Ultragenyx (RARE) Q2 2026 Earnings Call Transcript

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DATE

Tuesday, Aug. 4, 2026 at 5:00 p.m. ET

CALL PARTICIPANTS

• Chief of Staff and Vice President of Investor Relations - Joshua Higa
• Chief Executive Officer and President - Emil Kakkis
• Chief Financial Officer - Howard Horn
• Chief Commercial Officer - Erik Harris
• Chief Medical Officer - Eric Crombez

TAKEAWAYS

• Total Revenue -- $214 million in the second quarter of 2026, representing the highest quarterly revenue in the history of Ultragenyx Pharmaceutical (NASDAQ:RARE).
• Crysvita Revenue -- $156 million, reflecting steady demand growth in North America and the timing of regional orders in Latin America and Turkey.
• Dojolvi Revenue -- $27 million.
• Evkeeza Revenue -- $21 million, growing 50% year over year driven by increased demand from new country launches and early access programs.
• Mepsevii Revenue -- $10 million, continuing steady treatment for patients in the ultra-rare indication.
• Full-Year 2026 Revenue Guidance -- $730 million to $760 million, excluding potential revenue from upcoming product launches.
• Net Loss -- $92 million, or $0.90 per share, compared to a net loss of $115 million in the second quarter of 2025.
• Cash Position -- $436 million in cash, cash equivalents, and marketable securities as of June 30, 2026.
• Net Cash Used in Operations -- $97 million for the quarter, a significant decrease from the first quarter.
• Combined R&D and SG&A Expense Guidance -- Flat to down low single digits in 2026 compared to 2025 levels.
• 2027 Expense Guidance -- Decrease of at least 15% in combined R&D and SG&A expenses compared to 2025 as part of the path to profitability.
• DTX401 PDUFA Date -- Aug. 23, 2026, for the treatment of glycogen storage disease type Ia following the FDA's acceptance of the BLA in February.
• UX111 PDUFA Date -- Sept. 19, 2026, for the treatment of Sanfilippo syndrome type A following the resubmitted BLA for accelerated approval.
• GTX-102 Clinical Catalyst -- Top-line phase III data from the ASPIRE study in Angelman syndrome expected in the September or October 2026 timeframe.
• Crysvita North America Royalties -- $94 million, generated through the partnership with Kyowa Kirin Co., Ltd.
• Crysvita Latin America and Turkey Sales -- $54 million.
• Dojolvi Reimbursed Patients -- Approximately 675 patients in North America, with an additional 300 patients in Europe treated through early access programs.
• Evkeeza Global Reach -- More than 500 patients across 25 countries currently receiving treatment outside of the U.S.
• Angelman Syndrome Enrollment -- 129 patients randomized one-to-one to receive GTX-102 or sham in the ASPIRE study.
• GSDIa Patient Population -- Estimated at 6,000 patients in the developed world, with 1,500 to 2,000 patients in the U.S.
• Sanfilippo Syndrome Population -- Estimated at 3,000 to 5,000 patients globally, with approximately 300 to 400 patients identified in the U.S.
• Stock-Based Compensation -- $34 million in non-cash expenses included in total operating expenses of $289 million.

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RISKS

• Crombez stated, "neither study hit statistical significance for the primary endpoints of annualized fracture reductions," referring to the phase 3 ORBIT and COSMIC studies for setrusumab in osteogenesis imperfecta.
• Crombez indicated, "Based on the discussion with the MHRA, we believe that a new randomized study may be needed before they would consider reviewing an application for approval," suggesting potential regulatory delays for setrusumab in the U.K.

SUMMARY

Management reported that the company achieved its highest quarterly revenue to date and confirmed that Ultragenyx remains on track for profitability in 2027. The company is preparing for two potential gene therapy launches in the second half of 2026, supported by established commercial infrastructure. Management stated that development programs for DTX401 and UX111 are progressing toward their respective PDUFA dates in August and Sept. 2026. The company indicated that the second half of 2026 will be the most significant period in its history, headlined by pivotal data from the Angelman syndrome program.

• CEO Kakkis stated that the company expects a "clear path to profitability in 2027" driven by double-digit revenue growth and monetization of priority review vouchers.
• CFO Horn indicated that the company intends to monetize priority review vouchers associated with both DTX401 and UX111 upon their potential approval to provide "incremental non-dilutive capital."
• Chief Medical Officer Crombez explained that the phase III ASPIRE study for Angelman syndrome utilizes a split statistical alpha, with 80% allocated to the Bayley-4 cognitive raw score and 20% to the Multidomain Responder Index.
• Erik Harris noted that the commercial team has secured contracts with Qualified Treatment Centers (QTCs) to support patient access for DTX401 and UX111 beginning on the first day of potential approval.
• Kakkis explained that the MDRI endpoint for Angelman syndrome is designed to be "tenfold more powerful to detect change" in complex disorders by aggregating clinically meaningful improvements across five domains.
• The company reported that the FDA has shown "openness to considering alternative approaches to fracture analysis" for setrusumab after the program failed its primary endpoints in previous phase III studies.
• Management confirmed that the last patient in the ASPIRE study has completed their 48-week visit, with the database currently being cleaned for the upcoming top-line readout in Sept. or Oct. 2026.

INDUSTRY GLOSSARY

• AAV8/AAV9: Adeno-associated virus vectors used to deliver gene therapy into a patient's cells.
• ASO: Antisense oligonucleotide, a short strand of synthetic nucleotides that can bind to RNA to alter gene expression.
• ASPIRE: The phase III pivotal clinical trial evaluating GTX-102 in patients with Angelman syndrome.
• Bayley-4: A standardized assessment tool used to measure developmental raw scores in domains such as cognition and motor skills.
• BLA: Biologics License Application, a request for permission to introduce a biologic product into interstate commerce.
• GSDIa: Glycogen Storage Disease Type Ia, a rare genetic disorder affecting glucose metabolism.
• MDRI: Multidomain Responder Index, a composite endpoint that measures clinically meaningful changes across multiple developmental areas.
• MPS IIIA: Mucopolysaccharidosis Type IIIA, also known as Sanfilippo syndrome type A, a fatal neurodegenerative lysosomal storage disease.
• PDUFA Date: The goal date by which the FDA must complete its review of a drug application.
• PRV: Priority Review Voucher, a transferable voucher that entitles the holder to an expedited FDA review for a future drug application.

Full Conference Call Transcript

Operator: Good afternoon, welcome to the Ultragenyx Second Quarter 2026 Financial Results Conference Call. At this time, all participants are in a listen-only mode. At the end of the prepared remarks, you will have an opportunity to ask questions during the Q&A portion of the call. It is now my pleasure to turn the call over to Joshua Higa, Chief of Staff and Vice President of Investor Relations.

Joshua Higa: Thank you. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Howard Horn, Chief Financial Officer, Erik Harris, Chief Commercial Officer, and Eric Crombez, Chief Medical Officer. I'd like to remind everyone that during today's call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil.

Emil Kakkis: Thanks, Josh, good afternoon, everyone. In the second quarter, we continued our pattern of strong execution across the development and commercial organizations. The commercial team delivered the highest quarterly revenue in the history of the company, which supports our reaffirmed full-year revenue guidance. As they have done in prior quarters, they continue to find new patients and expand access to Crysvita, DOJOLVI, Evkeeza, and MEPSEVII around the world. The commercial and field teams are also preparing for our first two potential gene therapy launches, which are anticipated in the coming months. If approved, both these therapies would represent first-ever treatments for diseases with significant unmet needs and high urgency to treat.

The PDUFA date for DTX-401 for GSD 1A is just a few weeks away. Patients with GSD 1A have to drink a slurry of cornstarch every few hours around the clock, day and night, knowing that a single missed dose could lead to their death. This is a constant reminder of their disease and the severe consequence of missing a dose. In our phase I/II and phase III studies, patients treated with DTX-401 have been able to significantly reduce the amount and frequency of cornstarch doses to a pre-specified, clinically meaningful degree. More importantly, this gene therapy allows patients to have a more normal glucose metabolism, staying in the normal range a larger fraction of the day.

The expression of the missing G6Pase enzyme from the DTX-401 vector should allow their liver to break down glycogen to produce glucose during times of fasting or metabolic stress. The ability to regulate glucose better has reduced the burden of disease and reduced the potential for rapid decline to dangerous glucose levels. Transitioning now to UX-111. I've been in and around the MPS community for many years, and I've seen so many Sanfilippo patients have to watch helplessly as their children decline and die. Sanfilippo syndrome type A has an urgent need to treat, yet there has been nothing for them. Sanfilippo syndrome is a horrible neurodegenerative disease, and kids are losing brain cells every day.

Patients between the age of two and six years progressively lose their cognitive functions. By 10 years old or so, they're often bedridden and tube-fed and in and out of the hospital for many years. They can end up non-responsive for the last five or 10 years and often die as teenagers. Until now, families have had no option but to watch helplessly as their children decline and die. Based on our clinical data, treatment with UX-111 reduces heparan sulfate in these patients and enables them to stabilize and retain cognitive function compared to natural history.

While patients across the age range in the study showed benefits following treatment with UX-111, it's also clear that treating earlier demonstrated better results by protecting their brains before they had lost too much function. With a disease like Sanfilippo syndrome, there's no greater urgency to treat. As long as you wait, the less function you may have. Our development organization under Dr. Crombez has been working with regulatory agencies around the world on BLA submissions for both DTX-401 for GSDIa and UX-111 for Sanfilippo A syndrome. These include preparing the applications, responding to information requests, and supporting facility inspections. This would be a lot for a single BLA.

Our team is working simultaneously with the process for two BLAs that have PDUFA dates a month apart. We remain confident in the work our team is doing to support these applications. Shifting to GTX-102 for Angelman syndrome, where we have the most advanced clinical ASO program. In the phase III ASPIRE study, the last patient in has had their 48-week visit, and the team is in the process of cleaning and locking the database. For a global study like this, the process could take months, and we expect to unblind and share top-line results with you in September or October timeframe.

With three major catalysts on the horizon, the second half of 2026 is poised to be the most significant period in our company's history. We're positioned to deliver another exciting series of potential firsts for our company, the communities we serve, and the broader field of rare disease medicine, including the first gene therapy approvals for Ultragenyx, the first FDA approvals for two devastating and intractable rare diseases, and the first late-stage clinical data in Angelman syndrome.

It's a privilege to continue to lead the future of rare disease medicine, and we believe the combination of continued growth from our current products accelerated by contribution from potential upcoming launches and disciplined expense management gives a clear path to profitability in 2027. I'll now turn the call over to our Chief Commercial Officer, Erik Harris, who'll provide details on the commercial business and launch readiness activities in the second quarter.

Erik Harris: Thank you, and good afternoon, everyone. As Emil mentioned, we are pleased with our steady, successful commercial execution, and we continue to see the benefit of our global infrastructure across products and regions. As we described on the last call, underlying demand for our products remains strong, but seasonal factors can cause quarter-to-quarter variability in revenue. In the second quarter, we saw the strong rebound in orders that we were expecting, reinforcing our confidence that we are on track to deliver against our full-year guidance. Starting with Crysvita in North America, where our partner, KKC, is commercializing, we continue to see steady growth in the underlying demand.

Eight years post-launch, it's extremely gratifying to continue to see the steady addition of new patients starting this therapy. In Latin America, Crysvita performance was strong in the second quarter, supported by the combination of continued patient growth and timing of regional orders, including Brazil and Argentina. Approximately 50 patients began commercial therapy in the quarter, bringing the total number of patients on Crysvita to 1,000 in the region. As discussed, we expect that ordering patterns will continue to create some quarter-to-quarter variability, and we are confident that the underlying demand will continue to grow steadily. In Turkey, there are over 100 patients being treated with Crysvita through the named patient program.

As has been the case in other countries, there is accelerating demand as HCPs and patients see the benefits this transformative therapy offers. Shifting now to DOJOLVI, the trend of steady growth continues. In North America, our team generated approximately 30 start forms in the quarter, and we now have approximately 675 patients on reimbursed therapy. In Europe, approximately 300 patients are being treated through named patient or early access programs, with notable growth in the MENA region following marketing authorization approval in Kuwait. We also recently began treating patients with DOJOLVI in Japan, following its listing on the National Health Insurance (NHI) Drug Price List.

We are off to a strong start in demand, reinforcing our belief that this country represents another meaningful opportunity for continued growth over time. Evkeeza continues to be an important and growing contributor to our revenue base. In our territories outside of the U.S., we are responsible for commercialization. There are more than 500 patients across 25 countries receiving Evkeeza, as our teams continue to navigate country-by-country reimbursement, support early access, and convert appropriate patients to reimbursed therapy. Beyond the individual product performance, the real strength of this business is the scale, reach, and experience of our global commercial infrastructure. Rare disease commercialization requires deep market-by-market expertise to include patient finding, reimbursement navigation, and field execution.

That is what our global team provides every quarter in giving us high confidence that we will be prepared for the next potential launches. I'll close briefly with a couple of comments on the team's work preparing to successfully launch DTX401 and UX111. Launching two gene therapies in parallel is a big undertaking. We are up to the task and ready to deliver for patients. We are preparing thoughtfully and deliberately to support not only patients and caregivers but clinicians and payers beginning on day one. As we prepare for these potential launches, we are actively working with Qualified Treatment Centers, or QTCs, with contracting and activities progressing as planned.

We believe their strong engagement reflects their sense of urgency for patients and families impacted by GSDIa and Sanfilippo syndrome type A, and their understanding of the clinical potential of our investigational gene therapies. Our market access preparations are also progressing well, informed by extensive education and engagement efforts. Across more than 200 engagements with payers, we've been pleased that they recognize the significant unmet need associated with both diseases and understand the particular urgency to treat in Sanfilippo syndrome. The foundation necessary to support broad and timely access is set. With a focus on minimizing barriers for eligible patients following approval, we've been building toward these potential launches for years.

We stand ready to add these products to our existing portfolio and expand our mission of helping patients with rare disease. I'll turn the call to Howard to share more details on our financial results and guidance.

Howard Horn: Thank you, Erik, and good afternoon, everyone. I'll focus on our second quarter financial results, guidance for the year, and provide a few comments on our path to profitability. Starting with revenue, total revenue for the second quarter of 2026 was $214 million. Crysvita contributed $156 million, including $94 million from North America, $54 million from Latin America and Turkey, and $8 million from Europe, which were consistent with the anticipated quarterly timing and trends Erik just mentioned. DOJOLVI contributed $27 million, consistent with our expectation for steady demand growth. Evkeeza contributed $21 million, representing 50% growth over the second quarter of 2025 as demand continues to build following launches in our territories outside of the United States.

MEPSEVII contributed $10 million as we continue to treat patients in this ultra-rare indication. Total operating expenses for the quarter were $289 million, which included cost of sales of $34 million and combined R&D and SG&A expenses of $255 million. Total operating expenses included $34 million of non-cash stock-based compensation. For the quarter, net loss was $92 million or $0.90 per share. As of June 30, we had $436 million in cash equivalents, and marketable securities. Net cash used in operations for the quarter was $97 million, a significant decrease from the first quarter and consistent with the expectations we discussed on our last call.

As noted in our press release, we are reaffirming our financial guidance for revenue and combined R&D and SG&A operating expenses. Finally, I want to share a few thoughts on how we plan to achieve our path to profitability in 2027. There are three primary factors. First, continued double-digit revenue growth from our current products, plus contributions from our potential upcoming launches. Second, continued expense discipline and strategic capital allocation to support our launches, as outlined in our operating expense guidance. Third, incremental non-dilutive capital to bolster our balance sheet from monetization of the priority review vouchers associated with DTX401 and UX111, if approved. With that, I'll turn the call to our Chief Medical Officer, Eric Crombez.

Eric Crombez: Thank you, Howard, and good afternoon, everyone. I'll start with GTX-102, or apazunersen, our antisense oligonucleotide for the treatment of Angelman syndrome. As Emil mentioned, and something that I am sure you are tracking closely, we are approaching the phase III ASPIRE data readout expected in the September or October timeframe. The ASPIRE study is a randomized, double-blind, sham-controlled study that enrolled patients with a full maternal UBE3A gene deletion, and our criteria for success are well-defined. In the 48-week study, the primary statistical alpha is split between the Bayley-4 cognitive raw score at 80% and the Multi-Domain Responder Index, or MDRI, at 20%. This is not a hierarchical evaluation, meaning both endpoints are tested in parallel.

If the Bayley cognition endpoint reaches a P value equal or less than .04, or if the MDRI reaches a P value equal or less than .01, we will have a statistically successful phase III study. We designed and powered the study to hit both endpoints, but we do not need both endpoints to achieve statistical significance in order to have a successful study. Across the phase I/II program, patients have now been on continuous therapy for an average of three years, with the longest approaching five years, which represents the most significant and mature data set in the field. These patients continue to demonstrate meaningful improvements across multiple development domains while maintaining a consistent safety profile.

The phase I/II open-label single-arm data demonstrates substantial clinical benefit well beyond what might be considered with placebo, though it is in an open-label setting. We believe that the long-term experience beyond the first year of treatment remains even more important as we evaluate the potential for GTX-102 to provide meaningful benefit with chronic dosing in the commercial setting. Shifting to UX143, or setrusumab, our monoclonal antibody for the treatment of osteogenesis imperfecta. At the end of last year, we shared the results from the phase III ORBIT and COSMIC studies.

While neither study hit statistical significance for the primary endpoints of annualized fracture reductions, we did see clear signals of biologic activity, statistically meaningful improvements in bone mineral density and patient-reported outcomes, and meaningful reductions in fractures in certain bones and in patients with higher fracture frequencies. Since then, we have continued analyzing the data and have had discussions with regulators in the U.S. and U.K. Based on the discussion with the MHRA, we believe that a new randomized study may be needed before they would consider reviewing an application for approval.

The FDA indicated openness to considering alternative approaches to fracture analysis, and we will need additional conversations with them to further define what additional clinical data would be needed to support a potential BLA. I'll now turn the call back to Emil to provide a reminder of our catalyst for 2026 and some closing remarks.

Emil Kakkis: Thank you, Eric. I'll close with a few of the important catalysts we have later this year. A full list can be seen in the corporate deck posted to our website. Starting with DTX401 for the treatment of Glycogen Storage Disease Type Ia, where we continue to work with FDA ahead of our PDUFA action date of August 23rd. Next, UX111 for the treatment of Sanfilippo syndrome. Similar to DTX401, we continue to work with FDA ahead of the PDUFA action date of September 19th. Lastly, GTX-102 for the treatment of Angelman syndrome, where we're on track to read out top line phase III data from the ASPIRE study in the September or October timeframe.

The second quarter reinforced the continued strength of our global commercial business and our expertise in developing first-ever medicines for patients with rare diseases. We are ready for potential launches, continue to execute across the portfolio, and are approaching a set of milestones that could meaningfully expand our impact for patients and accelerate the next phase of growth for Ultragenyx. With that, let's move on to your questions. Operator, please provide the Q&A instructions.

Operator: Thank you. At this time, we will be conducting a question and answer session. Please limit yourselves to one question and one follow-up question for each time you enter the queue. To ask a question, press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Our first question comes from Kristen Kluska with Cantor Fitzgerald. Please state your question.

Kristen Kluska: Hi, good afternoon. Congrats on a really strong quarter. For Angelman syndrome, was hoping you could provide a little bit more context on these endpoints. Specifically, if the FDA has signed off whether one endpoint or not would be sufficient for filing. Also understanding what's clinically meaningful. Understand that these both endpoints were powered for success, but were they also powered to show results that the community would deem clinically acceptable? Thank you.

Emil Kakkis: We had our discussion with the FDA on the sharing of primary alpha, and that was agreed to in the phase III and pulse discussions on the two endpoints. Sharing of alpha means that either endpoint can be positive in their analysis. With regard to powering, we are powering based on the effects we've seen. We think a five or six-point change, for example, in the Bayley should be sufficient to achieve significance, and that would be the six-point level is considered clinically meaningful. For the MDRI, it only scores if there's clinically meaningful results. That is, each domain improvement requires a threshold of clinical meaningfulness.

In that, previously, we've seen, as you remember in phase III, about two domains net positive that were in the clinically meaningful range. Because of the design, we would see MDRI would be positive only with clinically meaningful results. At this point, we feel comfortable about the two-endpoint approach, we think the powering will be positive with clinically meaningful results, based on our plan. We will see the data when they come. Thanks, operator. Let's move to the next question.

Operator: Thank you. Your next question comes from Yaron Werber with TD Cowen. Please state your question.

Yaron Werber: Great. Thanks so much. Maybe on the MDRI endpoint, which I think has generated some confusion from investors, as you noted, it's the first and most important secondary, but it's really a co-primary. It's not been used before in Angelman, but you've used it in some of your other MPS disorders. Can you talk about the level of sensitivity and whether it's a better endpoint in cognition, just given that it's a co-primary? Thank you so much.

Emil Kakkis: Yes. The MDRI approach simply captures efficacy across multiple domains using a clinically meaningful threshold in order to capture any positive results. What we're saying is, any of, let's say, five or six endpoints, if there's a clinically meaningful change in the patient, count that and add up all those clinically meaningful changes together. We used it previously in the MEPSEVII program, which it was significant in our 12-patient trial. In our analyses published in our paper, the MDRI was, for example, tenfold more powerful to detect change in an enzyme replacement therapy trial compared to individual endpoints, right? That's what we've published before. We think it's substantially more sensitive.

When you look at the Angelman phase III data, even in the 15-patient trial, we show substantial power with P values less than 001, even in small studies. It's more powerful because we capture more efficacy in it. Its sensitivity is very good, but its meaning is greater, and it's one of the reasons we want it. It's not just sensitivity. Being able to show through five important domains for family what a drug is doing, I think is a better assessment of what a drug does in a disease as complex as Angelman, as you know, since you've worked in the area. We think it's just a better way of describing.

However, it is new and it's different, but we're confident in its clinical meaningfulness and its power in detecting change in diverse, complex disorders like Angelman syndrome.

Operator: Thank you. Your next question comes from Yigal Nochomovitz with Citi. Please state your question.

Yigal Nochomovitz: Yeah. Hi, how are you? I just wanted to ask with regard to the filing plans, are you going to file on the data coming up in September or October? The additional study and additional genotypes will also support the Angelman's filing. Can you just comment on the order of operations with regard to what data sets will be included? Thank you.

Emil Kakkis: Yeah. Thank you, Yigal. We haven't discussed publicly what we're going to do about filing. It's something under consideration, and at this point, we're not going to describe what our plan is. We're collecting data in all the types in our program. Our expectation is to get approval in all the types, but we won't discuss at this point what our filing timeline is. Thank you.

Yigal Nochomovitz: Okay.

Operator: Your next-

Yigal Nochomovitz: Thank you.

Operator: Thank you. Your next question comes from Maury Raycroft with Jefferies. Please state your question.

Maury Raycroft: Hi. Congrats on the quarter, thanks for taking my question. I'll ask one on Angelman as well. Wondering if there have been any cases of lower extremity weakness or neuroinflammation based on DMC feedback during the study, and how are you setting expectations on this for the top-line disclosure? I guess, what's the latest you can say on the dropout rate from the phase III?

Emil Kakkis: Yeah. We usually don't describe all the details and operation of the study. Honestly, the safety and efficacy will have to get evaluated together. The study has never stopped or had any issue during its conduct. It's continued smoothly through at this point, right? There's been no safety issue to cause a problem that stops the study. I would say we're comfortable where we are. I think we don't expect to see a different safety profile from what we've seen before and going forward.

Maury Raycroft: Will-

Emil Kakkis: Got it.

Maury Raycroft: Do you want to comment on the discontinuation rates that we saw?

Emil Kakkis: Yeah. Well, we wouldn't comment on that. It's also part of study conduct at this point. If you look past it to phase III program, we've had very few, and usually it's more toward the beginning. Among patients that get, let's say, after six, eight, seven, eight months, we had a very good persistence of those patients long term.

Maury Raycroft: Got it. Thank you.

Operator: Your next question comes from Eliana Merle with Barclays. Please state your question.

Eliana Merle: Hey, guys. Thanks for taking my question. Another two on Angelman. First, I guess, what are your latest expectations for the placebo arm performance on MDRI and the Bayley Cognition score and your confidence that there won't be a placebo effect? Second, I guess if you show a trend on both endpoints but do not reach statistical significance, curious how you would approach that with the regulators in terms of a potential filing. Thanks.

Emil Kakkis: Great. We have talked about the placebo effect before. I think in the Bayley Cognition, where we have both natural history and the randomized data from another study, the effect has been one point or less in the Bayley Cognition, so it doesn't change. Honestly, placebo effects usually don't happen in things like a Bayley score because the patient is not cognitive of what the change should be. It can happen if you're using parent input. In this case, we think it's unlikely to see a placebo effect for the Bayley. In the MDRI, we're looking at multiple different endpoints. It is possible that some of those could change.

However, we think that the threshold of clinical meaningful change means just a little bit of change from bias view things wouldn't score. It has to be a really pretty big change before you can score. I think that should filter out, I would call random placebo changes. At this point, we feel both. I don't think placebo effect would be an issue. It is neurology, though, I always say, and we always have to consider we learn things. We think we've designed it to manage any placebo effect and on both endpoints. Thank you.

Operator: Your next question comes from-

Emil Kakkis: That's it.

Operator: Oh. My thanks. The next question comes from Anupam Rama with JPMorgan. Please state your question.

Anupam Rama: Hey, guys. Thanks so much for taking the question. Emil, could you just clarify your comments a little bit on GTX-102 and Bayley? I think you said you needed a five- to six-point change to hit stats relative to placebo. I think that's the first time you've really quantified that. I'm assuming that's raw score, right? Using GSV, if I remember back to your phase III, you showed a similar-ish effect, right, in phase III. I was just wondering if you could clarify those comments. Thanks so much.

Emil Kakkis: Yeah. I wasn't saying that's the threshold for powering. I was saying that a five, six point is a clinically meaningful change, and we are powered to detect that average change. That's what I meant to say. I didn't mean to say we're only powered for that threshold. We are well powered to detect anything that would be considered clinically meaningful in that range. In the data we put out recently, we said it was near 10 score when you combine all the data together at one year. If you look at all the various sets of the data, it's in that range that we would expect the data to be. What I'm saying is we're powered.

Whatever we would detect should be a clinically meaningful change, and we are confident we can do that.

Anupam Rama: Great. Thanks for the clarification.

Operator: Your next question comes from Jack Allen with Baird. Please state your question.

Jack Allen: Great. Thanks for taking the questions and congrats on the progress made over the course of the quarter. I'll keep the train rolling here as it relates to GTX-102. I wanted to ask a quick clarifying question around the allocation of the alpha. I understand on the call and on the more recent calls, you've been discussing how you have an 80% allocation of alpha to the Bayley-4 cognition endpoint and a 20% allocation to MDRI. I was looking at the completion of enrollment press release from July of last year, I think it was a 90/10 alpha allocation there.

I'm just curious if there was a change to the statistics between the completion of enrollment and the potential readout here, and what educated that change?

Emil Kakkis: Yes. Our current plan is to do 80/20. 90/10 are very similar. I don't really think they're materially different. We decided to make it 80/20. There was no particular date or other reason for it. It was just our take on the split between the two. It doesn't, I don't think, meaningfully change things, but the MDRI is very powerful. We think 10% or 20% is probably adequate for that. We had given 80%, 90% to the Bayley. In our discussion with FDA, that was the split we had, but they're comfortable with what we are proposing at this point.

Jack Allen: Thanks for the reply.

Emil Kakkis: Okay. Let's go to the next.

Operator: Your next question comes from Allison Bratzel with Piper Sandler. Please state your question.

Allison Bratzel: Hey, good afternoon, and thanks for taking the question. Just as clarification on setrusumab, I think in the prepared remarks, you said FDA had indicated openness to alternatives to the fracture analysis, but you need to further define what would be needed for a BLA. Could you just clarify that? Do you feel you have a fileable package from the existing COSMIC and ORBIT dataset? Just how important is that open-label extension data that's being generated now? Just what's the next point you would be able to update The Street on FDA interactions and the path forward in the U.S.? Thanks.

Emil Kakkis: Yes. Our comments were basically around the type of fractures and type of patients that we were talking about with regard to what fracture analysis they would want. What we said, though, is that our discussions suggest some additional clinical data will be required, and we need to define what that is, which is not fully defined yet. We cannot state at this point whether extension data alone or whether there's any additional data required at this point in time. All right. We are discussing with them. I think they've been very open to a discussion and a path forward, and we just need to come up with a good plan to get us to that fileable package.

Operator: Thank you. Your next question comes from Maxwell Skor with Morgan Stanley. Please state your question.

Maxwell Skor: Great. Thank you very much for taking my question. Another on Angelman. With the centralized raters, have you seen a reduction in variability in the blinded baseline data compared to the phase I/II? Thank you.

Emil Kakkis: We have not personally looked at the data. We're not aware. We don't look at the blinded data at the management level. The team would be doing that. We would expect that these reviewers, which are highly professional and consistent, would help reduce overall study variation. That was the importance of it, to control it, to absolutely make sure that a changing evaluator or variable in quality and experience at different locations might cause a problem. It was our attempt to control the endpoint. I can't tell you at this point that effect of that. I believe it is the kind of thing that will help assure consistency and give us the best chance for less noise in the program.

Right now, we don't have any data to tell you that.

Maxwell Skor: Great. Thank you.

Operator: Your next question comes from Tazeen Ahmad with Bank of America. Please state your question.

Tazeen Ahmad: Hi, guys. Thanks for taking my questions. On the financial front, how are you feeling about where you are with your cash balance and any potential need to do any kind of financing? Related to that, how should we be thinking about the investment needed for the upcoming launches that you have for your two programs for 401 and 111, assuming that both of them do get approved on time? Lastly, can you just remind us of what you think the market size for each of those two indications could be? Thanks.

Emil Kakkis: Sure. Well, I'll let Howard go through the cash financing piece, but I'll touch on the market size first. For DTX401 GSDIa, we think there's about 6,000 in the developed approachable world, which means around 1,500-2,000 in the U.S. For Sanfilippo syndrome, there are 3,000-5,000 globally, but inside the U.S., there's probably, we think of it as 20% or 25% of that. The addressable population will depend on what label says, but we are looking at patients that are generally going to be probably more likely under 10 than over 10. Those are roughly where we are on population currently. I'll let Howard talk about the financials.

Howard Horn: Yes. Thanks, Tazeen. First on the investments, I guess I'll remind folks of the guidance we gave for combined R&D and SG&A. It was all based on this year or next year versus 2025. This year was flat to down low single digits. In 2027, it's a decrease of at least 15%. Both of those were inclusive of the launch investments we're planning to make for 111 and 401. There is new money going in there. I think also important to note is that those programs fall into a sales structure or bag that we already carry. It's a highly leveraged situation, it's targeted investments. That's an answer to that part of the question.

With regard to cash balance, we reported $436 million as of the end of the quarter. As it relates to fundraising plans, our focus is on monetization of PRVs. Upon approval, our intent would be to monetize our DTX401 PRV and also the UX111 PRV.

Operator: Thank you. Your next question comes from Ben Burnett with Wells Fargo. Please state your question.

Ben Burnett: Hey, thank you. Congrats on the quarter and congrats on the good Crysvita number. I wanted to ask about setrusumab and just follow up. I'm just curious, have any of the regulatory agencies that you've spoken with, have they indicated a willingness to use or rely on bone mineral density as sort of a determinant of efficacy? Or do they still also need to see efficacy be defined in some way in terms of fracture rate?

Emil Kakkis: Thanks, Ben. That's a good question. At this point, there hasn't been the kind of proof for BMD's predictive value for fractures as there has been for osteogenesis, I'm sorry, for osteoporosis, where it has been accepted. We're still in the point of proving it. There's a question of whether the underlying bone disease creates that connection. We have evaluated, we believe it does, but at this point, we're looking at fracture endpoints of some form as the primary way to get approval and not using BMD. I think we all agree BMD demonstrates the profound activity of this drug in these patients. With a whole Z-score gain in a year is a profound improvement in their bones.

It gives us confidence, and I think the regulators are also confident that the drug is doing something meaningful. Right now there's, I would say, acceptance of BMD as a primary for approval has not yet been enabled.

Operator: Thank you. Your next question comes from Salveen Richter with Goldman Sachs. Please state your question.

Lydia Erdman: Hi, this is Lydia on for Salveen. Thanks so much for taking our question and congrats on the progress. Just as a follow-up to a previous question on Angelman, related to the lower extremity weakness, has the FDA provided any sort of threshold on what would be acceptable on the safety front, particularly as it pertains to that lower extremity weakness? Thanks so much.

Emil Kakkis: No thresholds were provided or any limits. In fact, I believe in our final conversation, I'm not sure if Eric you want to say something to this. We really have not had much concern, at least end of phase II as little at all. Eric, what's your take on the FDA? I don't think we've had any limits provided to us or how much maximum could be incurred or something.

Eric Crombez: No, exactly. During our end of phase II meeting, there was no discussion on lower extremity weakness and as I said, we maintain a consistent safety profile.

Emil Kakkis: I think our sense from them is that we've gotten past the issue with them, and I think we're in good shape. We've not had discussions further.

Operator: Your next question comes from Luca Issi with RBC Capital Markets. Please state your question.

Shelby Hill: Hi, team. This is Shelby on for Luca. Maybe on GSDIa. With the PDUFA just weeks away, could you provide any color on your level of confidence headed into that decision and talk about how the review has progressed? I guess specifically whether there's been any information requests from the FDA and are there any additional manufacturing sections that you need to clear before the decision date? Any color there much appreciated. Thanks.

Emil Kakkis: Sure. Well, yes, we have obtained information requests during the review for both CMC and clinical, and we've been answering them. We can't provide an answer yet during progress. Things are underway like that. We feel the review has proceeded normally, and we feel like we're in good shape. However, we can't predict to you what the FDA's action are. They will have to do it. At this point, everything we have been doing is answer their questions and move in a normal fashion forward.

Operator: Your next question comes from Laura Chico with Wedbush. Please state your question.

Thomas Yip: Good afternoon, everyone. This is Thomas Yip on for Laura. One question from us. Of the 300, 400 Sanfilippo patients that are identified in the U.S., how many are likely within the age range that you would expect the label to support and are clinically appropriate to treat? Also, what's the incidence rate for new patients being captured on an annual basis? Thank you.

Emil Kakkis: Are you talking for Sanfilippo syndrome?

Thomas Yip: Yes, that's right. Sanfilippo.

Emil Kakkis: Yeah, I thought you were mentioning Sanfilippo. Yeah. We haven't put out precise numbers yet on the prevalence, exact prevalence or diagnosed prevalence of patients. We know that the incident rate appears to be about one in 100,000 or about 30-40 new kids diagnosed per year. If you imagine that they're living until their teenage years, you can get a sense for what the number or prevalent number is like, right? Does that make sense? We have treated patients up to, I think, eight or nine years old in the trial.

We don't know what age range will be in the labeling, but we've shown even in the older patients that we stabilize function with regard to ambulation, feeding, communication at the state they're in when we are able to treat them. We think there's a justification for treating patients that age, but we don't know what the label will be. There is a meaningful population of patients in that age range out there, and we have a sense it's a lot of urgency in wanting to get treated. Hopefully, that gives you at least a feel for it.

Thomas Yip: Understood. Thank you so much for taking the question.

Operator: Your next question comes from Joseph Schwartz with Leerink Partners. Please state your question.

Erik Harris: Thanks. I have a two-part question on Angelman. In phase I/II, were there particular Bayley cognition items or skill clusters that appeared most sensitive to apazunersen? Are those the same skills you expect to drive separation in ASPIRE? Relatedly, because ASPIRE's primary endpoint removes caregiver input and requires the child to demonstrate skills during a single testing session, how should we think about the risk that meaningful home-based gains might not be fully captured by the Bayley Cognition assessment?

Emil Kakkis: Good. Let's start with the last one. The Bayley Cognition has a relatively small number of caregiver assessments, and our endpoint team's assessment is that it shouldn't have a material effect on the raw scores at this point. We're not concerned about that. Regarding the MDR areas, the areas we studied and presented before in our slides have all been the same ones as we're using. The five domains are Bayley cognition with a threshold set by the Bayley people. We also have communication score, receptive communication for the Bayley. We're using a sleep score, and we have a behavior scale, ABC behavior score, and finally a motor score, which is either the ASA or the Bayley.

Those are the five domains. Those domains are ones we saw some meaningful improvement in and the ones that are of importance to patients. All of them are contributing. If you look at the prior descriptions where we've shown the heat map, I think you can see all the endpoints are contributing pretty significantly. It's really not one or another that's dramatic. For sleep, for example, there are patients who have a very big effect on sleep because they're very sleep-deprived kids. Other kids who don't have sleep problems where you might not see it. If you look across those endpoints, we see contribution from all of those endpoints that are built into the MDRI.

There's no one or other that's, let's say, driving the majority of what the MDRI feels. We'll see. This is why the MDRI is so powerful. If you have multiple endpoints all contributing, you gain a lot more power when you're capturing efficacy from all areas of the patient's benefit.

Operator: Thank you. Your next question comes from Gavin Clark-Gartner with Evercore ISI. Please state your question.

Yi Zhong: Hi, this is Yi Zhong for Gavin. Thanks for taking our question. Just a follow-up on the Angelman phase I/II study. Looks like the study originally enrolled 74 patients, and efficacy we have seen so far is based on the 40 patients cohort. The last quarter you mentioned, based on the most recent data cut-off, there are 53 patients that have reached the 12-month milestone. Can you remind us when do you plan to share those data? Also, especially for the efficacy part, if the data has been consistent with the earlier cohort? Thank you.

Emil Kakkis: All right. Well, you're talking about different cohorts and time. It depends on whether you're talking about the titration group, or we're talking about the expansion group. Those are the two groups. In the most recent release, we talked about all the patients who've been on therapy, and we have a few people who left early on in the study. The combination data we presented at the last quarterly call was including all the people together.

We presented on the expansion, which wasn't everything, but we mentioned the last call, which was the near 10 score on all patients together combined for the Bayley cognition was the most complete set of data that had at least a year of treatment on it. That's included in that data. We are not planning to put out more phase III data at this point, because we are where we are with the phase III program. I hope that gives you a feel for it. I would say is we presented previously, for example, A and B cohort data, that cohort is very similar to what we're seeing and we think is in the phase III.

Basically, it's from the same centers that are in the international study. At this point, we feel comfortable that what we have learned from phase III, we have disclosed to you as an adequate assessment of the patients in the countries, and at the sites that we are using in phase III.

Yi Zhong: Thank you.

Operator: Your next question comes from Raghuram Selvaraju with H.C. Wainwright. Please state your question.

Ahmed Gadelkareem: This is Ahmed on for Raghuram. Thank you for taking our questions. I was wondering if you could give some color to the launch readiness for the next two products. How do you see the timing to first patient infusions? How sensitive is the 2027 profitability target to slower-than-expected ramp for the products? Thank you.

Emil Kakkis: Okay. Let me touch on it, I'll let Erik talk about launch readiness, and maybe you can talk about profitability. We're absolutely driving to assure that we can get patients treated as promptly as possible because there are a number of patients that really urgently want to be treated. We're setting up to do that. Because we already have two products in the space of inborn errors, we already have a team in the field. We already are operating, and we're going to prepare to build out with a more measured addition. Maybe, Erik, you can talk about what we're doing in the QTCs and how we're going to help assure patients get infusions as promptly as we can.

Erik Harris: Yeah, just to add on something that you said, that we've been preparing now for a few years following the initial filings. There's about a 75% overlap with the DOJOLVI and MEPSEVII with the institutions and the healthcare providers that we'll be calling on. We'll be able to leverage our current infrastructure, which we expanded to meet the demands of our previous commercial products. I just want to also emphasize, this will be our fifth and sixth launches. We've successfully launched four products previously. We certainly know what we're doing, and we'll be prepared. We have a number of QTCs already under contract, and we'll be expanding that as we prepare in our final preparations for commercialization.

Emil Kakkis: Should be ready to go when we get launched.

Erik Harris: We'll be. Good.

Howard Horn: We'll be ready. Maybe last to your question about the sensitivity of profitability to the launches. You heard my comments earlier on the call about the different factors that play into profitability. We haven't been more specific on the exact contribution from launches, but we do imagine one as part of profitability. I think the important thing to remember is that there's lots of levers to get to a profitable year, and so it's not as though every launch is a must. That's a fortunate place to be in, where we have lots of different revenue sources and lots of different ways to manage our allocation of capital.

Ahmed Gadelkareem: Thank you.

Operator: Thank you. At this point, we have reached the end of the question and answer session. I will now turn the call over to Joshua Higa for closing remarks.

Joshua Higa: Thank you. This concludes today's call. If there are additional questions, please reach out to us by phone or at ir@ultragenyx.com. Thank you for joining us.

Operator: Thank you. All parties may now disconnect. Have a good day.

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