Ultragenyx (RARE) Q4 2025 Earnings Call Transcript

Image source: The Motley Fool.

DATE

Thursday, Feb. 12, 2026 at 5 p.m. ET

CALL PARTICIPANTS

• Chief Executive Officer — Emil D. Kakkis
• Chief Financial Officer — Joshua Higa
• Chief Commercial Officer — Erik Harris
• Chief Medical Officer — Eric Crombez

TAKEAWAYS

• Total Revenue -- $673 million in 2025, representing 20% year-over-year growth and surpassing the upper end of company guidance.
• Crysvita Revenue -- $481 million in 2025, including $275 million from North America, $177 million from Latin America and Turkey, and $29 million from Europe; 17% year-over-year growth, exceeding guidance.
• Dojolvi Revenue -- $96 million in 2025, showing 9% year-over-year growth.
• Evkeeza Revenue -- $59 million in 2025, reflecting 84% year-over-year growth attributed to demand outside the United States.
• Mepsevii Revenue -- $37 million in 2025, serving patients with an ultra-rare indication.
• Commercial Reach -- Products distributed in more than 35 countries in 2025, each contributing to annual revenue.
• Total Operating Expenses -- $109 million in cost of sales and combined R&D and SG&A expenses of $1.1 billion for 2025.
• Net Loss -- $575 million for 2025, or $5.83 per share.
• Liquidity -- $738 million in cash, cash equivalents, and marketable securities as of December 31, 2025.
• 2026 Revenue Guidance -- Expected total revenue between $730 million and $760 million, indicating 8%-13% projected growth, excluding possible new product launches.
• 2026 Crysvita Guidance -- Anticipated revenue of $500 million to $520 million, with underlying demand growth partially offset by anticipated ordering patterns in Brazil.
• 2026 Dojolvi Guidance -- Projected revenue of $100 million to $110 million.
• 2026 Expense Outlook -- Combined R&D and SG&A expenses expected to be flat to down low single digits compared to 2025.
• 2027 Expense Plan -- Combined R&D and SG&A projected to decrease by at least 15% from 2025, with a 38% R&D reduction (~$280 million), offset by higher SG&A for new product launches.
• Strategic Restructuring -- 10% workforce reduction (~130 employees) to align resources on near-term value drivers and aid efforts toward 2027 profitability.
• Gene Therapy Regulatory Update -- UX111 BLA resubmission led to an incomplete response letter from the FDA, requiring more CMC supportive documentation; prompt resubmission planned.
• Regulatory Milestones -- Rolling BLA for DTX401 completed in December 2025, with a PDUFA action date expected in Q3 2026; pivotal Angelman syndrome data (GTX102) expected in 2026; UX701 full cohort data readout anticipated in 2026.
• Commercial Launch Expansion -- Preparations underway for launches in UX111, DTX401, and GTX102 within the next two years.
• Evkeeza Market Penetration -- Formal reimbursement achieved in all major EMEA markets, serving ~350 patients across 20 countries as of call date.
• Dojolvi Regulatory Approvals -- Early marketing authorization granted in Kuwait and approval of early access in the UK during 2025; conditional approval in Japan, with full approval anticipated in 2026.

Need a quote from a Motley Fool analyst? Email pr@fool.com

RISKS

• UX111 BLA resubmission received an incomplete response letter from the FDA, with additional CMC documentation required, potentially delaying approval timelines.
• Guidance for Crysvita in 2026 reflects expected variability, "particularly evident in Latin America, where Brazil’s Ministry of Health places the largest orders," affecting revenue timing.
• Management acknowledged that cost controls include "severance and other one-time nonrecurring restructuring costs," indicating short-term operational disruption risk following a 10% workforce reduction.
• Continued FDA skepticism regarding reliance on biomarker endpoints, as "FDA’s ruling there would appear to show more pushback toward the biomarker," may pose regulatory uncertainty for current and future gene therapy filings.

SUMMARY

Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE) reported 2025 total revenue of $673 million, delivering 20% annual growth and outperforming the upper guidance threshold. Management initiated a 10% workforce reduction as part of a broader restructuring to focus resources on near-term pipeline approvals and commercial launches. The company is preparing to launch three major programs—including two gene therapies and one pivotal Angelman syndrome trial—while preserving significant cash resources for execution. Operating expenses are forecast to decline materially by 2027, with investments focused on advancing late-stage assets and expanding international commercial reach. Management reiterated an objective to achieve profitability in 2027 through disciplined expense control, base business growth, and monetization of potential priority review vouchers upon regulatory approvals.

• The UX111 BLA resubmission was met with an incomplete response letter, requiring prompt provision of additional CMC documentation prior to FDA review continuation.
• Crysvita and Evkeeza achieved double-digit revenue gains, with Evkeeza expanding to 350 reimbursed patients in 20 countries across EMEA and Japan following new approvals.
• Dojolvi realized regulatory progress with approvals in Kuwait, the UK, and conditional approval in Japan, positioning for further global expansion.
• Upcoming catalysts include potential regulatory decisions for two gene therapies (DTX401 and UX111), a pivotal Angelman syndrome data readout, and full cohort data for UX701 targeting Wilson disease.
• Management flagged inherent revenue variability linked to Latin American ordering cycles, especially Brazil, as a key factor in 2026 guidance ranges.
• Two priority review vouchers may be monetized promptly upon product approvals, though modeling assumes a valuation slightly above $100 million each.
• The FDA's focus on clinical endpoints over biomarkers adds regulatory risk, particularly for novel gene therapy programs targeting ultra-rare diseases.

INDUSTRY GLOSSARY

• BLA (Biologics License Application): FDA submission for permission to introduce, or deliver for introduction, a biologic product into interstate commerce.
• CMC (Chemistry, Manufacturing, and Controls): Regulatory dossier section detailing product composition, manufacturing process, quality control, and compliance systems.
• PDUFA (Prescription Drug User Fee Act) action date: FDA target date to complete review of a drug application.
• PRV (Priority Review Voucher): Transferable voucher awarded by the FDA for certain rare pediatric or tropical disease drug approvals, granting expedited review of another product.
• CSF HS (Cerebrospinal Fluid Heparan Sulfate): Biomarker measured to assess disease activity in MPS IIIA and other lysosomal storage disorders.
• NPS (Named Patient Sales): Regulatory pathway allowing access to medicines prior to formal approval on a per-patient basis, commonly used in rare diseases and international markets.
• Bayley Cognition: Neurodevelopmental assessment tool used as a primary endpoint in clinical trials for pediatric cognition outcomes.
• MDRI (Multidomain Responder Index): A trial endpoint methodology combining multiple domains (e.g., cognition, communication, sleep, behavior, motor function) for holistic assessment of clinical benefit.
• GSD 1A (Glycogen Storage Disease type Ia): Genetic metabolic disorder targeted by DTX401 gene therapy candidate.
• MPS IIIA (Sanfilippo syndrome type A): Rare lysosomal storage disorder targeted by UX111 gene therapy candidate.
• OTC (Ornithine Transcarbamylase) deficiency: Rare urea cycle disorder with DTX301 as investigational gene therapy.

Full Conference Call Transcript

Emil Kakkis: 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 top 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 expert 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 and durable clinical effect of UX111, regardless of age or stage disease, all supported by consistent improvement in the 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, relationships we have established around the world to commercialize three additional treatments over the next two years. Erik Harris will outline for you our results across Bergmann’s 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.

Operator: Howard will now go through some of the details

Emil Kakkis: but these actions were necessary to keep us on path to profitability in 2027 while still advancing a meaningful pipeline of new products.

Joshua Higa: You, Amor, 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.

Joshua Higa: Today, in connection with the restructuring, we announced a 10% workforce reduction impacting approximately 130 full-time employees.

Joshua Higa: Reductions in force are a challenging part of operating a business. We are grateful to these colleagues for their contributions to Ultragenyx Pharmaceutical Inc.

Emil Kakkis: 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.

Joshua Higa: Twenty five, we reported total revenue of $673,000,000, representing 20% growth over 2024 and exceeding the upper end of our guidance range.

Emil Kakkis: Crysvita contributed $481,000,000, including $275,000,000 from North America, $177,000,000 from Latin America and Turkey, and $29,000,000 from Europe.

Joshua Higa: In total for Crysvita, this represents 17% growth over 2024 and also exceeded the upper end of our guidance range. Dojolvi contributed $96,000,000, which represents 9% growth over 2024. Evkeeza contributed $59,000,000, representing 84% growth over 2024 as demand continues to build following launches in our territories outside of the United States. Lastly, Mepsevii contributed $37,000,000 as we continue to treat patients in this ultra-rare indication.

Emil Kakkis: Total operating expenses for 2025 included cost of sales of $109,000,000 and combined R&D and SG&A expenses of $1,100,000,000. For the year, net loss was $575,000,000, or $5.83 per share. As of December 31, we had $738,000,000 in cash, cash and equivalents, and marketable securities.

Joshua Higa: Shifting now to guidance, I will start with revenue.

Emil Kakkis: Total revenue in 2026 is expected to be between $730,000,000 and $760,000,000, which represents 8% to 13% growth over 2025 and excludes potential revenue from new product launches. Crysvita revenue is expected to be between $500,000,000 and $520,000,000, which includes all regions and all forms of Crysvita revenue to Ultragenyx Pharmaceutical Inc.

Eric Crombez: 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 $100,000,000 and $110,000,000. Turning now to R&D and SG&A expenses. With the implementation of the strategic restructuring plan I discussed earlier, we expect 2026 combined R&D and SG&A expenses to be flat to down low single digits versus 2025. This guidance nets the restructuring reductions from the restructuring with severance and other one-time nonrecurring restructuring costs and targeted launch investments in UX111 and DTX401.

We expect 2027 R&D expenses to decrease from 2025 levels by 38% or approximately $280,000,000, driven by the completion of clinical and manufacturing spend on multiple Phase III studies and the reduction of early-stage research efforts. 2027 SG&A expenses are expected to increase in support of new product launches and our existing approved products. On a combined basis, R&D and SG&A expenses are expected to decrease at least 15% in 2027 versus 2025. With that, I will turn the call to our Chief Commercial Officer, Erik Harris, who will provide detail on his team’s efforts in 2025.

Operator: Thank you, Howard.

Erik Harris: 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 growth partially offset by the expected timing of ordering patterns that we expect will normalize 2027. Moving on to the 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 UK in April 2025. In Japan, last year, we announced Dojolvi was granted conditional approval, and we look forward to the full approval and launch of the product in Japan in 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 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.

Operator: In December, we achieved

Erik Harris: 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.

Erik Harris: 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. Thank you, Erik, and good afternoon, everyone.

Eric Crombez: I will spend a couple of minutes to highlight the upcoming clinical and regulatory catalysts for 2026.

Erik Harris: I will start with DTX401 for the treatment of glycogen storage disease type 1a.

Joshua Higa: We completed the submission of our rolling BLA at the December, and we expect to have a PDUFA action date in the third quarter of this year.

Erik Harris: Next, UX111 for the treatment of Sanfilippo syndrome type A.

Joshua Higa: We recently presented the encouraging long-term data at the WORLD’s that Emil mentioned earlier in the call. 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

Eric Crombez: 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.

Eric Crombez: Lastly, GTX102 for the treatment of Angelman syndrome. We are continuing to treat patients in the 48-week ASPIRE study, continuing to enroll patients in the supportive AURORA study. We expect to share ASPIRE Phase III data in 2026.

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

Emil Kakkis: Thank you, Eric.

Emil Kakkis: 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 III 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.

Joshua Higa: The primary endpoint for your Phase III study is Bayley-4 cognition while data by illness is the expressive communications domain. Your decision to use cognition over expressive communication based on the greater

Erik Harris: problem of their success or because that is higher on the list of

Joshua Higa: parents’ desirability or priority list? And are you able to share what percentage of the patients coming out of Phase III have opted to roll over into the long-term extension portion of the study? Thank you.

Operator: Right. So

Emil Kakkis: 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. Express 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 own trial, though, 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. It 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. Regard to your second question, which was rolling over, we had very few, I do not even know how many, dropouts in our program. Everyone has continued on treatment.

I do not know, Eric, if you want to comment on the extension or rollover of patients

Eric Crombez: Yes. 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 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: Thank you.

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

Eric Crombez: Hi, thanks for taking my question. I will also ask one on Angelman.

Erik Harris: Wondering if you could just talk more about the patient baseline profile,

Eric Crombez: 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

Joshua Higa: on cognition? What are your latest expectations for what you can show on cognition in the treatment and control arm?

Operator: Yes. Well,

Emil Kakkis: 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 are going to run the Phase III. So the point of that was 50 extra patients and potentially evaluate Phase III patient-type patients from all the different countries. 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 III program.

Operator: So we are comfortable with that.

Emil Kakkis: That what we are seeing in Phase III is comparable to what we saw in the 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 data and natural history and randomized control phase is 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 a quality and of the assessment so that they are done in a very consistent way. So we feel pretty comfortable with the amount of change we will see in this trial 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 multimillion responder index, which gives us another opportunity to look at these patients in a broader way with more power.

Erik Harris: Got it. That is helpful. Thanks for taking my questions.

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

Priyanka: 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 $466,000,000? And can you remind us how many drug launches will contribute to the 2027 top line?

Operator: Sure. I think

Emil Kakkis: 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 reiterate some of the clarity of how we are making those that move in pro toward profitability.

Eric Crombez: Yeah. 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. But our pathway to profitability assumes a few things. Emil mentioned that on the revenue side continued growth from our current products in the double-digit range plus contribution from some of the upcoming launches. On the expense side, we, or I mentioned a little bit ago, 2026, we should expect combined R&D and SG&A to be flat to down low single digits versus ’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 $735,000,000 that we noted today. We are also considering two PRVs as part of our plan to get the 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, 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, inventory that is being sold during the launch. So those are some dynamics to think about as you go through your modeling. I think I will stop there.

Emil Kakkis: And I think it is important that part of the expense in ’26 are building that inventory that is launched. And so really happening, some of the expenses you are talking about now are actually building inventory that will be launched. So those combination, 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 are working on will put us in good position to be keep 2027 profitable

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

Emil Kakkis: Hey, guys. This is Will Soheking on for Joseph Schwartz.

Joshua Higa: I have one on Angelman and then a quick follow-up. So for GTX102, the company has consistently stated that it is the most

Operator: potent ASO in development. We are just wondering, is this claim based on the ATS knockdown or perhaps

Joshua Higa: its 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 Kakkis: Well, obviously, knockdown and expression can really only be monitored in an animal model. Right? Because we are not doing brain biopsies in our patients. Right? So to be clear, those estimates have to come from nonhuman primates. Now because our ASO is identical to the nonhuman primate sequence, we conduct an experiment in the nonhuman primate, for example, that Ionis cannot conduct because they do not have homology in nonhuman primate. So our experiments in nonhuman primate have shown that we are knocking down the antisense transcript substantially across the brain and or inducing UBE3A expression. And we do it at levels of around one to two 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 ASF presentation last year, that we showed an effect on Bayley cognition and other endpoints and that Ionis only showed a similar effect on Bayley cognition in a six-month time frame, though they did not show our higher-level benefit over time. And that is happening at doses in our that are in the 5 to 14 range while they are using 40 to 80 milligrams and Roche used even higher doses. So we are achieving Bayley cognition comparable in substantially different doses. So that substantiates what we found in nonhuman primates before.

That what we predicted was true and that our effect we have seen in our primates translates to humans, with a potent effect at a lower dose level.

Operator: Great. Thanks so much. And then just one quick, 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 Kakkis: Yes. So the DTX301 program, which a gene therapy for ornithine transcarbamylase or OTC, the Phase III is continuing. And we expect to roll out data from the ammonia endpoint sometime this year.

Erik Harris: Great. Thank you so much.

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

Joshua Higa: Hi, this is Rick Miller on for Kristen. Thanks for taking our questions. For the IRL received 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?

Emil Kakkis: Yeah. So on the IRL, the list of issues on the CRL are known to both 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 are handling each thing, SOP changes, CAPA agreements, things that we are doing, we put them all in there, so they all of it. But they actually want all the supportive documentation, like the SOPs and the follow-ups on effectiveness, etcetera, which we normally would not think be part of a BLA. But 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 them full documentation, which is substantial amount, but we will 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 is in Phase III and a fourth for Wilson disease that is in Phase II 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, their late stage, out and approved. That open the door to us in 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. So while we have another gene therapy program, we also have two other INDs, for example. They are teed up. They are not gene therapy. Because we do want to be a diversified company and do not want to be all in one place.

So the restriction will actually nail us to put more of our early-stage programs into play as we finish up our Phase III program. 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.

Priyanka: 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, I guess, are you seeing a clear correlation between increased physical activity levels and fracture rates in the treated arm that could support that narrative? Or is there any way to validate that hypothesis? Any more insights on that would be appreciated.

Emil Kakkis: Well, as we said, we are continuing to vouch the data deeply. What we presented before showed that the treated setrusumab arm in Orbit had improved activity and function reported, and decreased bone pain. So they clearly did feel better and were doing more. Establishing how that directly results in refractures is something we are looking at. We do not have any information to provide. We continue to do the evaluation at this point in time. But certainly, the data suggests patients were reporting they had better physical function and less bone pain. So it is consistent with that.

We continue to evaluate data on the program, and we 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

Steven Eynon: another on Angelman following up to a question before. Given you are using a different endpoint than Ionis, I guess, what is the regulatory bar and how confident are you that is kind of established going into it? Thank you.

Operator: Well,

Emil 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. In the end of the day, whatever is primary, whatever is secondary, you talk about the commercial, it is going to look at everything. It is 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 do not have that built into the primary endpoint. We are looking for a continuous variable change. And what we know is we can see changes as single-digit size changes. We had 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 observe in the A and B cohorts and presented before. That will be sufficient to be able to get approved.

Now with it, in addition to that, we believe, though, that 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 do think it is a way forward for neurology with heterogeneous diseases. And that bar something we are setting for each endpoint based on what the clinical meaningful changes are, what are the minimum change for what is considered an important change for a disease.

Those things we have discussions on with the agency and are setting those in understanding with them. We 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, key variable analysis of Bayley cognition, and then the minimally important difference-driven changes in the MDRI will put forth what we think is clinically important and regulatory sufficient data to achieve a filing for this disease, assuming the trial is successful.

Steven Eynon: Thanks so much.

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

Eric Crombez: This is Steven Eyenov on for Yaron. Thanks a lot for the update and the guidance. A couple of questions here. We have got the opportunity for two PRVs coming in 2026. Any sense of how soon you will 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 UX701 program, 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 as well? Is that being pushed out to later given the full-year 2026 timeline or are we misreading that? Thanks.

Emil Kakkis: Right. On the two PRVs, well, first step, you have to get both products approved, so you get the PRV issued. I do not know if, Howard, you want to comment on our timeline for dealing with PRVs and sale.

Eric Crombez: Yes. I think I would say, we would monetize them promptly. And 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 Kakkis: Great. So on the Wilson program, the timeline for data is highly dependent on how the patients are progressing. We believe that we needed at least 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 there to give ourselves opportunity to continue to see what goes on with those patients. But 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 that we are provided, 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 is just being a little less precise, but not a fundamental change.

Operator: Thank you very much.

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

Steven Eynon: Okay. I think that might be me. Hi, guys.

Priyanka: I wanted to ask a couple of questions. First, can you just clarify, I am sorry if I missed this earlier, 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 responses the agency is looking for,

Steven Eynon: and then

Priyanka: 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 launch trajectory to expect? One of these kind of slow and steady, or could it be steep from the outset? Thanks.

Operator: Great. So

Emil Kakkis: on the IRL timeline, so what we just submitted was a resubmitted BLA to the complete response letter we received. So what is 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 out built into the BLA, and we would 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 have not determined yet how long it takes us to get the documents together and put it in, but we are working diligently in putting that together. Now with your other question with regard to GSD 1A, launch. Is that correct? And yes. And pricing.

Operator: Yeah. That is right. Yeah.

Emil Kakkis: GSD 1A is a very urgent disease in the sense that patients are drinking starch every few hours all day long and all at night. Right? So 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 little more steady fashion than, for example, MPS IIIA where the patients have an urgent absolutely must get treated immediately to try to stave off loss of brain. Right? So MPS IIIA will happen probably more urgently than GSD 1A.

But we do expect there to be a strong steady demand, but I would not expect it to be, like, all at once at the beginning. Now with GSD 1A, we have not set pricing at all, but we have talked about a $1,000,000 to $2,000,000 range of pricing, whereas with MPS IIIA, we have talked about a $2,000,000 to $4,000,000 range.

Operator: Our next

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

Joshua Higa: 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 us say, older pediatric patients versus younger ones? Thank you.

Emil Kakkis: Thank you. Well, very detailed tech question, but important one. The conduct of the Bayley is very important. First off, as a company, we have always put more emphasis on endpoint design, evaluation, training than most any company. We have an entire department that does this activity that you are talking about, which is our Endpoint Development Strategy group, or EDS group. That group is run by a senior PhD and has a group of PhDs who are basically experts in trial design, endpoint design, and as well as training and evaluation. So we developed a comprehensive training for a broader site.

In addition to that, for the Bayley cognition, Bayley scores specifically, as many sites as we could, we have installed a centralized company to provide the Bayley scoring with experts who are knowledgeable about Angelman and how to conduct the Bayley in an Angelman patient. And 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. But you are right. This is a very important area, and we have done a lot to do that.

And I would say, I do not think there is any other company that has a department of people that actually do this very activity.

Erik Harris: So I want to thank,

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

Joshua Higa: Great. Thank you.

Operator: Our next

Operator: question comes from Yigal Nochomovitz with Citi. You may proceed with your question. Yes. Hi, thanks. I just had a follow-up on OTC.

Joshua Higa: Can you just describe a little bit more about that study? It is not one that you

Emil Kakkis: you speak about much. 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

Operator: to hit?

Emil Kakkis: And then with regard to the IRL, Emil, you mentioned that

Erik Harris: some of these requests would have otherwise occurred during inspection.

Emil Kakkis: So does that mean that the inspection would be limited or not occur or be different?

Operator: Thank you.

Emil Kakkis: Yeah. So the OTC program with Phase III, we, you know, we try to prioritize what we discussed and just all the time, and we have so many different programs. It is definitely a burden for everyone to put everything on everything that is going on. But it is there, and it is continuing. And I think OTC is a real important disease and has a really serious need for better treatments. We have the Phase III trial which enrolled around 37, I believe, the randomized control trial, and the data we would be looking at was on the change in ammonia between the treated and control groups. That ammonia number in the trial people, however, variable.

Some are normal at the beginning. Some are high. We are looking at do we improve 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, how well they get off standard of care. It is an important program, but it is not our top priority program. So we are pursuing it. We will get the data. It gives us another opportunity for us as a company, another value as available asset going forward, and we will read out data this year on it.

With regard to the IRL, I have no doubt the FDA will come and inspect as well as they should. I think providing the documentation is to provide them greater confidence upfront that we have actually done everything they want. We have described the answers and what we have done, but they actually want to see the materials of the things we have done. Right? Not just describe changes in SOPs, but actually show me the SOPs, etcetera. 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, by the way, and a lot of documents. But we will provide it to them upfront so they can see that we have done everything they have asked.

Operator: Thank you.

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

Joshua Higa: Great. Yes, thanks so much for taking my question.

Mitchell Kapoor: Maybe, Emil, kind of going back to the FDA, maybe a little bit bigger picture. I guess, what was your reaction to the REGENXBIO CRL the other day? You know, sounds like the FDA has some reservation around using serum biomarker compared to natural history for ultra-rare disease. Is that just a one-off related to their program specifically, or is the conclusion at this point that this FDA has essentially raised the bar for all the companies developing drugs for rare or ultra-rare diseases? Again, any thoughts there, much appreciated. And then maybe, Howard, a quick one.

When you guide $730,000,000 to $760,000,000 top line for twenty six, what is the simple kind of back-of-the-envelope math for what proportion of that is cash versus noncash? Thanks so much.

Emil Kakkis: Very good. Thank you. So with regard to the Regenxbio decision, look, we put in our script today that heparan sulfate data presented at the Reagan-Udall meeting are definitive in demonstrating a relationship. And that how you measure spinal fluid heparan sulfate can be done by multiple different methods that give very similar patterns of response and are, I believe, equally predictive. The FDA’s ruling there would appear to show more pushback toward the biomarker. We received also in our review more emphasis on our clinical endpoints than the biomarkers. But we believe that the biomarkers are disease-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 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 really tell what you are 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, 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 Sami Corwin with William Blair. You may proceed with your question.

Priyanka: I guess 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 Kakkis: Okay. So you got that PRV and path to profitability, Howard. You know, we just did not answer that other question. I just noticed

Eric Crombez: Okay. But as it relates, as it relates

Emil Kakkis: on the cash. We will follow up seven three. We will follow up with Luca offline on that one.

Eric Crombez: To PRVs, we were not modeling what had recently been seen, meaning not modeling the $200,000,000 range. We are modeling something a little bit north of $100,000,000. 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 have 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 $100,000,000 as our base assumptions. So anything that would exceed that would add to our balance sheet.

Operator: Thank you. This now concludes

Operator: 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 ir@ultragenyx.com. Thank you for joining.

This article is a transcript of this conference call produced for The Motley Fool. While we strive for our Foolish Best, there may be errors, omissions, or inaccuracies in this transcript. Parts of this article were created using Large Language Models (LLMs) based on The Motley Fool's insights and investing approach. It has been reviewed by our AI quality control systems. Since LLMs cannot (currently) own stocks, it has no positions in any of the stocks mentioned. As with all our articles, The Motley Fool does not assume any responsibility for your use of this content, and we strongly encourage you to do your own research, including listening to the call yourself and reading the company's SEC filings. Please see our Terms and Conditions for additional details, including our Obligatory Capitalized Disclaimers of Liability.

The Motley Fool has no position in any of the stocks mentioned. The Motley Fool has a disclosure policy.