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DATE

Thursday, February 12, 2026 at 12 a.m. ET

CALL PARTICIPANTS

  • Chief Executive Officer — Emil D. Kakkis
  • Chief Financial Officer — Howard Horn
  • Chief Commercial Officer — Eric Harris
  • Chief Medical Officer — Eric Crombez

TAKEAWAYS

  • Total Revenue -- $673 million, reflecting 20% growth; exceeded upper end of prior guidance.
  • Crysvita Revenue -- $481 million, including $275 million from North America, $177 million from Latin America and Turkey, and $29 million from Europe; 17% growth; above guidance ceiling.
  • Dojolvi Revenue -- $96 million, up 9%.
  • Evkeeza Revenue -- $59 million, representing 84% growth; driven by demand in non-U.S. territories.
  • Mepsevii Revenue -- $37 million.
  • Geographic Reach -- Treated patients in more than 35 countries contributed to revenue in the period.
  • Headcount Reduction -- 10% workforce reduction, approximately 130 full-time employees affected as part of a strategic restructuring.
  • Operating Expenses -- Cost of sales were $109 million; combined R&D and SG&A expenses totaled $1.1 billion.
  • Net Loss -- $575 million, or $5.83 per share.
  • Cash Position -- $738 million in cash, cash equivalents, and marketable securities at period-end.
  • 2026 Revenue Guidance -- $730 million to $760 million, projecting 8%-13% growth; does not include potential new product launches.
  • 2026 Crysvita Guidance -- $500 million to $520 million; growth reflects demand but is partially offset by expected Brazil ordering timing.
  • 2026 Dojolvi Guidance -- $100 million to $110 million.
  • 2026 R&D and SG&A Expenses Guidance -- Expected to be flat to down low single digits versus prior year, including effects from restructuring, severance, and launch investments.
  • 2027 R&D Reduction Target -- 38% decline from 2025, or $280 million lower, due to completion of Phase 3 spend and reduced early-stage research.
  • 2027 Combined R&D and SG&A Guidance -- At least 15% reduction from 2025 levels expected.
  • Profitability Target -- Company intends to achieve profitability in 2027 as stated by management.
  • UX111 (MPS IIIA) Regulatory Update -- Biologics License Application (BLA) resubmitted; received an incomplete response letter from FDA requiring added supporting documentation on Chemistry, Manufacturing, and Controls (CMC) responses.
  • Strategic Restructuring Objectives -- Plan focuses resources on near-term value drivers, prioritizing pipeline and aligning spend.
  • Gene Therapy Pipeline Advancements -- Two BLAs at regulatory stage: UX111 for MPS IIIA and DTX401 for glycogen storage disease type 1a; additional pivotal data in Angelman syndrome (GTX-102) expected.
  • DTX401 BLA Submission -- Rolling BLA completed in December; PDUFA action date anticipated in third quarter.
  • Evkeeza Patient Uptake -- Over 350 patients across 20 EMEA countries on reimbursed therapy; registration achieved in Saudi Arabia and continued expansion in Japan.
  • Dojolvi Regulatory Milestones -- Received early marketing authorization in Kuwait (September); U.K. early access approval (April); conditional approval in Japan with launch expected in 2026.
  • Future Product Launch Plans -- Three additional launches targeted in next two years supported by commercial infrastructure.

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RISKS

  • The FDA issued an incomplete response letter for the UX111 BLA, requesting additional supporting documentation on CMC-related responses before resubmission will be accepted.
  • Management stated, "the FDA has requested that we provide these [supporting documents]", which may extend regulatory timelines for UX111.
  • Profitability projections for 2027 depend on achieving cost reductions and securing approvals and subsequent launches for at least two new products.
  • Revenue guidance for Crysvita is partially offset by "expected timing of ordering patterns in Brazil we anticipate will normalize in 2027."

SUMMARY

Ultragenyx Pharmaceutical (RARE +2.11%) reported 20% revenue growth to $673 million, with commercial performance surpassing guidance and broad international contribution. Management announced a strategic restructuring plan, including a 10% workforce reduction and focused resource allocation, to position the company for targeted profitability in 2027. Major regulatory milestones are anticipated in 2026, including a resubmission for the UX111 program following an FDA request for additional documentation and a third-quarter PDUFA date for DTX401. Near-term guidance calls for continued high single-digit to low double-digit revenue growth and disciplined expense control, excluding new launch upside. The company is preparing to commercialize three new treatments over two years while executing pivotal studies and global expansions across its rare disease portfolio.

  • Management clarified that the current profitability pathway includes two potential priority review vouchers, with internal PRV monetization modeled "just north of $100 million" per voucher.
  • For Angelman syndrome, the primary endpoint in the Phase 3 ASPIRE study is a continuous analysis of Bayley cognition, with a multimodal responder index also powering the outcome assessment.
  • Phase 3 data from the ongoing clinical trial of DTX301 (ornithine transcarbamylase deficiency) will focus on ammonia reduction as the primary endpoint, with a follow-up phase evaluating withdrawal from standard of care.
  • Commercial strategy leverages increasing global reimbursement—such as Mexico, Colombia, EMEA expansion, and new regulatory accesses in APAC—to drive revenue diversity and product adoption.
  • Crysvita demand growth remains solid across Latin America and EMEA but faces near-term revenue variability linked to large, uneven government procurement cycles, notably in Brazil.

INDUSTRY GLOSSARY

  • BLA (Biologics License Application): The regulatory submission required for approval to market a biologic product in the United States.
  • PDUFA (Prescription Drug User Fee Act) date: The deadline by which the FDA must review and respond to a new drug or biologics license application.
  • CRL (Complete Response Letter): An official FDA communication that additional information is required before a biologics or drug application can be approved.
  • CMC (Chemistry, Manufacturing, and Controls): The regulatory section focusing on product manufacturing processes and quality data submitted in support of drug applications.
  • PRV (Priority Review Voucher): Transferable FDA-issued incentive awarded upon approval of drugs targeting rare pediatric diseases, granting an expedited review for a future product.
  • MDRI (Multidomain Responder Index): A clinical trial endpoint measuring multi-faceted patient response, such as cognition, communication, sleep, behavior, and motor function, used in rare disease studies.
  • NPS (Named Patient Supply): Case-by-case access for patients to a medicine in countries where commercial approval is not yet in place, often supporting revenue in rare disease markets.

Full Conference Call Transcript

Emil D. Kakkis: 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 1a, and a pivotal data readout in Angelman syndrome. These programs are excellent examples of our mission to bring important first-ever treatments to patients and families while also delivering meaningful long-term value to shareholders. Just last week, we presented updated data at the WORLD Symposium from the UX111 for MPS IIIA program.

The new data reflect an additional year of follow-up and continue to demonstrate sustained and significant further separation of early treated patients in multiple neurologic endpoints, including the Bayley cognitive and communication scores compared to the decline observed in MPS IIIA natural history. The data also show a significant and durable reduction in the toxic substrate heparan sulfate and other disease-caused biomarkers that show a restoration of lysosomal function regardless of age or stage of disease. This reduction in CSF HS can be effectively measured by any of a number of different assay methods available and all HS measures correlate significantly to stabilization or improvement in clinical function.

These results in humans and animal models were thoroughly discussed, substantiated, and ratified by highly trained and qualified academic, clinician, 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 meaningful and durable clinical effect of UX111, regardless of age or stage of disease, all supported by consistent improvement in multiple relevant direct measures of disease activity, including CSF HS. We resubmitted the UX111 BLA to FDA late last month, and earlier today, we received an incomplete response letter.

We had provided complete responses to each CRL item, but now the FDA is requiring additional details within supportive documentation on the CMC CRL responses made and their impact. This information is typically provided during an inspection and we were prepared to do so, but we will now provide this supportive documentation as a part of our BLA resubmission. Our efforts to bring these transformational therapies to patients are supported by our established and still-growing commercial business, which again delivered significant 20% year-over-year growth in 2025. We are 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 our brands 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 UX103 trials, we made the necessary decision to implement a strategic restructuring plan to reduce our operating expenses and ensure our resources are squarely aligned with our highest-impact opportunities going forward.

Howard will now go through some of the details, but these actions were necessary to keep us on path to profitability in 2027 while still advancing a meaningful pipeline of new products.

Howard Horn: Thank you, Emil, and good afternoon, everyone. Before I go through our financials and our guidance, I want to expand on the objectives of our strategic restructuring plan. The plan refocuses our headcount and expenses on our near-term value drivers, while reducing internal and external spend from areas across the business including manufacturing, clinical, early-stage research, and G&A. It is an important part of our broader strategy to become profitable in 2027, together with continuing to grow our base business of four commercial products and investing in three successful launches for UX111, DTX401, and GTX102. 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. We are grateful to these colleagues for their contributions to Ultragenyx Pharmaceutical Inc. Now turning to the financials, I will focus on the full year 2025. Please refer to our press release for details on the fourth quarter. In 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 will 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 Pharmaceutical Inc. This range reflects growing underlying global demand, offset partially by expected timing of ordering patterns in Brazil 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 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 3 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 will turn the call to our Chief Commercial Officer, Eric Harris, who will provide detail on his team's efforts in 2025.

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

Our partnership with Kyowa Kirin in the U.S. remains strong, and we continue to find and treat commercial patients across Latin America and Turkey. In Latin America, the Crysvita business is anchored in Brazil and Argentina, with solid reimbursement growth in Mexico and Colombia over the past year translating into meaningful revenue contribution from those countries. Additionally, we continue to respond to NPS 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, 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 U.S. 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 U.K. in April 2025. In Japan, last year, we announced that Dojolvi was granted conditional approval, and we look forward to the full approval and launch of the product in Japan in 2026.

Finally, with Evkeeza, which is another powerful case study of Ultragenyx Pharmaceutical Inc.'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 just in 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 commercialize Evkeeza in Japan.

We have 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 will turn the call to Dr. Crombez to share the clinical and regulatory milestones for the coming year.

Eric Crombez: Thank you, Eric, and good afternoon, everyone. I will spend a couple of minutes to highlight the upcoming clinical and regulatory catalysts for 2026. I will start with DTX401 for the treatment of glycogen storage disease type 1a. We completed the submission of our rolling BLA in December, and we expect to have a PDUFA action date in the third quarter of this year. Next, UX111 for the treatment of Sanfilippo syndrome type A. We recently presented the encouraging long-term data at the WORLD Symposium that Emil mentioned earlier in the call.

In response to the CRL 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; we expect to share data from all four cohorts later this year. Lastly, GTX-102 for the treatment of Angelman syndrome. We are continuing to treat patients in the 48-week ASPIRE study and continuing to enroll patients in the supportive AURORA study. We expect to share ASPIRE Phase 3 data in 2026.

I will now turn the call back to Emil to provide some closing remarks.

Emil D. Kakkis: 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 3 data from the Angelman study. At the same time, the commercial team will continue expanding the geographic reach of our four commercial products and prepare to launch three more programs. All these efforts continue our mission of leading the future of rare diseases with first-ever treatments. With that, let us move on to your questions.

Operator, please provide the Q&A instructions.

Operator: Thank you. We will now be conducting a question-and-answer session. We ask that you please limit yourselves to one question and one follow-up. Our first question comes from Joon Lee with Truist. You may proceed with your question.

Joon Lee: The primary endpoint for your Phase 3 study is Bayley-4 cognition, while data by 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 is higher on the list of parents' desirability or priority list? And are you able to share what percentage of the patients coming out of Phase 3 have opted to roll over into the long-term extension portion of the study? Thank you.

Emil D. Kakkis: Right. So the Bayley cognition is a fundamental activity. And by the way, you cannot have communication without cognition as well. It is 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 will have data on it, we did not think it made sense as a primary endpoint given its heterogeneity and the complexities of its development. Now our trial will not only depend on Bayley cognition.

We also have allocated some of the power of the study to the MECFID domain responder index, which will give us a combination of cognition, receptive communication, sleep, behavior, and motor function, which will give a broader assessment that 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 both to patients and doctors, and we will include all information, including things on expressive communication. Regarding your second question, which was rolling over, we had very few dropouts in our program. Everyone has continued on treatment. Eric, if you want to comment on the extension or rollover of patients?

Eric Crombez: Yes. Similar to what we saw in Phase 1/2, the Phase 3 studies do have a very high retention rate, including patients electing to continue in a long-term extension study. I think parents really do understand this is the opportunity for their children to grow, develop, and gain and learn new skills, which is not something you see by natural history.

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

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

Emil D. Kakkis: Yes. Well, if you remember, Maury, in our Phase 2 trial, we did an expansion. That trial was intended to look at eight countries where we are going to run the Phase 3. So the point of that was 50 extra patients and to evaluate Phase 3–type patients from all the different countries. The baseline data that we saw and presented on cohorts A and B, which are the ex-U.S., is pretty reflective of what we are seeing in our Phase 3 program.

So we are comfortable that what we are seeing in Phase 3 is comparable to what we saw in the program, which is what the expansion was about, giving us a sense for what the broader population would be in multiple countries, not just U.S. With regard to the cognition in control, we assume both from data and natural history in randomized control phases only one point or less of cognitive change in the Bayley. It is a very rigorous measure. It is very hard to move. It is 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 is providing the testers on the patients with Angelman in our study. That helps assure quality of the assessment so that they are done in a very consistent way. We feel pretty comfortable that the amount of change we will see in this control group is small. We do not think that we have much placebo effect. But, of course, there is always variation. This is neurology. And we have a study we think of appropriate size to help manage variation.

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

Operator: The next question comes from the line of Priyanka Grover with JPMorgan, on for Anupam Rama. You may proceed.

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

Emil D. Kakkis: Sure. I think Howard went through some things about major cost reductions that are occurring based on the progress of programs. I will 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 is some contribution potentially from the others. And, Howard, maybe you can provide a little more and reiterate some of the clarity of how we are making that move toward profitability.

Howard Horn: Yes, happy to. I will go through it now. Also, I will note there is a page or two on this in our corporate deck, if you want to refer to that later as well. 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, I mentioned a little bit ago, in 2026 we should expect combined R&D and SG&A to be flat to down low single digits versus 2025 and in 2027 for combined to be down 15% or more.

We have, as part of our cash plan, the $735 million that we noted today. We are also considering two PRVs as part of our plan to get to profitability. Maybe I will also note that while we are in launch mode, some of the dynamics of the P&L that are also important to consider would be things like R&D trends that tend 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 is being sold during the launch. Those are some dynamics to think about as you go through your modeling. I think I will stop there.

Emil D. Kakkis: And I think it is important that part of the expense in 2026 is building that inventory for launch. Some of the expenses you are talking about now are actually building inventory that will be launched. Those combinations, hopefully, give you a magnitude of effect that will push us there. We do need to get two approvals. We do have two PRVs in our financial plan. We think with the cuts we put in place today, and additional things we are working on, we will be in good position to be profitable in 2027.

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

Will Soghikian: Hey, guys. This is Will Soghikian on for Joseph Schwartz. I have one on Angelman and then a quick follow-up. For GTX-102, the company has consistently stated that it is the most potent ASO in development. Is this claim based on the ATS knockdown or perhaps UBE3A mRNA or protein increases preclinically? And can you just remind us what type of relationship you have seen between knockdown and protein expression? Then I have a quick follow-up. Thanks.

Emil D. Kakkis: Well, obviously, knockdown and expression can really only be monitored in an animal model because we are not doing brain biopsies in our patients. To be clear, those estimates have to come from non-human primates. Now because our ASO is identical to the non-human primate sequence, we can conduct experiments in the non-human primate, for example, that Ionis cannot conduct because they do not have homology in non-human primate. Our experiments in non-human primate have shown that we are knocking down the antisense transcript substantially across the brain and 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 us say, 10 to 14 milligrams translated into humans. We know now also that, based on our AES presentation last year, we showed an effect on Bayley cognition and other endpoints, and that Ionis showed a similar effect on Bayley cognition in a six-month time frame, though they did not show our higher-level benefit over time. That is happening at doses in our program that are in the 5 to 14 milligram range, while they are using 40 to 80 milligrams and Roche used even higher doses. We are achieving Bayley cognition benefits comparable at substantially lower doses.

That substantiates what we found in non-human primates before: that what we predicted was true and that our effect we have seen in primates translates to humans, with a potent effect at a lower dose level.

Will Soghikian: 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. Just wondering if you could give us a quick update on what is going on there.

Emil D. Kakkis: Yes. The DTX301 program, which is a gene therapy for ornithine transcarbamylase deficiency, or OTC, the Phase 3 is continuing. We expect to roll out data from the ammonia endpoint sometime this year.

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

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

Emil D. Kakkis: Yes. On the CRL, the list of issues are known to both the FDA and us. We have the same list, but the question is what you put in the package. We put in answers to how we are handling each thing, SOP changes, CAPA agreements—things that we are doing—we put them all in there. But they actually want all the supportive documentation, like the SOPs and the follow-ups on effectiveness, et cetera, which we normally would not think should be part of a BLA. FDA has requested that we provide these. We believe we have the answers to what they have requested.

I think these are important issues, certainly, and we have addressed them before, but we will provide the full documentation, which is substantial, 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 is in Phase 3 and a fourth for Wilson disease that is in Phase 2 currently. We have another IND-stage program with 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—the late-stage programs—out and approved. That will open the door to us doing more. We do not plan on decreasing our future in gene therapy, but we do not plan our future of being only in gene therapy. 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 want to be a diversified company and do not 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 3 programs. We will continue some work in gene therapy, but it will not be the exclusive place for our pipeline going forward.

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

Allison Bratzel: Hey, thanks for taking my question. Maybe just a quick one going back to setrusumab. I think you had 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, 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.

Emil D. Kakkis: 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. They clearly did feel better and were doing more. Establishing how that directly results in refractures is something we are looking at. We do not have any additional information to provide at this point in time, but certainly the data suggest patients were reporting better physical function and less bone pain. It is consistent with that. We continue to evaluate data on the program and will provide more information when a definitive answer for the program is determined.

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

Lydia Erdman: Hi, this is Lydia on for Salveen. Thanks so much for taking our questions. Maybe another on Angelman following up to a question before. Given you are using a different endpoint than Ionis, what is the regulatory bar and how confident are you that is established going into it? Thank you.

Emil D. Kakkis: I realize there are 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 or secondary, the totality of data matters. The commercial setting is going to look at everything. The regulatory bar is defined by the study design, which is 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 5–6 points, but we do not have that built into the primary endpoint. We are looking for a continuous variable change. We know we can see changes of single-digit size.

We have some patients that get into the double-digit range for improvements. There is a range of response we have presented before. 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. In addition, we believe other endpoints will be successful, and the multimodal responder index is our way to take a broader view of the disease and capture more of the benefit. For the FDA, it is a new type of endpoint analysis; however, they have allowed us to put it in there and include an alpha allocation.

We think it is a way forward for neurology with heterogeneous diseases. That bar is something we are setting for each endpoint based on what the clinically meaningful change is—the minimally important change for what is considered an important change for the disease. Those things we have discussions on with the agency, and we are setting those with them. We will provide validation data that comes from the Phase 3 to help substantiate the regulatory bar of a responder for the MDRI.

The combination of both those things—a key continuous analysis of Bayley cognition, and 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.

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

Analyst: This is Steven Eyenov on for Yaron. Thanks a lot for the update and the guidance. A couple of questions here. You have the opportunity for two PRVs coming in 2026. Any sense of how soon you will be able to monetize, assuming all goes well? Are you planning to engage potential buyers beforehand? Maybe an update on timeline? And then separately on the UX701 program, I think you had previously mentioned the 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 2026 timeline, or are we misreading that? Thanks.

Emil D. Kakkis: Right. On the two PRVs, first step is you have to get both products approved so you get the PRVs issued. Howard, do you want to comment on our timeline for dealing with PRVs and sale?

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

Emil D. Kakkis: Great. 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 six to eight months of time in our first cohorts to show the effect on copper efficiently. So we are just providing less precision on the timeline to give ourselves the opportunity to continue to see what goes on with those patients. It is not meant to be an important change; it is just being less specific as we want to watch how these patients do with the higher dose.

We also want to make sure they have enough time to have their standard of care withdrawn if they achieve the proper copper control. It is just being a little less precise, but not a fundamental change.

Operator: Our next question comes from Tazeen Ahmad with Bank of America. You may proceed with your question.

Tazeen Ahmad: Hi, guys. I wanted to ask a couple of questions. First, can you just clarify, with the CRL, when you resubmit, can you define what timelines are possible on review to final decision from the time that you now resubmit responses the agency is looking for? And then a question on DTX401 for GSD1a. Do you have any updated thoughts on what pricing could look like there? And do you have a sense on what kind of potential launch trajectory to expect—one of these kind of slow and steady, or could it be steep from the outset? Thanks.

Emil D. Kakkis: Great. On the CRL timeline, what we previously submitted was a resubmitted BLA to the complete response letter we received. What is 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 built into the BLA, and we would 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, a PDUFA date would get set approximately six months after the resubmission.

The question of how long it takes to get there—we have not determined yet how long it takes us to get the documents together and put it in, but we are working diligently. Now with your other question regarding GSD1a launch and pricing: GSD1a is a very urgent disease in the sense that patients are drinking starch every few hours all day long and all night. There is a lot of urgency.

We would expect there to be a lot of interest early on, but I would say that market is probably going to develop in a more steady fashion than, for example, MPS IIIA, where the patients have an urgent absolutely must-get-treated-immediately need to try to stave off loss of brain function. So MPS IIIA will happen more urgently than GSD1a. We do expect strong, steady demand, but I would not expect it to be all at once at the beginning. With GSD1a, we have not set pricing at all, but we have talked about a $1 million to $2 million range of pricing, whereas with MPS IIIA, we have talked about a $2 million to $4 million range.

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

Maxwell Skor: Great, thank you for taking my question. Regarding the ASPIRE study, can you describe what site training looks like for uniform conduct of Bayley-4? Are there any practical considerations or added complexity when administering the assessment in older pediatric patients versus younger ones? Thank you.

Emil D. Kakkis: Thank you. Very detailed technical question, but an important one. The conduct of the Bayley is very important. First, as a company, we have always put more emphasis on endpoint design, evaluation, and training than most any company. 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 Ph.D. and has a group of Ph.D.s who are experts in trial design and endpoint design, as well as training and evaluation. We developed comprehensive training for the broader site network.

In addition to that, for the Bayley cognition scores specifically, at as many sites as we could, we have installed a centralized company to provide the Bayley scoring with experts who are knowledgeable about Angelman and how to conduct the Bayley in an Angelman patient. We are providing those testers at 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 are doing, in addition to our own training program. I do not think there is any other company that has a department of people that actually do this very activity. So I want to thank Dr.

Schreiner, who runs our group, for all the work she has done in putting this together for our endpoint program. It took her and her team a lot of work to get it done.

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

Yigal Nochomovitz: Yes, hi, thanks. I just had a follow-up on OTC. Can you describe a little bit more about that study? It is not one that you speak about much. Is it 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 CRL, you mentioned that some of these requests would have otherwise occurred during inspection. Does that mean that the inspection would be limited, not occur, or be different? Thank you.

Emil D. Kakkis: The OTC Phase 3 program—we try to prioritize what we discuss, and we have many different programs. It is definitely a burden to put everything in, but it is there and it is continuing. OTC is a real important disease and has a serious need for better treatments. We have a Phase 3 trial which enrolled around 37 in the randomized controlled trial, and the primary data we would be looking at is the change in ammonia between the treated and control groups. In the trial people, ammonia is variable—some are normal at the beginning, some are high. We are looking at whether we lower ammonia better as the primary endpoint for the blinded portion of the study.

In the second portion of the study, we will look at whether patients can get off standard of care or not, and how well they get off standard of care. It is an important program, but it is not our top-priority program. We are pursuing it; we will get the data. It gives us another opportunity and another value-creating asset going forward, and we will read out data this year on it. With regard to the CRL, I have no doubt the FDA will come and inspect, as they should. Providing the documentation is to provide them greater confidence upfront that we have actually done everything they want.

We have described the answers and what we have done, but they actually want to see the materials of the things we have done—not just describe changes in SOPs, but actually show 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 will provide them a more comprehensive, complete set of supporting documentation, which is a very large volume of information, but we will provide it upfront so they can see that we have done everything they have asked.

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

Luca Issi: Great. Yes, thanks so much for taking my question. Maybe, Emil, going back to the FDA, bigger picture: 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 is the conclusion at this point that the FDA has essentially raised the bar for all the companies developing drugs for rare or ultra-rare diseases? Any thoughts there are appreciated. And then maybe, Howard, a quick one.

When you guide $730 million to $760 million top line for 2026, what is the simple back-of-the-envelope math for what proportion of that is cash versus non-cash?

Emil D. Kakkis: Very good, thank you. With regard to the REGENXBIO decision, we put in our script today that heparan sulfate data presented at the Reagan-Udall meeting are definitive in demonstrating a relationship, and that how you measure spinal fluid heparan sulfate can be done by multiple different methods that give very similar patterns of response and are, I believe, equally predictive. The FDA’s ruling there would appear to show more pushback toward the biomarker. We received also in our review more emphasis on our clinical endpoints than the biomarkers. But we believe that the biomarkers are disease-caused measurements and are an accurate way of measuring disease and efficacy, and we continue to support them with the FDA and publicly.

Is 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 that they are supportive of accelerated approval and rare disease products. It will be important to see that those statements turn into action for all the patients that deserve these treatments for diseases like Hunter that REGENXBIO 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 tell what you are doing and how effectively.

While there may be pushback and the bar may be raised there, we need to make sure that the FDA hears what the needs of patients are and can appreciate the science behind biomarkers we have chosen and why they are meaningful ways to measure disease and predict appropriate clinical outcomes.

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

Samantha Corwin: I was curious what you are modeling for the potential sale of the priority review vouchers internally and if the recent renewal of the rare pediatric disease PRV legislation changed those assumptions at all? And then just how much a change in price could impact your path to profitability in 2027? Thanks.

Emil D. Kakkis: Okay. So you have PRVs and path to profitability, Howard. We also owe Luca a follow-up on the cash versus non-cash composition; we will follow up with Luca offline on that one.

Howard Horn: As it relates to PRVs, we were not modeling what had recently been seen—meaning we were not modeling the $200 million range. We are modeling something a little bit north of $100 million. We were very excited to see that the legislation was reapproved. I think that gives us an opportunity to not only get the two PRVs for the gene therapies, but for GTX-102 and for other programs in the future. Right now we continue to have just north of $100 million as our base assumption for PRV monetization. Anything that would exceed that would add to our balance sheet.

Operator: 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.

Joshua Higa: Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at [email protected]. Thank you for joining.