Ultragenyx Pharmaceutical Inc.

Good afternoon, and welcome to the Ultragenyx 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.

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 Kakas, Chief Executive Officer and President, Howard Horn, Chief Financial Officer, Eric Harris, Chief Commercial Officer, and Eric Cromdes, 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 MPS3A or Sanfilippo type A syndrome and glycogen storage disease type 1A, and a pivotal data readout in Angerman 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 MPS3A 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 MPS3A 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 eight 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 the multiple relevant direct measures of disease activity, including CSFHS. We resubmitted the UX111 BLA to FDA late last month, and earlier today 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'll 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 relations 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, Amal, 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 UX 111, 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. CRISFIDA contributed $481 million, including $275 million from North America, $177 million from Latin America and Turkey, and $29 million from Europe. In total for CRISFIDA, this represents 17% growth over 2024 and also exceeded the upper end of our guidance range. DiGioia contributed $96 million, which represents 9% growth over 2024. Evkiza contributed $59 million, representing 84% growth over 2024, as demand continues to build following launches in our territories outside of the United States. Lastly, Mepsevi 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 and equivalents, and marketable securities. Shifting now to guidance, I'll start with revenue. Total revenue in 2026 is expected to be between $730 and $760 million, which represents 8% to 13% growth over 2025, and excludes potential revenue from new product launches. CRISVIDA revenue is expected to be between 500 and 520 million, which includes all regions and all forms of CRISVIDA 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. The Jolvi revenue is expected to be between 100 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 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 three 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, Eric 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 Amos' 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. CRISPIDA remains an important part of our base business. Our partnership with KiawaKeren in the US remains strong, and we continue to find and treat commercial patients across Latin America and Turkey. In Latin America, the CRISPIDA 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 CRISPR 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 De Jovi. Five 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 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 UK in April 2025. In Japan, last year we announced that Jovi 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 FKISA, 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 nearly all major markets, with approximately 350 patients across 20 countries who are receiving FKESA today. In December, we achieved a significant milestone with the registration of EFKISA in the Kingdom of Saudi Arabia, reinforcing our commitment to bringing life-changing therapies to patients globally. We also commercialized EFKISA 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 FKESA 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. Krombes to share the clinical and regulatory milestones for the coming year.

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 DTX401 for the treatment of glycogen storage disease type 1A. 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 San Felipe 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 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, GTX102 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 three 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 two BLA submissions, and prepare to read out phase three data from the ancient 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 on to your questions. Operator, please provide the Q&A instructions.

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 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 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.

Hi. Thanks for taking our questions. The primary endpoint for your phase three Angelman study is Bayley-4 cognition, while that of Ionis is the expressive communications of 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 three have opted to roll over into the long-term extension portion of the study? Thank you.

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 and 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 its development. Now, our own trial, though, will not only depend on Baylor cognition. We also have allocated some of the power of the study to the Mentally Domain Responder Index, which will give us a combination of cognition, receptive communication, sleep, behavior, and motor function, which will give a broader assessment. It's 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 both to patients and doctors, and will include all information, including things on expressive communication. 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.

Yeah, similar to what we saw in Phase I, 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, 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.

Thank you.

The next question comes from the line of Maury Raycroft with Jefferies. You may proceed with your question.

Hi. Thanks for taking my question. I'll also ask one on Angelman. I'm 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. Well, if you remember, Maury, in our Phase II trial, we did an expansion trial. That trial was intended to look at eight countries where we're going to run the phase three. So the point of that was 50 extra patients. It essentially evaluates phase three patients, type patients from all the different countries. The baseline data that we saw and presented on cohorts A and B, which are the XUS, is pretty reflective of what we're seeing in our phase three program. So we're comfortable with that, that what we're seeing in phase three 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 based on natural history and randomized control studies, there's only one 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 angioma in our study. That helps assure a quality of the assessment so that they're done in a very consistent way. So we feel pretty comfortable with the amount of change we'll see in the TRO group. It's small. We don't think there'll be as much 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-main 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.

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

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?

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, reiterate some of the clarity of how we're making that move toward profitability.

Yeah, happy to. I'll go through it now. Also, I'll note 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 in 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 two PRVs as part of our plan to get to profitability. Maybe I'll also note that, you know, 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 expenses 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 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 a good position to keep 2027 profitable.

The next question comes from the line of Joseph Schwartz with Lear Inc. Partners. Please proceed.

Hey, guys. This is for Joseph Schwartz. Thanks for taking our question. I have one on Angelman and then a quick follow-up. So, for GTX102, 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 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.

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 conduct an experiment in the non-union primate, for example, that ionists can't conduct because they do not have homology in non-union primate. So our experiments in non-union primate have shown that we are knocking down the antisense transcript substantially across the brain and are inducing EB3 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 10 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, and that Iona showed a similar effect on Bayley cognition in a six-month timeframe, though they didn't show our higher level benefit over time. And that is happening in doses in our study that are in the 5 to 14 range while they're 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 non-E primates before, that what we predicted was true, and that our effect with seeing non-primates translates to humans with a potent effect at a lower dose level.

Great. Thanks so much. 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. Thank you.

Yes. The DTX301 program, which is a gene therapy for ornithine transcript amylase, or OTC, the phase three is continuing. And we expect to roll out data from the MONI endpoint sometime this year. Great. Thank you so much.

The next question comes from the line of Kristen Kleska with Cantor Fitzgerald. You may proceed with your question.

Hi. This is Rick Miller on for Kristen. Thanks for taking our questions. 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?

Yeah, so on the IRL, the list of issues on the CRL are known to both parts, to the FDA and us. Obviously, we have the same list, but the question is, what do you put in the package? And we put in with 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 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 two gene therapies right at the BLA stage at this point. We have a third gene therapy, OTC, that's in phase three, and a fourth for Wilson disease that's in phase two currently. We have another IND stage program with CDKL5 that is on the sidelines. With the restriction, 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 in 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 that are 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 three program. We'll continue some work in gene therapy, but it won't be the exclusive place for our pipeline going forward. Thank you.

The next question comes from the line of Allison Bratzel with Piper Sandler. You may proceed with your question.

Hey, thanks for taking my question. Maybe just a quick one going back to cetruzumab. 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? Is there any way to validate that hypothesis? Any more insights on that would be appreciated.

Well, as we said, we are continuing to validate the data deeply. What we presented before showed that the treated subcutaneous arm in Orbert 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 continue to do the evaluation 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. We continue to evaluate data on the program, and we'll provide more information when a definitive answer for the program is determined.

The next question comes from the line of Salveen Richter with Goldman Sachs. You may proceed with your question.

Hi, this is Lydia. I'm for Salveen. 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 I own it, I guess what is the regulatory bar and how confident are you that that's kind of established going into it?

Thank you. 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. At 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 to 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, in addition to that, we believe, though, that other endpoints will be successful, and the Multi-Mean 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 an important change for a disease. Those things we have discussions on with the agency. Our sentinels, 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 those things, the continuous 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.

Thanks so much.

Our next question comes from the line of Yaron Werber with TD Cowan. You may proceed.

Hi, this is Steven Ionov 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 timeline and then separately on the UX 701 program I think you'd previously mentioned a first half 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 timeline or are we misreading that thanks

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.

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.

Right. So on the On the Wilson program, the timeline for data is highly dependent on how the patients are progressing. We believe that we needed at least six months of time. And what we showed before is like 68 months of time in our first cohorts to show the effect on copper sufficiently. So we're just providing less precision on the timeline. 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. So it's just being a little less precise but not a fundamental change.

Thank you very much.

Our next question comes from Tara Ahmad with Bank of America. You may proceed with your question.

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 resubmit, can you just define what timelines are possible 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 GSD 1A. Do you have any updated thoughts on what pricing could look like there? And do you have a sense on what kind of potential loans trajectory to expect? Would it be kind of slow and steady or could it be steep from the outset? Thanks.

Great. So, on the IRL timeline. What we just submitted was a resubmitted BLA to the complete response letter 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 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, the other question with regard to GSD1A launch, is that correct?

Yes, that's right.

GSD1A 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'd 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, 3A, MPS3A, where the patients have an urgent, absolutely must get treated immediately to try to stave off loss of brain, right? So MPS3A will happen probably more urgently at GSD1A. 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 GST 1A, we haven't set pricing at all, but we have talked about a $1 million to $2 million range of pricing, whereas with MPS 3A, we've talked about a $2 million to $4 million range.

Our next question comes from the line of Maxwell Score with Morgan Stanley. Please proceed.

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.

Thank you. Well, 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 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 program 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 engagement and how to conduct the Bayley in an engagement 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. Skreiner, who runs our group, for all the work she's done in putting this together on our ANGEN program. And it took her and her team a lot of work to get it done.

Great. Thank you. Our next question comes from Yigal Nokomovitz with Citi. You may proceed with your question.

Yeah, hi, thanks. I just had a follow-up on OTC. You know, could 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 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.

Yeah, so the OTC program with phase three, we try to prioritize what we discuss 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 has a really serious impact. need for better treatments. What we have, the phase three trial, which enrolled around 37, I believe, the randomized control trial, and the data we'd be looking at was on the change in ammonia between the treated and control groups. That ammonia, remember, in the trial, people 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. In the second portion of the study, we'll look at whether a patient can get off-standard care or not or how well they get off-standard 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 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 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 up front so they can see that we have done everything they've asked.

Thank you. Our next question comes from Luca Issy with RBC Capital. Please proceed with your question.

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 Regenexx Bio CRL the other day? You know, it sounds like the FDA has some reservations around using serum biomarker compared to natural history for ulterior disease. Is that just a one-off related to their program specifically? is the conclusion at this point that this FDA has essentially raised the bar for all the companies developing drugs for rare or ultra rare diseases. Again, any thoughts there, much appreciated. And then maybe Howard, a quick one. When you guide $730 to $760 million top line for 2036, what is the simple kind of back of the envelope math for what proportion of that is cash versus non-cash? Thanks so much.

Very good. Thank you. So, with regard to the reject-bio decision, look, we put in our script today that heparin sulfate data presented at the Reagan-Yield meeting are definitive in demonstrating a relationship, and that how you measure spinal fluid heparin sulfate can be done by multiple different methods that give very similar patterns of response and are, I believe, equally predictive. The FDA is ruling they're would appear to show more pushback toward the biomarker. We received also, in our review, more emphasis on our clinical endpoints than the biomarkers. We believe that the biomarkers are disease-caused 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 Rejects works on, as well as Sanfilippo and other neuronal-like diseases that are waiting for their first-ever treatments. 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 hears what the needs of patients are and can appreciate the science behind the biomarkers we have chosen and why there are meaningful ways to measure disease and predict appropriate clinical outcomes.

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

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 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 of profitability, Howard. You know, we just didn't answer that other question. I just noticed on the patch.

Yeah, we'll follow up with Luca offline on that one. Okay. 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. 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.

Thank you.

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.ultragenics.com. Thank you for joining.