Ultragenyx Pharmaceutical Inc. Q4 FY2025 Earnings Call

Good afternoon, and welcome to the Ultragenyx Fourth Quarter and Full Year 2025 Financial Results Conference Call. It is now my pleasure to turn the call to 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; Howard Horn, Chief Financial Officer; Erik 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.

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 2 potential approvals in MPS IIIA or Sanfilippo Type A syndrome and Glycogen Storage Disease Type Ia and the 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 WORLDSymposium from the UX111 for MPS IIIA program. The new data reflects an additional year of follow-up and continues 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 in other disease cause biomarkers that show 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 human and animal models were thoroughly discussed, substantiated, and ratified by highly trained and qualified academic clinicians and industry leaders, who are 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. Overall, these data continue to support a clinically meaningful and durable clinical effect of UX111 regardless of age or stage disease, all supported by consistent improvement in multiple relevant direct measures of disease activity, including CSF HS. We resubmitted the UX111 BLA to the FDA late last month, and earlier today, we received a complete 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 the inspection, and we were prepared to do so, but we will not provide the 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 3 additional treatments over the next 2 years. Eric 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 the path to profitability in 2027 while still advancing a meaningful pipeline of new products.

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 head count 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 4 commercial products and investing in 3 successful launches for UX111, DTX401, 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% 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 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 nonrecurring restructuring costs and targeted launch investments in UX111 and DTX401. 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.

Thank you, Howard, and good afternoon, everyone. 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 4 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 contributions 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. 5 years post-launch, the product continues its steady growth with more than 100 start forms in the U.S. for the third straight year. In EMEA, we have seen continuous NPS growth across the region, while also achieving 2 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' 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 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 entered 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 2 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.

Thank you, Erik, 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 DTX401 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 WORLDSymposium that Emil mentioned earlier in the call. In response to the complete response letter we received earlier today, our manufacturing and regulatory teams are urgently working to provide the detailed support of documentation that 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 5 patients in the fourth dosing cohort last year, and we expect to share data from all 4 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 support of the Aurora study. We expect to share Aspire Phase III data in the second half of 2026. I'll now turn the call back to Emil to provide some closing remarks.

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 2 BLA submissions, and prepare to read out Phase III data from the Angelman study. At the same time, the commercial team will continue expanding the geographic reach of our 4 commercial products and prepare to launch 3 more programs. All of these efforts continue our mission of leading the future of rare diseases with first-ever treatments. With that, let's move on to your questions. Operator, please provide the Q&A instructions.

Our first question comes from Joon Lee with Truist.

The primary endpoint for your Phase III Angelman study is Bayley-4 cognition, while Ionis focuses on the expressive communications domain. Was your choice to prioritize cognition over expression based on a higher likelihood of success or because it's rated more highly on parents' priority lists? Also, can you disclose what percentage of the patients from Phase III have chosen to transition into the long-term extension segment of the study?

The Bayley cognition is a fundamental activity, and communication is closely tied to cognition. We consider the Bayley cognition a core and crucial function for these patients, and we're seeing a significant improvement in that area. While expressive communication is also important, it requires more time to develop and evolve. We believe that while we are assessing expressive communication in our program and will collect data on it, it didn't seem appropriate to use it as a primary endpoint due to its complexity and variability. Our trial will not solely focus on Bayley cognition; we have also dedicated part of the study's power to the multi-domain responder index. This index will encompass cognition, receptive communication, sleep, behavior, and motor function, providing a more comprehensive assessment that is very important to parents. We think this combination will offer valuable insights into how patients are progressing, which will be beneficial for both patients and doctors, while also including information about expressive communication. Regarding your second question about rollover, we have had very few dropouts in our program; virtually everyone has remained on treatment. Eric, do you have anything to add about the extension or rollover of patients?

Yes. Similar to what we saw in Phase I and II, the Phase III studies do have a very high retention rate, including patients electing to continue in a long-term extension study. I think parents really do understand this is the opportunity for their children to grow, develop, and gain and learn new skills, which isn't something you see by natural history.

The next question comes from the line of Maury Raycroft with Jefferies.

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 I/II 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?

Yes. In our Phase III trial, we conducted an expansion trial across eight countries to evaluate an additional 50 patients and gain insights into the diversity of Phase III patient types from these different nations. The baseline data we presented for cohorts A and B, which includes data outside the U.S., aligns well with findings from our Phase III program, and we are confident in this consistency. The observations we've made in Phase III are similar to those in the expansion program, which aimed to give us a broader context for the population across various countries, not just the U.S. Concerning cognition and control, we anticipate minimal cognitive change, specifically one point or less in the Bayley measure during the randomized control phase, which is a rigorous assessment that is resistant to placebo effects. We are carefully managing the oversight of this study and have enlisted a central firm to ensure that the assessments for patients with Angelman syndrome are conducted consistently and with high quality. While we expect a small amount of change in the control group and do not anticipate a placebo effect, we recognize that variation is inherent in neurology studies. We've designed the study with an appropriate sample size to address that variation and included a multi-domain responder index, which allows us to analyze the patients more comprehensively and with greater statistical power.

The next question comes from the line of Anupam Rama with JPMorgan.

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?

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 details 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. Howard, maybe you can provide a little more reiterate some of the clarity of how we're making that move in the pathway toward profitability.

Yes, I'm happy to go through it now. I want to point out that there are a couple of pages in our corporate deck that you can refer to later. Our pathway to profitability relies on a few factors. Emil noted that on the revenue side, we expect continued double-digit growth from our current products along with contributions from upcoming launches. Regarding expenses, I mentioned earlier that by 2026, we should anticipate combined R&D and SG&A costs to remain flat or decrease by low single digits compared to 2025. In 2027, we expect those combined costs to decline by 15% or more. As part of our cash plan, we have referenced the $735 million noted today, and we're also considering two PRVs as part of our strategy to achieve profitability. Additionally, while we are in launch mode, it's important to consider dynamics of the P&L, such as R&D trends that may decrease due to capitalization of manufacturing costs after approval. Gross margins are likely to increase because of prior expenses related to pre-approval inventory that will be sold during the launch. These are some dynamics to keep in mind as you work through your modeling. I think I'll stop there.

And I think it's important that part of the expense in '26 is building that inventory that's launched. What's really happening is some of the expenses you're talking about now are actually for building inventory that will be launched. So those combinations hopefully give you a magnitude of effect that will push us there. We do need to get 2 approvals and we do have the PRVs in our financial plan. However, we think with the cuts we put in place today and additional things we're working on will put us in a good position to remain profitable by 2027.

The next question comes from the line of Joseph Schwartz with Leerink Partners.

This is Will Soghikian on for Joseph Schwartz. 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 ATS knockdown or perhaps it's mRNA or protein increases preclinically? 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.

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. So to be clear, those estimates have to come from nonhuman primates. Because our ASO is identical to the nonhuman primate sequence, we conduct an experiment in the nonhuman primate, for example, that Ionis can't conduct because they do not have homology in nonhuman primate. Our experiments in nonhuman primate have shown that we are knocking down the antisense transcript substantially across the brain and are inducing UBE3A expression. We do it at levels of around 1 to 2 milligram dosing over a few doses, which would be in the range of, let's say, 10 to 14 milligrams translated into humans. We know now also that based on our ASF presentation last year that we showed an effect on Bayley cognition in other endpoints. Ionis showed a similar effect in Bayley cognition in a 6-month time frame, 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 to 14 range, while they are using 40 to 80 milligrams and Roche used even higher doses. We are achieving daily cognition comparable in substantially different doses. This substantiates what we found in nonhuman primates before our predictions were true and that the effect we're seeing in nonhuman primate translates to humans with a potent effect at a lower dose level.

Great. And then just one quick follow-up, if I may. I think the DTX301 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.

Yes. So the DTX301 program, which is a gene therapy for ornithine transcarbamylase deficiency, or OTC, is the Phase III continuing, and we expect to roll out data from the ammonia endpoint sometime this year.

The next question comes from the line of Kristen Kluska with Cantor Fitzgerald.

This is Rick Miller on for Kristen. 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?

Yes. So on the IRL, the list of issues on the IRL is known to both parties, the FDA and us. Obviously, we had the same list. The question is, what do you put in the package? We included in our answer how we're handling each issue, including SOP changes, CAPA agreements, and other actions, so they understood all of it. They actually want all the supportive documentation like the SOPs and follow-ups on effectiveness, which we normally wouldn't think would 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 properly as we can in a resubmission for the BLA. Regarding the restructuring and gene therapy pipeline, we obviously have a big footprint in gene therapy with 2 gene therapies at the BLA stage at this point. We have a third gene therapy OTC that's in Phase III and a fourth, the Wilson disease, that's in Phase II 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; they are late-stage out and approved, which will open the door to us 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. While we have another gene therapy program, we also have 2 other INDs, for example, that are not gene therapy. We want to be a diversified company and don't want to be all in one place. The restructuring will actually enable us to put more of our early-stage programs into play as we finish up our Phase III program. We'll continue some work in gene therapy, but it won't be the exclusive place for our pipeline going forward.

The next question comes from the line of Allison Bratzel with Piper Sandler.

Maybe just a quick one, going back to setrusumab. I think you previously discussed a hypothesis that Orbit missed. You guys treated patients, felt better, became more active, and that’s more likely to fracture. As you dig into the data, 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.

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 fractures is something we're looking at. We don't have any information to provide. We're continuing to do the evaluation. At this point in time, the data suggests that patients were reporting they had better physical function and less bone pain. So it's consistent with that. We continue to evaluate data on the program, and we'll provide more information with a definitive answer when the program is determined.

The next question comes from the line of Salveen Richter with Goldman Sachs.

This is Lizzy on for Salveen. Maybe just another on Angelman following up to the question before. Given you are using a different endpoint than Ionis, what is the regulatory bar and how confident are you that it’s established going into that?

Well, I realize many people are making a point about the differences. I actually think both programs have a lot of the same endpoints. Whatever is primary or secondary, the commercial future will be decided on everything. 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 daily cognition. The FDA appreciates that we believe the magnitude of clinical benefit is around 5 to 6 points, but we don't have that built into the primary endpoint. We're essentially looking for a continuous variable change. What we know is we can see changes of single-digit size. We had some patients that get in the double-digit range for improvements. So there is variation. 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 will be sufficient to be able to get approved. Additionally, we believe that other endpoints will be successful, and the multi-domain 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 include it, and we do think it provides a way forward for neurology with heterogeneous diseases. The combination of the continuous variable analysis of Bayley cognition and the minimally important difference driven changes in the MDRI will substantiate what we think is clinically important in regulatory sufficient data to achieve a filing for this disease, assuming the trial is successful.

Our next question comes from the line of Yaron Werber with TD Cowen.

This is Stephen on for Yaron. A couple of questions here. We've got the opportunity for 2 PRVs coming in 2026. Any sense of how soon you'll be able to monetize, assuming it 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 previously mentioned a first half of this year update on the cohort with the highest dose as well as on the prior cohorts. Is that being pushed out to later given the full year '26 timeline? Or are we misreading that?

On the two PRVs, the first step is to get both products approved in order to have the PRV issued. Howard, would you like to share your thoughts on our timeline for handling the PRVs and their sale?

Yes, I think I'd say we would monetize them promptly. Whether we would pre-monetize them with an option agreement or monetize them the normal way after they were in our hands remains to be seen.

Right. So on the Wilson program, the timeline for data is highly dependent on how the patients are progressing. We believe that we needed at least 6 months of time. What we showed before is 6 to 8 months for that first cohort to show the effect on copper efficiently. We're providing less precision on the timeline there to give ourselves the opportunity to continue to see how those patients do with the higher dose. It’s not meant to be key information. It’s just being less specific as we want to watch how these patients do with the higher dose that were 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. This is just being slightly less precise but not a fundamental change.

The next question comes from Tara Ahmad with Bank of America.

Okay, I think that might be. 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 resubmit, can you just define what timelines are possible on review and the 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 would you expect? Would it be kind of slow and steady? Or could it be steep from the outset?

Great. So on the IRL timeline, what we just submitted was a resubmitted BLA to the complete response letter that we received. What's happening here is that we have to resubmit that resubmission essentially. The timeline is similar to what we had before; we would resubmit with the additional information not built into the BLA, and we'd expect a couple of weeks for them to determine if this has all the pieces of documents they want at that point. Then a PDUFA date would get set approximately 6 months after the original submission. The question is how long it takes to get there; we haven't determined yet how long it takes us to compile the documents, but we're working diligently to put that together. Regarding the other question with GSDIa launch, patients are drinking starch every few hours all day long and all night; so there's a lot of urgency. We expect there to be a lot of interest early on. I would say that market is probably going to develop in a steady fashion than, for example, MPS IIIA, where the patients have an urgent, absolutely must get treated immediately to try to stave off loss of brain function. MPS IIIA will likely happen more urgently than GSDIa. We do expect there'll be strong steady demand, but I wouldn't expect it to be all at once at the beginning. For GSDIa, we haven't set pricing at all, but we have discussed a $1 million to $2 million range of pricing, whereas with MPS IIIA, we’ve discussed a $2 million to $4 million range.

Our next question comes from the line of Maxwell Skor with Morgan Stanley.

So regarding the Aspire study, can you just describe what site training looks like for uniform conduct of Bayley-4? And are there any practical considerations or added complexity when administering the assessment in, let's say, older pediatric patients versus younger ones?

Very detailed technical question but an important one, because conduct of the Bayley is very important. First off, as a company, we've always put more emphasis on endpoint design evaluation training than most any companies. We have an entire department that does this activity, which is our endpoint development strategy group or EDS group. That group is run by a senior PhD with experts in trial design, endpoint design, and training and evaluation. We developed comprehensive training for all sites. In addition to that, for the Bayley cognition, Bayley score specifically, as many sites as we could, we have installed central companies to provide the Bayley scoring with experts knowledgeable about Angelman and how to conduct the Bayley in an Angelman patient. We are providing those testers to as many sites as possible to help assure the quality and consistency of the evaluation of the Bayley. We think that will help provide consistency. 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. Shreiner who runs our group for all the work she has done to put this together for our Angelman program.

Our next question comes from Yigal Nochomovitz with Citi.

I just had a follow-up on OTC. Can you just describe a little bit more about that study? It's not one that you speak about much. Is it sort of lower prominence in your expectation set around success or not? What would you need to see for the study to hit? With regard to the IRL, Emil, you mentioned that some of these requests would have otherwise occurred during inspection. Does that mean that the inspection would be limited or not occur or be different?

Yes. The OTC program is Phase III; we try to prioritize what we discuss all the time, and we have so many different programs. However, it is ongoing and is an important disease. There’s a serious need for better treatments. The Phase III trial enrolled around 37; the randomized controlled trial data we'd be looking at is on the change in ammonia between the treated and control groups. We're looking to control ammonia better as the primary endpoint for the blinded portion of the study. The second portion of the study will look at whether a patient can get off standard of care or not. It is an important program, but it's not our top priority program. We'll get the data; it gives us another opportunity for us as a company, and we'll read out data this year on it. Regarding the IRL, I have no doubt the FDA will come and inspect as well as they should. Providing the documentation should provide them greater confidence upfront that we have actually done everything they wanted. We’ve described what we've done, but they actually want to see the materials rather than just describe changes and SOPs. They want to see the SOPs and all the parts that go along with that. They were requests that are important for developing a quality manufacturing program. We have done the work. Now we’ll provide them a more comprehensive set of supporting documentation, which is a large volume of information and documentation, but we'll provide it to them upfront so they can see that we have done everything they've asked.

The next question comes from Luca Issi with RBC Capital.

Great. Maybe, Emil, kind of going back to the FDA. What was your reaction to the REGENXBIO CRL the other day? It 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 has the FDA raised the bar for all the companies developing drugs for rare and ultra-rare diseases? Any thoughts there would be much appreciated. Then maybe, Howard, a quick one. When you guide $730 million to $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?

Very good. Regarding the REGENXBIO decision, we stated in our script today that the heparan sulfate data presented at the Reagan-Udall meeting are definitive in demonstrating a relationship. How you measure spinal fluid heparan sulfate can be done by multiple methods that provide similar patterns of response, and are equally predictive. The FDA's ruling there shows more pushback toward the biomarker. We received also in our review more emphasis on our clinical endpoints than the biomarkers. We believe the biomarkers are disease cause measurements and an accurate way of measuring both disease and efficacy, and we continue to support them with the FDA. The FDA appears to be more resistant to the biomarkers than had been agreed upon at the Reagan-Udall meeting. However, they have stated publicly that they are supportive of its approval in rare disease products. It’s important to see those statements turn into action for all the patients that deserve these treatments. Biomarkers are an important way to measure what you're doing and how effectively. There may be pushback, and the bar may be raised, but we need to ensure that the FDA considers the needs of patients and appreciates the science behind the biomarkers, and why they are meaningful ways to measure disease and predict appropriate clinical outcomes.

The next question comes from Sami Corwin with William Blair.

I guess I was curious what you're modeling for the potential sale of the priority review vouchers internally. If the recent renewal of the rare PDS disease PRV legislation changed those assumptions at all? And how much could a change in price impact your path to profitability in 2027?

Okay. So you got that PRV and path to profitability, Howard. We just didn't answer that other question. I just noticed that the pricing question.

We'll follow up and look you up offline on that one. 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 the legislation was reapproved. I think that gives us an opportunity to not only get the 2 PRVs, but for 102 and for other programs in the future. 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.

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

Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at ir@ultragenyx.com. Thank you for joining.