Ultragenyx Pharmaceutical Inc (RARE) 2025 Q4 法說會逐字稿

Good afternoon, and welcome to the Ultragenyx fourth quarter and full year 2025 financial results conference call. (Operator Instructions)

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 two 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 of 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 continue to demonstrate sustained and significant further separation of early treated patients in multiple neurologic end points 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 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 human and animal models were thoroughly discussed substantiate and ratified by highly trained and qualified academic clinician and industry leaders that are the internationally recognized expert 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 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 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'll 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 three additional treatments over the next two 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 construction 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.

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 three 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 ultrarare 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 and 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 onetime 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 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 US remained 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 request 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 start forms in the US

for the third straight year. In EMEA, we have seen continuous NPS 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 UK 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 US 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 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.

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 IRR 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 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 support of 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 prepared 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 three 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.

(Operator Instruction)

Joon Lee, Truist.

The primary end point for your Phase III Angelman study is Bayley-4 cognition, while that of Ionis is the expressive communications domain. Was your decision to use cognition over 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 III have opted to roll over into the long-term extension portion of the study?

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. We think the Bayley cognition is a core, an important function of these patients.

And we are demonstrating substantial rise in that function. Expressive 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 this development. Now our own trial though will not only depend on Bayley cognition, we also have allocated some of the power of the study to the multi-domain responder index, which will give us a combination of cognition, receptive communication, sleep, behavior and motor function, which will give a broader assessment, which is very important to parents as well. So we think the combination of what we have will provide the important insight in how their patients are doing that will be important in both the patients and doctors and will include all information, including things on expressive communication.

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?

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.

Maury Raycroft, 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 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?

Yeah. Well, if you remember, Maury, in our Phase III trial, we did an expansion trial. That trial was intended to look at 8 countries where we're going to run the Phase III. So the point of that was 50 extra patients and potentially evaluate Phase III patients type patients from all the different countries. The baseline data that we saw and presented on cohorts A and B, which is the ex-US, is pretty reflective of what we're seeing in our Phase III program.

So we're comfortable with that. That what we're seeing in Phase III 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 US With regard to the cognition and control, there's the natural history in randomized control phase is only 1 point or less 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 quality and of the assessments, so they're done in a very consistent way. So we feel pretty comfortable with the amount of change we'll see in the control group. It's small. We don't think there was a placebo effect.

But of course, there's always variation, this is neurology. And we have a study we think of an appropriate size to help manage variation. But what we also have done is built in the multi-domain responder index, which gives us another opportunity to look at these patients in a broader way with more power.

Got it. That's helpful. Thanks for taking my questions.

Anupam Rama, 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. And 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.

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

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, 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 '25. And in '27 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 2 PRVs as part of our plan to get to profitability.

Maybe I'll also note that while we're in launch mode, some of the dynamics of the P&L 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.

And I think it's important that part of the expense in '26 are building that inventory that's launched. And so what's really happening, some of the expenses you're talking about now are actually 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 two approvals. We do have the PRVs and our 2 PRVs and 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 a good position to keep 2027 profitable.

Joseph Schwartz, 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? 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.

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 nonhuman primates. Now 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. So our experiments in nonhuman primate have shown that we are knocking down the antisense transcript substantially across the brain and or inducing UBE3A expression. And we do it at levels of around 1 to 2-milligram dosing over a few doses.

So a relatively low dose that 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 end points. And that 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. And 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. So we're achieving daily cognition comparable in substantially different doses.

So that substantiates what we found in nonhuman primates before that what we predicted was true and that our effect we're seeing in on 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.

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

Kristen Kluska, Cantor Fitzgerald.

This is Rick Miller on for Kristen. For the IRL received for 111, 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 are known to both parts to FD and us, obviously, we had the same list. But the question is, what do you put in the package? And we put in with answer to how we're handling each thing, SOP changes, cap agreements, things that we're doing, 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 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. 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 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 that open the door to us and 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 2 other INDs, for example, they're teed up there, not gene therapy.

Because we do want to be a diversified company and don't want to be all in one place. So 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 an exclusive place for our pipeline going forward.

Allison Bratzel, Piper Sandler

Hey, thanks for taking my question. 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, 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.

Well, as we said, we are continuing to evalute the data deeply. What we presented before showed that the treated setrusumab arm in orbit had improved activity in function reported and decreased bone pain, so they clearly did feel better and we're 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, data suggests that patients were reporting they had better physical functional 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 for the program is determined.

Salveen Richter, 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, I guess what is the regulatory bar and how confident are you that's kind of established going into that ?

Well, I realize as many people making a point about the differences, I actually think both programs have a lot of the same end points. 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 continued 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. And what we know is we can see changes single-digit size changes. We had some patients that get in the double-digit range for improvements. So there is a variation arrange .

We presented on this before of whoever 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 in addition to that, we believe, though, 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 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 changes, what are the minimum change for what's considered an important change for disease. Those things we have discussions on with the agency are setting those in understanding with them will provide validation data that comes from the Phase III to help substantiate the regulatory bar of a responder for the MDRI. So the combination of both of those things, the continuous variable analysis of Bayley cognition and then the minimally important difference driven changes in the MDRI will put forth what we think is clinically important in regulatory sufficient data to achieve a filing for this disease, assuming the trial is successful.

Yaron Werber, TD Cowen.

Hi this is Steven lonov on Yaron. Thanks a lot for the update and the guidance. 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 kind of all goes well? And are you planning to engage potential buyers beforehand, maybe an update on time line?

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 as well. Is that being pushed out to later given the full year '26 time line? Or are we misreading that?

Right. On the 2 PRVs, well, first step is you have to get both products approved so you get the PRV issued. I don't know if Howard, do you want to comment on our timeline for dealing with PRVs and sale?

Yes. I think I'd say we would monetize them promptly. And 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.

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. And what we showed before is like 6 to 8 months of time in their first cohorts to show the effect on copper efficiently. So we're just providing less precision on the timeline there to give ourselves the 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 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. So it's ust being a little less precise but not a fundamental change.

Thank you very much.

Tazeen Ahmad, 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 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, so what we just submitted was a resubmitted BLA to the complete response letter that 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 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 in it that they want at that point, then a PDUFA date would get set approximately 6 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 and putting that together.

Now the other question with regard to GSDIa launch, is that correct?

Yeah and pricing.

Yeah. GSDIa is a very urgent disease in the sense that patients are drinking starch every few hours all day long, all at night, right? So there's a lot of urgency. We expect there to be a lot of interest early on. But I would say that, that market is probably going to develop in a little more 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, right?

So MPS IIIA will happen probably more urgently than GSDIa. But we do expect there'll 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 to $2 million range of pricing, whereas with MPS IIIA, we've talked about a $2 million to $4 million range.

Maxwell Skor, 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-4? 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. 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 valuation training than most any companies. 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 there's a group of 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 score specifically, as many sites as we could, we have installed a centralized company to provide the Bayley scoring with experts who are knowledge about Angelman and how to conduct the 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 have 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. Shreiner, who runs our group. All the work she've done in putting this together on our Angelman program, it took her and her team a lot of work to get it done.

Yigal Nochomovitz, 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 a 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 would have otherwise occurred during inspection. So does that mean that the inspection would be limited or not occur or be different?

Yeah. So the OTC program with Phase III, we try to prioritize what we discussed 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, and there's a really serious need for better treatments.

What we have, the Phase III 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 would have 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 a patient 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 valuable available asset going forward, and we'll read out data this year on it. With regard to the IRL, 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 upfront 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 and SOPs, but actually show me the SOPs, et cetera, and all the parts of 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.

Luca Issi, RBC Capital.

Great 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? It sounds like the FDA has some reservations around using serum biomarker compared to natural history for ultrarare 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 diseases?

Again, any thoughts there, much appreciated. And 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 noncash?

Very good. 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 end points 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 its IRL approval in 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 worked on as well as Sanfilippo and other neurologic diseases that are waiting for their first ever treatment. The biomarker is an 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 cares what the needs of patients are and can appreciate the science behind biomarkers we have chosen and why there are meaningful ways to measure disease and predict appropriate clinical outcomes.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 PDS disease PVR legislation change those assumptions at all? And then just how much a change in price could impact your path to profitability in 2027?

Sammy Corwin, William Blair.

Hi, thanks for taking my question. I guess I was curious in curious what you're modeling for the potential sale of the priority review vouchers internally and if the recent renewal of the rare PDF disease PVR legislation changed those assumptions at all, and then just how much a change in price could impact your path to profitability in 2027. Thanks.

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

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 that the legislation was reapproved. I think that gives us an opportunity to not only get the 2 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 is 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.