Ultragenyx Q4 2025 Earnings Call - FDA Asks for CMC Support on UX111; Restructuring Targets Profitability in 2027

Conference Operator: Good afternoon, and welcome to the Ultragenyx’s fourth quarter and full year 2025 financial results conference call. At this time, all participants are in a listen-only mode. At the end of the prepared remarks, you will have an opportunity to ask questions during the Q&A portion of the call. It is now my pleasure to turn the call to Joshua Higa, Vice President of Investor Relations.

Joshua Higa, Vice President of Investor Relations, Ultragenyx: Thank you. We’ve issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Howard Horn, Chief Financial Officer, Eric Harris, Chief Commercial 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.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Thanks, Josh, and good afternoon, everyone. 2026 is poised to be a significant year for the company as we reach key inflection points across multiple programs. This includes two potential approvals in MPS IIIA or Sanfilippo type A syndrome and glycogen storage disease type Ia, and a pivotal data readout in Angelman syndrome. These programs are excellent examples of our mission to bring important first-ever treatments to patients and families, while also delivering meaningful long-term value to shareholders. Just last week, we presented updated data at the World Symposium from the UX111 for MPS IIIA program. The new data reflect an additional year of follow-up and continue to demonstrate sustained and significant further separation of early-treated patients in multiple neurologic endpoints, including the Bayley, cognitive, and communication scores, when compared to the decline observed in MPS IIIA natural history.

The data also show a significant and durable reduction in the toxic substrate heparan sulfate and other disease-caused biomarkers that show a restoration of lysosomal function, regardless of age or stage of disease. This reduction in CSF HS can be effectively measured by any of a number of different assay methods available, and all HS measures correlate significantly to stabilization or improvement in clinical function. These results in humans and animal models were thoroughly discussed, substantiated, and ratified by highly trained and qualified academics, clinicians, and industry leaders that are the internationally recognized experts in this field at a Reagan-Udall convened workshop in 2023.

For the entire UX111 study program, we now have more than 8 years of follow-up, and overall, these data continue to support a clinically meaningful and durable clinical effect of UX111, regardless of age or stage of disease, all supported by consistent improvement in multiple relevant direct measures of disease activity, including CSF HS. We resubmitted the UX111 BLA to FDA late last month, and earlier today, we received an incomplete response letter. We had provided complete responses to each CRL item, but now the FDA is requiring additional details within supportive documentation on the CMC CRL responses made and their impact. This information is typically provided during an inspection, and we were prepared to do so, but we will now provide this supportive documentation as a part of our BLA resubmission.

Our efforts to bring these transformational therapies to patients are supported by our established and still growing commercial business, which again delivered significant 20% year-over-year growth in 2025. We’re now bringing treatments to patients in more than 35 countries, each of which contributed revenue in 2025. This commercial infrastructure will power our growth into 2026 and beyond as we leverage the investments, expertise, and relationships we have established around the world to commercialize three additional treatments over the next two years. Erik Harris will outline for you our results across programs last year and discuss our vision to expand and deepen our global commercial footprint in the coming years.

As noted in our press release earlier today, and following the UX111 CRL last year and the data from the UX143 trials, we made the necessary decision to implement a strategic restructuring plan to reduce our operating expenses and ensure our resources are squarely aligned with our highest impact opportunities going forward. Howard will now go through some of the details, but these actions were necessary to keep us on path to profitability in 2027, while still advancing a meaningful pipeline of new products.

Howard Horn, Chief Financial Officer, Ultragenyx: Thank you, Emil, and good afternoon, everyone. Before I go through our financials and our guidance, I want to expand on the objectives of our strategic restructuring plan. The plan refocuses our headcount and expenses on our near-term value drivers, while reducing internal and external spend from areas across the business, including manufacturing, clinical, early-stage research, and G&A. It is an important part of our broader strategy to become profitable in 2027, together with continuing to grow our base business of four commercial products and investing in three successful launches for UX111, GTX-401, and GTX-102. Today, in connection with the restructuring, we announced a 10% workforce reduction, impacting approximately 130 full-time employees. Reductions in force are a challenging part of operating a business, and we are grateful to these colleagues for their contributions to Ultragenyx. Now, turning to the financials.

I’ll focus on the full year 2025. Please refer to our press release for details on the fourth quarter. For 2025, we reported total revenue of $673 million, representing 20% growth over 2024 and exceeding the upper end of our guidance range. Crysvita contributed $481 million, including $275 million from North America, $177 million from Latin America and Turkey, and $29 million from Europe. In total, for Crysvita, this represents 17% growth over 2024 and also exceeded the upper end of our guidance range. Dojolvi contributed $96 million, which represents 9% growth over 2024. Evkeeza contributed $59 million, representing 84% growth over 2024, as demand continues to build following launches in our territories outside of the United States.

Lastly, Mepsevii contributed $37 million as we continue to treat patients in this ultra-rare indication. Total operating expenses for 2025 included cost of sales of $109 million and combined R&D and SG&A expenses of $1.1 billion. For the year, net loss was $575 million, or $5.83 per share. As of December 31, we had $738 million in cash, cash equivalents, and marketable securities. Shifting now to guidance, I’ll start with revenue. Total revenue in 2026 is expected to be between $730 million and $760 million, which represents 8%-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, offset partially by expected timing of ordering patterns in Brazil that we anticipate will normalize in 2027. Dojolvi revenue is expected to be between $100 million and $110 million. Turning now to R&D and SG&A expenses. With the implementation of the strategic restructuring plan I discussed earlier, we expect 2026 combined R&D and SG&A expenses to be flat to down low single digits versus 2025. This guidance nets the restructuring reductions from the restructuring with severance and other one-time non-recurring restructuring costs and targeted launch investments in UX111 and DTX-401.

We expect 2027 R&D expenses to decrease from 2025 levels by 38%, or approximately $280 million, driven by the completion of clinical and manufacturing spend on multiple Phase III studies and the reduction of early-stage research efforts. 2027 SG&A expenses are expected to increase in support of new product launches and our existing approved products. On a combined basis, R&D and SG&A expenses are expected to decrease at least 15% in 2027 versus 2025. With that, I’ll turn the call to our Chief Commercial Officer, Erik Harris, who will provide detail on his team’s efforts in 2025.

Eric Harris, Chief Commercial Officer, Ultragenyx: Thank you, Howard, and good afternoon, everyone. I want to, I want to begin by expanding a bit on Emil’s earlier comments about the strength and durability of our existing commercial business, which continues to deliver strong performance across markets and products. Since 2017, we have built a portfolio of four marketed products across multiple therapeutic areas, all of which continue to deliver strong growth and meet or exceed guidance year after year. That consistency comes from careful planning, disciplined investment, and repeated strong execution in some of the most complex rare disease markets globally. Crysvita remains an important part of our base business. Our partnership with Kyowa Kirin in the U.S. remains strong, and we continue to find and treat commercial patients across Latin America and Turkey.

In Latin America, the Crysvita business is anchored in Brazil and Argentina, with solid reimbursement growth in Mexico and Colombia over the past year, translating into meaningful revenue contribution from those countries. Additionally, we continue to respond to MPS requests in other LatAm markets, a testament to the growing underlying demand for this product. This steady progress is due to the thoughtful investments we have made, paired with strong local execution. As I have mentioned in previous earnings calls, we continue to expect some variability in revenue driven by uneven ordering patterns. This is particularly evident in Latin America, where Brazil’s Ministry of Health places the largest orders in the region. This pattern is reflected in the 2026 Crysvita guidance range Howard mentioned earlier, and includes growing global demand growth, partially offset by the expected timing of ordering patterns that we expect will normalize in 2027.

Moving on to Dojolvi. Five years post-launch, the product continues its steady growth with more than 100 started forms in the U.S. for the third straight year. In EMEA, we have seen continuous MPS growth across the region, while also achieving two regulatory wins last year, namely early marketing authorization in Kuwait in September 2025, and approval of the early access pathway in the U.K. in April 2025. In Japan, last year, we announced Dojolvi was granted conditional approval, and we look forward to the full approval and launch of the product in Japan in the second half of 2026. Finally, with Evkeeza, which is another powerful case study of Ultragenyx’s ability to drive growth in a relatively small market through relentless patient identification and effective commercialization pathways.

We began commercializing in our territories outside of the U.S. with formal reimbursement approvals in just the last couple of years. In the EMEA region, we now have patients on reimbursed therapy across all, nearly all major markets, with approximately 350 patients across 20 countries who are receiving Evkeeza today. In December, we achieved a significant milestone with the registration of Evkeeza in the Kingdom of Saudi Arabia, reinforcing our commitment to bringing life-changing therapies to patients globally. We also commercialized Evkeeza in Japan, where we’ve seen sustained, steady progress since the initial launch in January 2024, positioning us not only to launch additional new products in Japan, but also to serve as a foundation for broader APAC commercialization opportunities. Over time, we expect Evkeeza will continue to grow meaningfully and add to our expanding revenue base.

In summary, we enter 2026 with a proven commercial infrastructure and an experienced team that consistently executes with discipline and precision as we launch and scale complex rare disease therapies globally. With two potential gene therapy launches and pivotal Angelman data ahead, we are well-prepared and confident in our ability to deliver the next phase of growth required to reach profitability. With that, I’ll turn the call to Dr. Crombez to share the clinical and regulatory milestones for the coming year.

Eric Crombez, Chief Medical Officer, Ultragenyx: Thank you, Eric, and good afternoon, everyone. I’ll spend a couple of minutes to highlight the upcoming clinical and regulatory catalysts for 2026. I’ll start with DTX-401 for the treatment of glycogen storage disease type Ia. We completed the submission of our rolling BLA at the end of December, and we expect to have a PDUFA action date in the third quarter of this year. Next, UX111 for the treatment of Sanfilippo syndrome type A. We recently presented the encouraging long-term data at the World Symposium that Emil mentioned earlier in the call. In response to the IRL we received earlier today, our manufacturing and regulatory teams are urgently working to provide the detailed supportive documentation that will allow, will allow us to resubmit our BLA as quickly as possible, given the critical need for this life-changing therapy.

For UX701 for the treatment of Wilson disease, we completed enrollment of the five patients in the fourth dosing cohort last year, and we expect to share data from all four cohorts later this year. Lastly, GTX-102 for the treatment of Angelman syndrome. We are continuing to treat patients in the 48-week ASPIRE study and continuing to enroll patients in the supportive AURORA study. We expect to share ASPIRE phase 3 data in the second half of 2026. I’ll now turn the call back to Emil to provide some closing remarks.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Thank you, Eric. By implementing the strategic restructuring plan we announced today, we are focusing our resources and energy on the highest value opportunities in our commercial and development portfolio. The development team will support patients and investigators who are participating in our clinical studies around the globe, work through the two BLA submissions, and prepare to read out phase three data from the Angelman study. At the same time, the commercial team will continue expanding the geographic reach of our four commercial products and prepare to launch three more programs. All these efforts continue our mission of leading the future of rare diseases with first-ever treatments. With that, let’s move over onto your questions. Operator, please provide the Q&A instructions.

Conference Operator: Thank you. We will now be conducting a question and answer session. We ask that you please limit yourselves to one question and one follow-up. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Our first question comes from June Lee with Truist. You may proceed with your question.

June Lee, Analyst, Truist: Hi, thanks for taking our questions. The primary endpoint for your phase 3 Angelman study is Bayley-IV cognition, while that of Ionis is the expressive communications sub-domain. Was your decision to use cognition over expression, expressive communication based on the greater probability of success, or because that’s higher, on the list of parents’, desirability or priority list? And are you able to share what percentage of the patients coming out of phase 3 have opted to roll over, into the long-term extension portion of the study? Thank you.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Right. So the Bayley cognition is a fundamental activity, and by the way, you can’t have communication without cognition as well. It’s all intertwined. Communication is clearly important, but takes more time. It has to develop and evolve, and we feel while we are evaluating expressive communication in our program and we’ll have data on it, we didn’t think it made sense as a primary endpoint, given its heterogeneity and the complexities of its development. Now, our own trial, though, will not only depend on Bayley’s cognition, we also have allocated some of the power of the study to the Multidomain Responder Index, which will give us a combination of cognition, receptive communication, sleep, behavior, and motor function, which will give a broader assessment that’s very important to parents as well.

So we think the combination, what we have, will provide the important insight in how their patients are doing. It will be important both to patients and doctors, and we’ll include all information, including things on expressive communication. With regard to your second question, which was rolling over, we had very few, I don’t even know how many, dropouts in our program. Everyone has continued on treatment. I don’t know, Eric, if you want to comment on the extension or rollover of patients.

Howard Horn, Chief Financial Officer, Ultragenyx: Yeah, similar to what we saw in phase 1, 2. The phase 3 studies do have a very high retention rate, including patients electing to continue in a long-term extension study. I think, you know, parents really do understand this is the opportunity for their children to, you know, grow, develop and gain and learn new skills, which isn’t something you see by natural history.

Conference Operator: Thank you. The next question comes from the line of Maury Raycroft with Jefferies. You may proceed with your question.

Maury Raycroft, Analyst, Jefferies: Hi. Thanks for taking my question. I’ll also ask one on Angelman. Wondering if you could just talk more about the patient baseline profile now that you have the study fully enrolled, relative to your Phase 1, 2 enrolled patients, and what specific parameters in the baseline data do you expect to influence control arm performance on cognition? And what are your latest expectations for what you can show on cognition in the treatment and control arm?

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Yes. Well, if you remember, Maury, in our phase 2 trial, we did an expansion trial. That trial was intended to look at 8 countries where we’re going to run the phase 3. So the point of that was 50 extra patients and potentially evaluate phase 3 patients, type patients from all the different countries. The baseline data that we saw and presented on, on cohorts A and B, which are the ex-U.S., is pretty reflective of what we’re seeing in our phase 3 program. So we’re comfortable with that. That what we’re seeing in phase 3 is comparable to what we saw in the expansion program, which is what the expansion was about, again, at least giving us a sense for what the broader population would be in multiple countries, not just U.S.

With regard to the cognition and control, we assume both the natural history and randomized control phase is only 1 point or less of cognitive change in the Bayley. It’s a very rigorous measure. It’s very hard to move. It’s not something prone to placebo effect. We are taking great care in the conduct of this, and where possible, we actually have a central firm that’s providing the testers on the patients with Angelman in our study. That helps assure a quality and of the assessments, so they’re done in a very consistent way. So we feel pretty comfortable that the amount of change we’ll see in the control group is small. We don’t think there’ll be much placebo effect, but of course, there’s always variation. This is neurology, and we have a study we think of appropriate size to help manage variation.

But what we also have done is built in the Multidomain Responder Index, which gives us another opportunity to look at these patients in a broader way with more power.

Maury Raycroft, Analyst, Jefferies: Got it. That’s helpful. Thanks for taking my questions.

Conference Operator: The next question comes from the line of Anupam Rama with JP Morgan. You may proceed.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx8: Hi, guys. This is Priyanka on for Anupam. Can we get more color on how Ultragenyx is planning to achieve profitability in 2027, when burn in 2025 was around $466 million? And can you remind us how many drug launches will contribute to the 2027 top line?

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Sure. I think Howard went through some things about major cost reductions that are occurring based on the progress of programs. I’ll let him tell you the detail in one second. The combination that the base business of growth is going to be a real important part of where we get to. Certainly, there’s some contribution potentially from the others. And Howard, maybe you can provide a little more, or reiterate some of the clarity of how we’re making this move toward profitability.

Howard Horn, Chief Financial Officer, Ultragenyx: Yeah, happy to. I’ll go through it now. Also, I’ll note there’s some, there’s a page or two on this in our corporate deck, if you want to refer to that later as well. But our pathway to profitability assumes a few things. Emil mentioned that on the revenue side, continued growth from our current products in the double-digit range, plus contribution from some of the upcoming launches. On the expense side, we, or I mentioned a little bit ago, 2026, we should expect combined R&D and SG&A to be flat to down low single digits versus 2025, and in 2027 for combined to be down 15% or more. We have, as part of our sort of cash plan, we have the $735 million that we noted today.

We are also considering two PRVs as part of our plan to get to profitability. Maybe, maybe I’ll also note that, you know, while we’re in, while we’re in launch mode, some of the dynamics of the PNL that are also important to consider would be things like R&D trends, or rather, tends to be reduced due to capitalization of manufacturing costs post-approval. Also, gross margins tend to be elevated given prior expensing of pre-approval inventory that’s being sold during the launch. So those are some dynamics to think about as you go through your modeling. So I think I’ll stop there.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: And I think it’s important that part of the expenses in 2026 are building that inventory that’s launched. So what’s really happening, some of the expenses you’re talking about now are actually building inventory that will be launched. Those combinations hopefully give you a magnitude of effect that will push us there. We do need to get two approvals. We do have two PRVs in our financial plan. But we think with the cuts we put in place today and additional things we’re working on, will put us in good position to keep 2027 profitable.

Conference Operator: The next question comes from the line of Joseph Schwartz with Leerink Partners. Please proceed.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx5: Hey, guys, this is Will Soghikian, on for Joseph Schwartz. Thanks for taking our question. I have one on Angelman and then a quick follow-up. So for GTX-102, the company has consistently stated that it is the most potent ASO in development. We’re just wondering, is this claim based on the UBE3A knockdown or perhaps its mRNA or protein increases preclinically? And can you just remind us what type of relationship you’ve seen between knockdown and protein expression? And then I have a quick follow-up. Thanks.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Well, obviously, knockdown and expression can really only be monitored in an animal model, right? Because we’re not doing brain biopsies in our patients, right? So to be clear, those estimates have to come from non-human primates. Now, because our ASO is identical to the non-human primate sequence, we can conduct an experiment in the non-human primate, for example, that Ionis can’t conduct because they do not have homology in non-human primate. So our experiments in non-human primate have shown that we are knocking down the antisense transcript substantially across the brain and are inducing UBE3A expression. And we do it at levels of around 1-2 milligram dosing over a few doses. So a relatively low dose that would be in the range of 10, let’s say, 10-14 milligrams translated into humans.

We know now also that based on our ASPIRE presentation last year, that we showed a, an effect on Bayley cognition and other endpoints, and that Ionis showed a similar effect on Bayley cognition in a 6-month timeframe, though they didn’t show our higher level of benefit over time. That is happening at doses in our study that are in the 5-14 range, while they are using 40-80 milligrams, and Roche used even higher doses. We’re achieving Bayley cognition comparable in substantially different doses. That substantiates what we found in non-human primates before, that what we predicted was true and that our effect we’re seeing in our primates translates to humans with a potent effect at a lower dose level.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx5: Great. Thanks so much. And then just one quick follow-up, if I may. I think the DTX-301 program completed enrollment about a year ago now. So just wondering if you could give us a quick update on what’s going on there. Thank you.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Yes. So the DTX-301 program, which is a gene therapy for ornithine transcarbamylase, or OTC, is the Phase 3 is continuing, and we expect to roll out data from the ammonia endpoint sometime this year.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx5: Great. Thank you so much.

Conference Operator: The next question comes from the line of Kristen Kluska with Cantor Fitzgerald. You may proceed with your question.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx1: Hi, this is Rick Miller on for Kristen. Thanks for taking our questions. For the IRL received for UX111, would you characterize the issues raised there as expected? Is there any insight you can give us there? And then looking more broadly at the gene therapy pipeline, how should we be thinking about how the strategic restructuring impacts your priorities there, if at all?

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Yeah. So on the IRL, the list of issues on the CRL are known to both parties, to FDA and us. Obviously, we had the same list, but the question is, what do you put in the package? And we, we put in was answers to how we’re handling each thing, SOP changes, CAPA agreements, things that we’re doing, we put them all in there so they understood all of it. They actually want all the supportive documentation, like the SOPs and the follow-ups on effectiveness, et cetera, which we normally wouldn’t think to be part of a BLA, but the FDA has requested that we provide these. We believe we have the answers to what they’ve requested.

I think these are important issues, certainly, and we have addressed them before, but we’ll provide them the full documentation, which is a substantial amount, but we’ll provide full documentation as promptly as we can in a resubmission for the BLA. With regard to the restructuring and gene therapy pipeline, we obviously have a big footprint in gene therapy with 2 gene therapies right at the BLA stage, at this point. We have a third gene therapy, OTC, that’s in phase 3, and a fourth for Wilson disease that’s in phase 2 currently. We have another IND stage program for CDKL5 that is on the sidelines. With the restructuring, we were hoping to be able to move forward one more gene therapy into the clinic, but right now, the main purpose is to get what we have in play, their late stage, out and approved.

That opened the door to us then doing more. We don’t plan on decreasing our future in gene therapy, but we don’t plan on our future being only in gene therapy. So while we have another gene therapy program, we also have two other INDs, for example, that are teed up. They’re not gene therapy because we do want to be a diversified company and don’t want to be all in one place. So the restriction will actually enable us to put more of our early stage programs into play as we finish up our phase 3 programs. We’ll continue some work in gene therapy, but it won’t be the exclusive place for our pipeline going forward.

Conference Operator: The next question comes from the line of Allison Bretzel with Piper Sandler. You may proceed with your question.

Allison Bretzel, Analyst, Piper Sandler: Hey, thanks for taking my question. Maybe just a quick one. Going back to setrusumab, I think you’d previously discussed a hypothesis that ORBIT missed because treated patients felt better, became more active, and thus more likely to fracture. As you dig into the data, I guess, are you seeing a clear correlation between increased physical activity levels and fracture rates in the treated arm that could support that narrative? Or is there any way to validate that hypothesis? Any more insights on that would be appreciated.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Well, as we said, we are continuing to evaluate the data deeply. What we presented before showed that the treated setrusumab arm in ORBIT had improved activity and function reported and decreased bone pain. So they clearly did feel better and were doing more. Establishing how that directly results in refractures is something we’re looking at. We don’t have any information to provide. We’re continuing to do the evaluation and at this point in time, but certainly the data suggests that patients were reporting they had better physical function and less bone pain, so it’s consistent with that. But we continue to evaluate data on the program, and we’ll provide more information when a definitive answer for the program is determined.

Conference Operator: The next question comes from the line of Sabine Richter with Goldman Sachs. You may proceed with your question.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx7: Hi, this is Lydia on for Sabine. Thanks so much for taking our questions. Maybe just another on Angelman, following up to a question before. Given you are using a different endpoint than Ionis, I guess what is the regulatory bar and how confident are you that that’s kind of established going into it? Thank you.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Well, I realize there’s many people making a point about the differences. I actually think both programs have a lot of the same endpoints. In the end of the day, whatever is primary, whatever is secondary, you talk about the commercial, it’s going to look at everything. It’s not going to just decide the commercial future will be decided on what endpoint or not. The regulatory bar is defined by the pharmaceutical design here, which is basically a randomized sham-controlled trial that will have a continuous variable analysis of Bayley cognition. The FDA appreciates that we believe the magnitude of clinical benefit is around five or six points, but we don’t have that built into the primary endpoint. We are essentially looking for a continuous variable change. And what we know is we can see changes as single digit size changes.

We have some patients that get in the double-digit range for improvements. So there is a variation of range. We presented on this before of how they respond. Our expectation is we can demonstrate a statistically significant, clinically meaningful change in cognition, which is what we observed in the A and B cohorts and presented before, that that will be sufficient to be able to get approved. Now, with, in addition to that, we believe, though, that other endpoints will be successful, and the Multidomain Responder Index is our way to take a broader view of the disease and capture more of the benefit. For the FDA, it’s a new type of endpoint analysis. However, they’ve allowed us to put it in there and include an alpha allocation.

We do think it’s a way forward for neurology with heterogeneous diseases, and that bar is something we’re setting for each endpoint based on what the clinical meaningful change is or what are the minimum change for what’s considered a, an important change for a disease. Those things we have discussions on with the agency are setting those and understanding with them, will provide validation data that come from the Phase Three to help substantiate the regulatory bar of a responder for the MDRI. So the combination of both those things, the key variable analysis, Bayley cognition, and then the minimally important difference-driven changes in the MDRI, will put forth what we think is clinically important and regulatory sufficient data to achieve a filing for this disease, assuming the trial is successful.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx7: Thanks so much.

Conference Operator: Our next question comes from the line of Yaron Werber with TD Cowen. You may proceed.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx3: This is Steven Einhorn on for Yaron. Thanks a lot for the update and the guidance. A couple questions here. We’ve got the opportunity for two PRVs coming in 2026. Any sense of how soon you’ll be able to monetize, assuming kind of all goes well, and are you planning to engage potential buyers beforehand? Maybe an update on the timeline. And then separately on the UX701 program, I think you’d previously mentioned a first half of this year update on the cohort with the highest dose as well as on the prior cohorts as well. Is that being pushed out to later, given the full year 2026 timeline, or are we misreading that? Thanks.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Right. On the two PRVs, well, first step is you have to get both products approved, so you get the PRV issued. I don’t know if, Howard, you want to comment on our timeline for dealing with PRVs and sale?

Howard Horn, Chief Financial Officer, Ultragenyx: Yeah, I think I’d say, we would monetize them promptly, and, you know, whether we would pre-monetize them with an option agreement or we’d monetize them the normal way after they were in our hands, remains to be seen.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: ...Right. So on the, on the Wilson program, the timeline for our data is highly dependent on how, how the patients are progressing. We believe that we needed at least 6 months of time, and what we showed before is like 6-8 months of time, in our, in our first cohorts to show the effect on copper sufficiently. So we’re just providing, less precision on the timeline there to give ourselves an opportunity to continue to see what goes on with those patients. But it’s not meant to be an important change. It’s just being less specific as we want to watch how these patients do at the higher dose that we’re provided. We also want to make sure they have enough time to have their standard of care withdrawn, if they achieve the proper copper context.

It’s just being a little less precise, but not a fundamental change.

Conference Operator: Thank you very much. Our next question comes from Tara Ahmad with Bank of America. You may proceed with your question.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx4: Okay. I think that might be me. Hi, guys. I wanted to ask a couple of questions. First, can you just clarify, and I’m sorry if I missed this earlier, but with an IRL, when you, when you resubmit, can you just define what timelines are possible on, on review to final decision from the time that you now resubmit the responses that the agency is looking for? And then, a question on 401 for GSDIa. Do you have any updated thoughts on what pricing could look like there? And do you have a sense on what kind of potential launch trajectory to expect? Would it be kind of slow and steady, or could it be steep from the outset? Thanks.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Great. So, on the IRL timeline, what we just submitted was a resubmitted BLA to address the CRL we received. So what’s happening here is that we have to resubmit that resubmission, essentially. So the timeline is similar to what we had before. We would resubmit with the additional information now built into the BLA, and we’d expect a couple of weeks for them to determine if this has all the pieces of documents in it that they want. At that point, then a PDUFA date would get set approximately six months after the original submission. So the question, how long it takes to get there, we haven’t determined yet how long it takes us to get the documents together and put it in, but we’re working diligently on putting that together.

Now, your other question with regard to GSDIa launch, is that correct? And-

Conference Operator: Yes, that’s right.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx4: Yeah, that’s right.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Yeah. GSDIa is a very urgent disease in the sense that patients are drinking starch every two hours, all day long and all at night, right? So there’s a lot of urgency. We’d expect there to be a lot of interest early on, but I would say that that market is probably going to develop a little, in a little more steady fashion than, for example, IIIA, MPS IIIA, where the patients have an urgent, absolutely must get treated immediately to try to stave off loss of brain. Right? So MPS IIIA will happen probably more urgently at GSDIa, but we do expect there to be a strong, steady demand, but I wouldn’t expect to be like all at once at the beginning.

Now, with GSDIa, we haven’t set pricing at all, but we have talked about a $1 million-$2 million range of pricing, whereas with MPS IIIA, we’ve talked about a $2 million-$4 million range.

Conference Operator: Our next question comes from the line of Maxwell Skor with Morgan Stanley. Please proceed.

Maxwell Skor, Analyst, Morgan Stanley: Great. Thank you for taking my question. So, regarding the ASPIRE study, can you just describe what site training looks like for uniform conduct of Bayley-IV? And are there any practical considerations or added complexity when administering the assessment in, let’s say, older pediatric patients versus younger ones? Thank you.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Thank you. Well, very detailed technical question, but important one, because conduct of the Bayley is very important. First off, as a company, we’ve always put more emphasis on endpoint design, valuation, training than most any company. We have an entire department that does this activity that you’re talking about, which is our Endpoint Development Strategy group, or EDS group. That group is run by a senior PhD and has a group of PhDs who are basically experts in trial design, endpoint design, and as well as training and evaluation. So we developed a comprehensive training for all the sites. In addition to that, for the Bayley cognition, Bayley scores, specifically, as many sites as we could, we have installed a centralized company to provide the Bayley scoring with experts who are knowledgeable about Angelman and how to conduct a Bayley in an Angelman patient.

And we’re providing those testers where as many sites as we possibly can to help assure the quality and consistency of the evaluation of the Bayley. We think that will add a substantial amount of consistency to what we’re doing in addition to our own training program. But you’re right, this is a very important area, and we’ve done a lot to do that. And I would say I don’t think there’s any other company that has a department of people that actually do this very activity. So I want to thank Dr. Schreiner, who runs our group, for all the work she’s done in putting this together on our Angelman program. It took her and her team a lot of work to get it done.

Maxwell Skor, Analyst, Morgan Stanley: Great. Thank you.

Conference Operator: Our next question comes from Yigal Nochomovitz with Citi. You may proceed with your question.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx6: Yeah. Hi, thanks. I just had a follow-up on OTC. You know, can you just describe a little bit more about that study? It’s not one that you speak about much. You know, is it sort of in lower prominence in your expectation set around success or not? And what would you need to see for the study to hit? And then with regard to the IRL, Emil, you mentioned that some of these requests were would have otherwise occurred during an inspection. So does that mean that the inspection would be limited or not occur or be different? Thank you.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Yeah. So the OTC program with phase 3, we’ve, you know, we try to prioritize what we discuss just all the time, and we have so many different programs. It’s definitely a burden for everyone to put everything on everything that’s going on. But it’s there, and it’s continuing. And I think OTC is a real important disease, has a really serious need for better treatments. What we have, the phase 3 trial, which enrolled around 37, I believe, the randomized controlled trial, and the data we’d be looking at was on the change in ammonia between the treated and control groups. That ammonia member in the trial, people have a variable ammonia. Some are normal at the beginning, some are high. We’re looking at do we control ammonia better, as the primary endpoint for the blinded portion of the study.

Then the second portion of the study, we’ll look at whether patients can get off standard of care or not, or how well they get off standard of care. It is an important program, but it’s not our top priority program, so we are pursuing it. We’ll get the data. It gives us another opportunity for us as a company, another value available asset going forward, and we’ll read out data this year on it. With regard to the IRL, I, I have no doubt the FDA will come and inspect as well as they should. I think providing the documentation is to provide them greater confidence up front that we have actually done everything they want. We’ve described the answers and what we’ve done, but they actually want to see the materials of the things we’ve done, right?

Not just describe changes in SOPs, but actually show me the SOPs, et cetera, and all the parts that go along with that. They were requests that are important in developing a quality manufacturing program. We have done the work, so now we’ll provide them a more comprehensive, complete set of supporting documentation, which is a very large volume of information, by the way, and a lot of documents. But, we’ll provide it to them upfront so they can see that we have done everything they’ve asked.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx6: Thank you.

Conference Operator: Our next question comes from Luca Issi with RBC Capital. Please proceed with your question.

Luca Issi, Analyst, RBC Capital: Oh, great. Yeah, thanks so much for taking my question. Maybe, Emil, kind of going back to the FDA, maybe a little bit bigger picture. I guess, what was your reaction to the ReGenxBio CRL the other day? You know, sounds like the FDA has some reservations around using serum biomarker compared to natural history for ultra-rare disease. Is that just a one-off related to their program specifically, or is the conclusion at this point that this FDA has essentially raised the bar for all the companies developing drugs for rare ultra-rare diseases? Again, any thoughts there, much appreciated. And then maybe, Howard, a quick one. When you guide $730 million-$760 million top line for 2026, what is the simple kind of back-of-the-envelope math or what proportion of that is cash versus non-cash? Thanks so much.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Very good. Thank you. So with regard to the ReGenxBio decision, look, we put in our script today that heparan sulfate data presented at the Reagan-Udall meeting are definitive in demonstrating a relationship, and that how you measure spinal fluid heparan sulfate can be done by multiple different methods that give very similar patterns of response and are, I believe, equally predictive. The FDA’s ruling there would appear to show more pushback toward the biomarker. We received also, in our review, more emphasis on our clinical endpoints than the biomarkers. But we believe that the biomarkers are disease cause measurements and are an accurate way of measuring disease and efficacy, and we continue to support them with the FDA and publicly. Are the FDA pushing back? They appear to be more resistant to the biomarkers than had been agreed upon at the Reagan-Udall meeting.

They have said publicly, though, that they are supportive of accelerated approval and rare disease products, and it would be important to see that those statements turned into action for all the patients that deserve these treatments for diseases like Hunter, that ReGenxBio works on, as well as Sanfilippo and other neurologic diseases that are waiting for their first-ever treatment. The biomarkers are extremely important way to really tell what you’re doing and how effectively. So while there may be pushback and the bar may be raised there, we do need to make sure that the FDA hears what the needs of patients are and can appreciate the science behind the biomarkers we have chosen and why they are meaningful ways to measure disease and predict appropriate clinical outcomes.

Conference Operator: Our next question comes from Sammy Corwin with William Blair. You may proceed with your question.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx2: Hi, thanks for taking my question. I guess I was curious what you’re modeling for the potential sale of the priority review vouchers internally, and if the recent renewal of the rare pediatric disease, PRV legislation changed those assumptions at all. And then just how much a change in price could impact your path to profitability in 2027? Thanks.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Okay. So you got that PRV and path to profitability. Howard, you know, we just didn’t answer that other question I just noticed on the-

Howard Horn, Chief Financial Officer, Ultragenyx: Yeah. We’ll follow up. We’ll follow up with Luca offline on that one.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx: Okay.

Howard Horn, Chief Financial Officer, Ultragenyx: But as it relates to PRVs, we were not modeling what had recently been seen, meaning not modeling the $200 million range. We were modeling something a little bit north of $100 million. We were very excited to see that the legislation was reapproved. I think that gives us an opportunity to not only get the two PRVs that we’ve mentioned for the gene therapies, but for 102 and for other programs in the future. And right now, we continue to have that just north of $100 million as our base modeling assumption. So anything that would exceed that would add to our balance sheet.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx2: Got it. Thank you.

Conference Operator: This now concludes our question-and-answer session. I would like to turn the floor back over to Joshua Higa for closing comments.

Emil Kakkis, Chief Executive Officer and President, Ultragenyx6: 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.