and experienced team on what gives me confidence as we look toward the rest of the year. My team is preparing for two new product launches, DTX401 with a PDUFA date of August 23, 2026, and UX111 with a PDUFA date of September 19, 2026. The launch readiness work is well underway across both programs and we are building on the infrastructure and expertise we have already established. With that, I'll turn the call to Howard to share more details on our financial results and guidance.

Thank you, Erik, and good afternoon, everyone. I'll 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 Erik just mentioned. DOJOLVI 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 and as demand continues to build following launches in our territories outside of the United States. Lastly, MEPSEVI contributed $7 million as we continue to treat patients in this ultrarare 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 3 quarters because it includes items like the payment of annual bonuses. In addition, the first quarter 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 to 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 million 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 million and $520 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. This range reflects growing underlying global demand, partially offset by expected timing of [ organ ] patterns in Brazil that we anticipate will normalize in 2027. DOJOLVI revenue is expected to be between $100 million and $110 million. We are also reaffirming the R&D and SG&A guidance we provided on our last call. Specifically, we expect 2026 combined R&D and SG&A expenses to be flat to down low single digits versus 2025. We also continue to expect 2027 combined R&D and SG&A expenses to decrease at least 15% in 2027 versus 2025. With that, I'll turn the call to our Chief Medical Officer, Eric Crombez.

Thank you, Howard, and good afternoon, everyone. As Emil mentioned in the opening, I'll focus on the clinically meaningful Phase I/II data that we have generated with GTX-102, our antisense oligonucleotide for the treatment of Angelman syndrome. This data is from our Phase I/II open-label single arm studies, which informed the design of the Phase III double-blind sham-controlled ASPIRE study. Given the differences in study design, these Phase I/II results are not necessarily predictive of Phase III outcomes. In our press release earlier today, we highlighted that a total of 74 patients have been treated with GTX-102 as part of our Phase I/II program. This is one of our largest Phase I/II studies we have conducted and was designed to inform the dose, dose regimen and endpoints for our Phase III studies. There are now 66 patients in long-term extension studies with patients generally receiving the 14-milligram quarterly intrathecal maintenance dose. These patients have now been on continuous therapy for an average of 3 years and some patients are now in their fifth year of treatment. These patients continue to demonstrate improvement across multiple developmental demands with no new cases of transient lower extremity weakness. We took a cut of the data in March of this year to be able to highlight the long-term safety and efficacy of GTX-102 in a forthcoming manuscript, and I wanted to share a high-level summary today. Starting with the Bayley-4 Cognitive Raw Score, there are 53 patients in the Phase I/II study with a Bayley-4 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 5 different developmental domains and the Phase I/II 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 3 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 family's broader view of neurologic diseases like Angelman. It is the intersection of all these development changes that reflects how individual patients truly respond to a treatment in a holistic way. In the 48-week ASPIRE Phase III study we had primary statistical alpha split between the Bayley-4 Cognitive Raw Score and the MDRI. This is not a hierarch evaluation, meaning that both of these endpoints will be tested in parallel. If the Bayley cognition hits less than 0.04 or if MDI hits less than 0.01, we will have a statistically successful Phase III study. We also took a look at expressive communication in our Phase I/II study assessed by the Bayley-4. 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 I/II program, I remain confident that the developmental progress and continued learning of new skills in these patients support the meaningful benefit of using this ASO to provide UBE3A from [indiscernible]. I'm looking forward to seeing the results from our Phase III 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 catalysts for 2026 and some closing remarks.

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 23. The FDA has also informed us that an [ 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 a PDUFA action date of September 19. Lastly, GTX-102 for the treatment of Angelman syndrome is on track to read out top line Phase III data from the ASPIRE study in the second half of the year. Ultragenyx 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 who need them. The surge in late-stage programs in the last few 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. With that, let's move on to your questions. Operator, please provide the Q&A instructions.

[Operator Instructions] Our first question comes from Tazeen Ahmad with Bank of America.

This is Daniel on for Tazeen. I was just wondering if you could comment on the new update for Angelman, like what level of consistency are you seeing for patients improving on the Bayley and the MDRI -- and kind of how we should think about variability between the 2 endpoints for the Phase III...

I'll touch on it and 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 -- we're running a very high-quality operation in terms of how we will measure the test to help reduce variability. I think the consistency is something we can't comment on at this point in a Phase III study, but we can talk about what -- how it looked in Phase II. I think it should -- we expect it to be similar to what we've seen before. And I think the MRI has been a very robust and consistent measure just in its nature because it's 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-4 consistency?

Yes. So I think looking at the results from Phase I, II and very multiplied to how we designed Phase III. The most important thing we did was include patients with full dilation. This means they're expressing no UBE3A and gives you a very consistent patient population driving those consistent results we saw in Phase II 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 III study at AURORA.

It's a very good point, Eric. Consistent [ jet ] type will definitely help us get consistency, particularly considering what the placebo or the untreated the sham will do because without treatment, patients with them do not gain on the Bayley-4 significantly.

Our next question comes from Joseph Schwartz with Laurence Partners.

Great. So a couple of questions on GTX-102. In ASPIRE, are you stratifying randomization or prespecifying subgroups by any baseline factors -- it seems like in rare pediatric trials, even modest imbalances in 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?

Look, thanks, John. I'll let Eric action specific. In general, for all of our programs, we are very aware of the all [ skewing ] issue on the randomization. So we will always -- for primary endpoints will stratify our primary end point. I view our best we can, or nothing is perfect. So what are we doing for Angelman.

Yes. So specifically for ASPIRE, both by age and cognitive as or that being our primary end point, we want to make sure we have consistent balance there.

Okay. 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 that'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 end points, you do want to do it carefully. And so we're not being precise not only because we want to give resolves time to get everything straight before we do unblinding. We've said in the second half, but you can tell by when last patient in was roughly when the trial should have the last patient out, but the timing it takes to finish up a study with sham, there's EEG, -- there's a lot of things in there that it will take a little time. So we give a Phase I program, we want to take the time to make sure we're being a little nonspecific now but it's all on track.

Our next question comes from Maury Raycroft with Jefferies.

Congrats on the progress. The Phase I/II longer-term commentary is helpful. Just clarifying could we see the details as data ahead of the Phase [ III ] top line -- and it seems like you're seeing a clear static signal on MRI in the Phase I/II and based on the point improvement you mentioned for cognition, I'm wondering if you're seeing a [ SATIP ] value for cognition versus your -- versus the natural history study data set.

Well, we -- I believe 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 analysis henry is just extremely powerful method. I think it's the way forward for live diseases. You question, will you see the detailed data -- probably not. I think we haven't set which science meeting the day 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 II data, but it's not necessarily ahead of Phase III at this point. But we wanted to put out a little bit of data and a use deep 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 continues to show good safety and the kind of cognitive benefit and our benefit that gives us confidence in the design and what we're conducting in Phase III.

Got it. That's helpful. And maybe one other question. Just wondering if prior to the database lock in stats plan, do you have to have any decisions with FDA on magnitude improvement on the primary endpoint? Or is it just showing a static benefit? Is that sufficient?

Yes. There's no regulatory step between us and unblinding at this point. We're all agreed. And there is no defined required minimal change for the Bayley. I think that is something that we don't need in the design is a continuous variable. However, we will always have what is known as a clinically important change of 5 points. We'll always look at data that way, but the powering of the primary endpoint for a [ onions ] 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.

Our next question comes from Anupam Rama with JPMorgan.

This is Joyce on for Anupam. Maybe just one on the two upcoming gene therapy launches, DTX401 and UX111 in the back half of the year. Can you just discuss where you are in terms of commercial manufacturing and product scale-up and just your overall readiness from a launch -- from a CMC launch perspective.

Yes. No, good question. I think we've been manufacturing actually since last year. And for DTX401, the drug subs and drug [ pare ] both made at the plant and in Bedford. And then for UX011, we have a contract manufacturer that's making drug substance in Ohio, and we're making -- or finishing the fill finish in our Bedford plant -- we've been running around last year and this year. I think 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 were going to are actually the same doctors and there's certain synergies that will happen by having the same quality. Most of the centers will be doing both products, somebody [ do ] 1 or the other. But the quality treatment centers are getting set up contracts in place. And I think the synergies of having 2 of them will be real, and we're excited about the possibility. Of course, we still need to get approval. But at this point, from both manufacturing and commercial standpoint, we're set up and moving forward, excited about the prospects of launching 2 gene therapy products.

Next question is from Eliana Merle with Barclays Bank.

Just can you give us any more color on how we should think about the time lines for getting data from the AURORA study? And if the data are positive in the Phase III ASPIRE trial, how are you thinking about what your base case will be for the agents and from a potential insulin label? And if this will include adults.

So AURORA is how we're going to expand the label to other indications, gene types and ages. So the main ASPIRE studies, 4 to 17, all deletion and so we have a younger group, the older group and the other gene types involved in AURORA. 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 update 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 make put together our plans. The study with or [ though ] is still more enrollment to do.

Our next question comes from Yaron Werber with TD Securities.

Really appreciate the color on Angelman. You mentioned the 14 mg was generally the maintenance dose being used. Can you give us some color on whether there might be more than 1 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 substantially over $100 million at this point. Any color on what you're modeling in terms of PRB monetization and whether we can expect that full year 2017 profitability to be sustainable.

Okay. Well, I'll touch on the dose at a high level. I don't know if Eric has anything more to add, but then I'll let Howard deal with the RB is a profitability question. So the vast majority of patients are 14. And from the main trial, the protocol actually ASPIRE brings them to 14 in terms of how it's done. There are some patients that have 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 it. I think it's a very high fraction on 14.

Yes. And that is what we expect to label on. So we expect a maintenance dose of 14 milligrams every 3 months. Once we get into commercialized setting, we have our DMP, we can explore potentially a different dosing. Maybe some patients would benefit from every 2 months, some could benefit from a higher dose there, too. But our plan is to prior -- after discussions with the FDA with a 14-milligram maintenance dose.

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 they've been selling. As part of our plans, we have 2 PRVs we plan to monetize, for 111 and one for 401. We -- I think we've stated in the past that 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. Our plan is to not just hang out at the Raiser'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 will be a fun conversation to have in due course.

Our next question comes from Salveen Richter with Goldman Sachs.

Ahead of the Phase III Angelman's data in the second half, can you speak to the path forward in the event that MDRI hits that Bayley-4 doesn't?

I think as Eric noted today in the script is that we still consider that a positive study that is we have essentially two ways to succeed. The Bayley Cog can succeed and the MDRI provides maybe a more robust option. We negotiated this position with the 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 neurologic disease. This is an opportunity to move in that direction. Our expectation is, as Eric had said, that a missed Bayley-4, but a positive MDRI is still a demonstration of efficacy in the program. Obviously, that would assume that, let's say, Bayley Cognition just missed and then MDRI hit. 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 Bayley 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 -- it's 2 ways to win for the program, and we're actually expecting both to hit. But as you know, we can always miss in 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.

Our next question is from Kristen Kluska with Cantor Fitzgerald.

For this latest Angelman cut that you looked at for the Phase I/II data -- can you tell us how the 1-year plus data is stacking for cohorts A and B relative to what you saw across different measures for Cohorts 4 and -- and whether that's further strengthened your position of the dosing regimen and techniques you took forward in Phase III?

Okay. Yes. So -- we've shown the cohort A and B before, and I think the cohort A and B is continuing to behave. And I would say -- remember, that's the most of the patients. CMD 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 that 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 III because the A and B was in all the international sites. So that included the 7 or 8 countries that we're also doing studies, including a high overlap with the 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 III, both from a sites, countries and patient type. So I think it is a good model. I think the data should be in line with what we expect in Phase III.

Our next question comes from Maxwell Skor with Morgan Stanley.

This is Selena on for Max. On Angelman, could you describe the contribution of caregiver input to Bayley-4 cognition in the Phase I/II and how that changes over time with the longer follow-up data?

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 ROS scores that we're using for the Bayley-4, 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-4 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 of items where caregiver input -- 2 or 3 that can have an effect. So when we look at [indiscernible] with or without caregiver, we don't think for Bayley-4 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 of 2 or 3 things we haven't seen it have an impact, but we are doing it without caregiver input in the Phase III trial.

Emil and Eric, I think the question was maybe more around the Phase I/II 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 I/II was run. Yes, that's correct. For Phase I/II, we did use caregiver input, and it was part of the conversation designing Phase III that the FDA made that require. we actually performed the test both ways in Phase III, but the primary endpoint does not use caregiver. And that's important to eliminate bias, and that's true for both your actively treated in your control group. So it's a reasonable request.

So we can analyze without those items, they will not have a meaningful impact. That's what I said that if we drop them out, they're not impacted because there's only a couple of items out of a very large number where it might impact them, right, okay? So the situation is those 2 or 3 items that the caregiver says that they think they're developing, but the doctor to see it, they see it, they could score a point or 2. 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 I/II is -- would be consistent with or without caregiver input, right? Does that answer the question, Josh, we did.

Our next question is from Jack Allen with Baird.

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. 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. And any comments you can make as it relates to what you need as it relates to success from the gene therapy programs in 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?

Well, I'll let Howard deal with the profitability 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 -- in Angelman and the controlled 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 -- development and changing by not having caregiver input, which is maybe why the FDA doesn't want it, it 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 that 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 a natural 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 1 point a year. So whether it's a randomized trial or even a natural history. So at this point, we're comfortable with it. But I understand your point right now, we seem comfortable with it. And we have adequate power even if there was a higher background signal, we should have power to overcome that with the treatment effect we expect.

And [ Jack ], regarding profitability and launch success assumptions, right now, what we've said for top line is that we assume continued double-digit growth from our current products plus contribution from upcoming launches, which could include 111, 401, -- 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 to profitability.

Our next question comes from Ben Burnett with Wells Fargo.

I wanted to ask about the GTX-102 program and great to hear about the long-term data. I think you mentioned there were 66 patients in the long-term extension. Could you comment on sort of the reasons for discontinuations? And then I have a follow-up.

Yes, we can do that. It's actually been a little here a little there, but it's mostly often in the beginning. Maybe you can comment on that, Eric.

Yes. 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 dose discontinuation study burden.

It sometimes happened kind of early, too, because some people realize they just couldn't do it. But yes, so it wasn't safety related.

Okay. Okay. 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 sort of ordering patterns. But I guess the question is, is to 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 in kind of the yearly guidance number for Crysvita?

Yes. I'll let Erik comment a little bit because Erik is very close to the team at Karen 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 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. Erik what gives you confidence in Crysvita going forward in the North American territory?

Yes. 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 be 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 lower Q1 and a rebound in Q2 and softer Q3 and a strong Q4. So we expect, as we have in previous years to continue to deliver on our commitment to the street.

Yes. I think the thing that we would see in Q1 though is like the start forms. What's the start? That's the demand you talked about. And so -- and continuations and so forth. So demand is strong in Crysvita. 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 plan. It's going to happen almost the same every year. So we feel comfortable how the year will go.

Our next question comes from Yigal Nochomovitz with Citi Group.

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 development improvement, give you confidence that the powering on the Bayley-4 is sufficient for the ASPIRE trial. And what would be the clinically meaningful delta that you'd want to see on Bayley-4?

Yes, Yigal, thanks for the question. I think, look, we -- I think Eric just talked about hitting around 10 points, let's say, in the 1-year time frame. So that's the part of the AMD cohort and the others together that have gotten to the 1-year mark. Some people are at the 3- to 5-year mark. What we're saying is that 1 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 were adequately powered and it's well above the MID at 1 year. So we're feeling comfortable about 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 or expert, including Kim Goodsky, who's our physician who was a abdominal specialist. He says, you just don't see this thing move. So 10 points is a big number. What we are saying and what Eric put forth is that when you continue to follow these kids over the longer haul, they continue to go up in dayly cognition. And so that kind of tells us that the patients are having a sustained benefit of the ASO on their function in their brain and they continue to gain ground. That to me is really important. And that's what the long term is telling you. I think Phase III, of course, is very important for getting filed an approval. But what is the commercial potential of a product I think the long-term safety and product treatment and continuing ground tells you this treatment that has the ability to help kids over a long period of time in the post-market setting. And so with Phase III in hand, being able to get to commercial setting, I think this gives us more confidence that the potential of the drug to be a long-term benefit for patients with Angelman syndrome.

Okay. 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?

Yes. We're having what I would call routine discussion with the 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.

Next question comes from Gavin Clarke with Evercore.

This is [indiscernible] for Gavin. So two from us. One is for Angelman MRI end point. So just a full clarification of the debt analysis, but what is the delta versus sham control is actually defined? Is there a difference in the medium net response between the 2 arms or the difference in the proportion of the of the patients that are treating a net response in a list on domain. And secondly, we have a question about 106 in maps, which we saw recently got IND clearance -- so wondering what is the key difference between this new molecule versus previous 1 that looks like also run through the same indication but failed in the Phase III. What are some key takeaways we can learn from that history study to inform the current time design?

Sure. Thanks. So for the MDI, what we'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 placebo controlled 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 2 domains or more on average per patient around that in that range. But those domain can be variable. There can be various combinations. There are some patients that had as many as 4 or 5 domains of improvement. So we'll look at those distribution curves for the net domains per patient, right? That's the statistical comparison. For genyopathy, I've been involved with that program from the very beginning. 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, sale acid replacement didn't work as well because the sal acid just didn't penetrate. What the new drug is a prodrug, one that we designed that has an enhanced hydrovicity that helps target uptake into muscle and gets released and transported by a sal acid transporter. So it allows it to get taken up into the lysosome and cleared across the lysomal membrane into the muscle. And that improved hydrovicity mechanism will allow us to, in the animals or in dogs to deliver large amounts of sic 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 particularly the biopsy work that these patients have an 85% depletion of s acid in their muscle. This drug should take us back to complete replacement, if not above replacement levels of s acid. So we have greater hope this can be an effective drug for geneopathy. It's a program I should point out, is funded through a venture [ philanthy ] 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 II proof of concept, which is allowing this program to move forward at this point in time.

Our next question comes from Luca Issi with RBC Capital Markets.

Maybe Emily and Eric, circling back on a couple of prior questions. What is your relative level of conviction on Bayley for cognition versus MDRI? It feels to me that during the call, it came across as incrementally more positive on MDRI versus Bayley for 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 Bayley for cognition? Again, any color there, much appreciated. And then maybe super quickly on OI, I did not see anything in the press release or in the prepared remarks. So should we assume that you have discontinued that program?

Discontinued OI.

I missed it. So the MDRI is a more powerful measure. It has 5 endpoints in it. The gain power from all those endpoints. It is a very powerful way. We've been promoting it. We used it in our MEPSEVI 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 Bayley-4, which is actually where you need the power because it's -- there's a sort of a smaller magnitude effect. The MDRI hits very strong statistical significance. So you don't really need more alpha upside MDRI even if you have higher confidence in it because it's a tremendous amount of power in it. so I think what we've done is the appropriate proportionate 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 and until we complete and get answers to key questions and make a determination.

Our last question comes from Raghuram Selvaraju with H.C. Wainwright.

This is Amit for Ram. I 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 what to expect a meaningful revenue from both UX111 and DTX401. And then the second question is on the GTX-102 in Angelman. You mentioned discontinuation rates due to non-safety burden. Are you preparing any way to reduce discontinuation rates in the commercial setting? Or do you not foresee that being an issue?

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 the launch together. I'm sure Eric could go through this in great detail. I'll just summarize for you, Eric, that there'll be obviously various policies at launch we'll have to manage. But eventually, we are talking to payers and appropriate meetings now to help lay sort of 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 PDUFA 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 has been working aggressively on getting all the pieces in place that 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 dis case rate very limited. Actually, it's really small handful. And usually, the treatment effect that patients start seeing is so meaningful that that's something that patients have been looking for the whole -- patient families are looking for their whole life. 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 bringing in a device to help make lower punctures easier. But we're going to do our best to make sure this is as [ burnless ] as possible. And I would say to you 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 [ Asgeman ] family, that was probably more of a factor. So at this point, based on what we've seen, 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 a convenience for a treatment that involves an intrathecal delivery of an ASO.

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 at [email protected]. Thank you for joining us.

This concludes today's conference. You may disconnect your lines at this time. And we thank you for your participation.