Q1 2026 Ultragenyx Pharmaceutical Inc Earnings Call

May 5, 2026

Operator: Good afternoon, and welcome to Ultragenyx's Q1 2026 financial results conference call. At this time, all participants are on 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 introduce your host, Joshua Higa, Vice President of Investor Relations.

Speaker #1: Good afternoon and welcome to Ultragenyx First Quarter 2026 Financial Results Conference Call. At this time, all participants are on a listen-only mode. At the end of the prepared remarks, you will have an opportunity to ask questions during the Q&A portion.

Speaker #1: Of the call. It is now my pleasure to introduce your host, Joshua Higa, Vice President of Investor Relations.

Speaker #2: Thank you. We've issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President; Eric Harris, Chief Commercial Officer; Howard Horn, Chief Financial Officer; and Eric Crombez, Chief Medical Officer.

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, Erik Harris, Chief Commercial Officer, Howard Horn, Chief Financial 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.

Speaker #2: 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 are actual results may differ materially.

Speaker #2: Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil.

Speaker #3: Thanks, Josh, and good afternoon, everyone. We are now in our 16th year since our founding, and this year is expected to be transformative, with growing revenue and multiple new drug approvals.

Emil Kakkis: Thanks, Josh. Good afternoon, everyone. We are now in our 16th year since our founding, and this year is expected to be transformative with growing revenue and multiple new drug approvals. We're on track to well exceed $700 million in revenue from our global commercial business with a consistent track record of double-digit annual revenue growth. We have a PDUFA date for 2 gene therapies that would bring first-ever treatments to patients and families with no other disease-modifying options. Also, we will unblind our phase 3 ASPIRE study evaluating GTX-102 in patients with Angelman syndrome in H2 of this year. We continue to execute global clinical trials across the largest late-stage pipeline in rare diseases. We're also manufacturing our gene therapy products in our new facility in Bedford, Massachusetts. I'll start with GTX-102 for Angelman syndrome.

Speaker #3: We're on track to well exceed $700 million in revenue from our global commercial business, with a consistent track record of double-digit annual revenue growth.

Speaker #3: We have a Paducah Day for two gene therapies that would bring first-ever treatments of patients and families with no other disease-modifying options. Also, we will unwind our Phase 3 Aspire study evaluating GTX102 in patients with Angelman Syndrome in the second half of this year.

Speaker #3: We are continuing to execute global clinical trials across the largest late-stage pipeline in rare diseases. We're also manufacturing our gene therapy products in our new facility in Bedford, Massachusetts.

Speaker #3: I'll start with GTX-102 for Angelman syndrome. The first patient enrolled in the Phase 3 ASPIRE study has reached their Day 338 visit and has transitioned to the open-label extension study.

Emil Kakkis: The first patients enrolled in the phase 3 ASPIRE study have reached their day 338 visit and have transitioned to open label extension study. The rest of the patients will be completing the blinded portion of the study in the next few months and crossing over to open label extension. With the AURORA study, we are expanding GTX-102 treatment to other ages and genetic types of Angelman syndrome, and enrollment in that study continues to go well. We prefer to develop the first-ever treatments for diseases that have not had significant breakthroughs in the past and so do not typically work in disease areas where there are other competitor programs at similar stages of development.

Speaker #3: The rest of the patients will be completing the blinded portion of the study in the next few months and crossing over to the open-label extension.

Speaker #3: With the Aurora study, we're expanding GTX102 treatment to other ages and genetic types of Angelman Syndrome, and enrollment in that study continues to go well.

Speaker #3: We preferred to develop the first-ever treatments for diseases that have not had significant breakthroughs in the past, and so do not typically work in disease areas where there are other competitor programs at similar stages of development.

Speaker #3: In the case of Angelman Syndrome, we made an exception given the size indication and the excellent work genetics had done with the scientist Scott Dindo to develop a potent ASO that worked in a large animal model rather than just mice, which often do not predict human biology.

Emil Kakkis: In the case of Angelman syndrome, we made an exception given the size indication and the excellent work GeneTx had done with the scientist Scott Dindot to develop a potent ASO that worked in a large animal model rather than just mice, which often do not predict human biology. The preclinical research Scott conducted in his lab at Texas A&M is a tour de force in molecular genetics. He was able to identify and target a separate and distinct region of the Angelman syndrome message transcript that has led to more efficient transcript knockdown and greater potency in the clinic. This list of superior science has led us to study Angelman syndrome. Later in the call, Dr. Crombez will walk through the longer-term efficacy, durability, and safety data from the Phase 2 study in his section.

Speaker #3: The pre-clinical research Scott conducted in his lab at Texas A&M is a tour de force in molecular genetics. He was able to identify and target a separate and distinct region of the antecedent message transcript that has led to more efficient transcript knockdown and greater potency in the clinic.

Speaker #3: This was a superior science that led us to study Angelman Syndrome. Later in the call, Dr. Crombez will walk through the longer-term efficacy, durability, and safety data from the Phase 1-2 study in his section, but I want to highlight now that we have 66 patients on therapy for an average of three years and with the longest approaching five years.

Emil Kakkis: I want to highlight now that we have 66 patients on therapy for an average of 3 years, and with the longest approaching 5 years, with continuing and improving benefits across multiple domains and with a favorable safety profile. Based on this longer-term data, we believe GTX-102 can deliver clinically meaningful treatment effects and can be safely administered in chronic dosing. What we see in the Phase 2 data, we believe GTX-102 is making an important difference in the lives of these patients and their families. Shifting now to our global commercial efforts. Our commercial business continues to deliver. We're now generating revenue in more than 35 countries, a result of strategically investing in high-quality teams who can efficiently navigate the complex approval and reimbursement processes around the world. This reflects the disciplined country-by-country execution our teams deliver every quarter.

Speaker #3: With continuing and improving benefits across multiple veins, and with a favorable safety profile, based on this longer-term data, we believe GTX102 can deliver clinically meaningful treatment effects and can be safely administered in chronic dosing.

Speaker #3: What we see in the Phase 1-2 data, we believe GTX102 is making an important difference in the lives of these patients and their families.

Speaker #3: Shifting now to our global commercial efforts, our commercial business continues to deliver. We're now generating revenue in more than 35 countries as a result of strategically investing in high-quality teams who can efficiently navigate the complex approval and reimbursement processes around the world.

Speaker #3: This reflects a disciplined, country-by-country execution of our teams, deliver every quarter. This base business is not only generating meaningful and growing revenue, it is the engine that will power our next phase of growth.

Emil Kakkis: This base business is not only generating meaningful and growing revenue, it is the engine that will power our next phase of growth. Our teams currently commercializing DOJOLVI and MEPSEVII are poised to add DTX-401 and UX-111 to their responsibilities as we look forward to approvals for these two products later this year. Our established global commercial business is bringing first-ever treatments to patients who need them, paving the path to profitability in 2027. I'll now turn the call over to our Chief Commercial Officer, Erik Harris, who will provide details on his team's efforts in the Q1.

Speaker #3: Our teams currently commercialize Doljovi and Metzevi, our poise to add DTX401 and UX111 to their responsibilities as we look forward to approvals for these two products later this year.

Speaker #3: Our established global commercial business is bringing first-ever treatments to patients who need them, paving the path to profitability in 2027. I'll now turn the call over to our Chief Commercial Officer, Erik Harris, who will provide details on his team's efforts in the first quarter.

Speaker #2: Thank you, and good afternoon, everyone. As Emil mentioned, the underlying business remains strong and we are well positioned. To capitalize on the potential upcoming launches.

Erik Harris: Thank you, and good afternoon, everyone. As Emil mentioned, the underlying business remains strong, and we are well-positioned to capitalize on the potential upcoming launches. Howard will share details, but we remain fully confident in our 2026 revenue guidance. Throughout the Q1, the commercial and field teams have continued to meet the growing demand for our products across the globe. I'll start with Crysvita and want to put the Q1 revenue in the right context. The revenue in North America, Latin America, and Turkey was consistent with our expectations and the ordering patterns we have seen in prior years. This is a business we know well. We see continued strength in the underlying demand across all of our regions, including in markets like Brazil, where bulk orders by the Ministry of Health can result in quarter-to-quarter variability.

Speaker #2: Howard will share details but we remain fully confident in our 2026 revenue guidance. Throughout the first quarter, the commercial and field teams have continued to meet the growing demand for our products across the globe.

Speaker #2: I'll start with Crisfida. I want to put the first quarter revenue in the right context. The revenue in North America Latin America and Turkey was consistent with our expectations in the ordering patterns we have seen in prior years.

Speaker #2: This is a business we know well. We see continued strength in the underlying demand across all of our regions including in markets like Brazil, where bulk orders by the Ministry of Health can result in quarter-to-quarter variability.

Speaker #2: In Latin America, approximately 30 patients began commercial therapy in the first quarter, bringing the total number of patients on Crisfida to more than 950 in the region.

Erik Harris: In Latin America, approximately 30 patients began commercial therapy in the first quarter, bringing the total number of patients on Crysvita to more than 950 in the region. We remain fully confident in the fundamentals and strength of the business and along with our partner, KKC in North America, our ability to continue to find and treat patients with XLH and TIO. Shifting now to DOJOLVI, where the trend of our steady growth continues 6 years post-approval. In the first quarter, our North American team generated more than 30 start forms, far exceeding their target for the quarter. In North America, we now have more than 675 patients on reimbursed therapy, and in Europe, there are approximately 300 being treated through named patient or early access programs.

Speaker #2: We remain fully confident in the fundamentals and strength of the business, and along with our partner KKC in North America, our ability to continue to find and treat patients with XLH and TIO.

Speaker #2: Shifting now to Dojovi with a trend of our steady growth continues. Six years post-approval. In the first quarter, our North American team generated more than 30 start forms.

Speaker #2: Far exceeding their target for the quarter. In North America, we now have more than 675 patients on reimbursed therapy, and in Europe, there are approximately 300 being treated through named patient or early access programs.

Speaker #2: The next stage of growth is likely to come from Japan where Dojovi was granted conditional approval last year and we look forward to the full approval and launch of the product this quarter.

Erik Harris: The next stage of growth is likely to come from Japan, where DOJOLVI was granted conditional approval last year, and we look forward to the full approval and launch of the product this quarter. I'll close with Evkeeza, which is another example of our experienced team's ability to successfully commercialize rare disease products. In our region outside of the United States, we are seeing exceptional growth from this program as our international commercial teams navigate the country-by-country reimbursement process and respond to requests for early access from patients and their physicians. In total, there are approximately 370 patients across 18 countries who are receiving Evkeeza. We expect this will continue to be an important and growing contributor to our revenue base.

Speaker #2: I'll close with Evkiza, which is another example of our experience team's ability to successfully commercialize rare disease products. In our region outside of the United States, we are seeing exceptional growth from this program as our international commercial teams navigate the country-by-country reimbursement process and respond to requests for early access from patients and their physicians.

Speaker #2: In total, there are approximately 370 patients across 18 countries who are receiving Evkiza. We expect this will continue to be an important and growing contributor to our revenue base.

Speaker #2: Beyond the individual product performance, I want to step back and highlight what I believe is the true strength of this business. The scale and reach of our global commercial infrastructure.

Erik Harris: Beyond the individual product performance, I want to step back and highlight what I believe is the true strength of this business, the scale and reach of our global commercial infrastructure. That depth of market presence across rare disease markets that require significant expertise, patient finding capability, and reimbursement navigation is a genuine advantage. It is what enables us to efficiently bring first-ever treatments to rare disease patients. Critically, this infrastructure and experienced team are what give me confidence as we look toward the rest of the year. My team is preparing for two new product launches, DTX-401, with a PDUFA date of 23 August 2026. UX111 with a PDUFA date of 19 September 2026. The launch readiness work is well underway across both programs, and we are building on the infrastructure and expertise we have already established.

Speaker #2: That depth of market presence across rare disease markets that require significant expertise patient finding capability and reimbursement navigation is a genuine advantage. It is what enables us to efficiently bring first-ever treatments to rare disease patients.

Speaker #2: And critically, this infrastructure and experienced team are what give me confidence as we look toward the rest of the year. My team is preparing for two new product launches.

Speaker #2: DTX401 with a Purdue for date of August 23, 2026 and UX111 with a Purdue for date of September 19, 2026. The launch readiness work is well underway across both programs and we are building on the infrastructure and expertise we have already established.

Speaker #2: With that, I'll turn the call to Howard to share more details on our financial results and guidance.

Erik Harris: With that, I'll turn the call to Howard to share more details on our financial results and guidance.

Speaker #3: Thank you, Eric, and good afternoon, everyone. I'll focus on our first quarter financial results and guidance for the year. Starting with revenue, total revenue for the first quarter of 2026 was $136 million.

Howard Horn: Thank you, Eric, and good afternoon, everyone. I'll focus on our Q1 financial results and guidance for the year. Starting with revenue, total revenue for Q1 2026 was $136 million. Crysvita contributed $93 million, including $39 million from North America, $46 million from Latin America and Turkey, and $8 million from Europe, which were consistent with the anticipated quarterly timing and trends Eric just mentioned. DOJOLVI contributed $18 million, consistent with our expectation for steady demand growth. Evkeeza also contributed $18 million, representing 64% growth over Q1 2025 as demand continues to build following launches in our territories outside of the United States. Lastly, MEPSEVII contributed $7 million as we continue to treat patients in this ultra-rare indication.

Speaker #3: Crisfida contributed $93 million including $39 million from North America $46 million from Latin America and Turkey and $8 million from Europe, which were consistent with the anticipated quarterly timing and trends Eric just mentioned.

Speaker #3: Dojovi contributed $18 million consistent with their expectation for steady demand growth. Evkiza also contributed $18 million representing 64% growth over the first quarter of 2025 as demand continues to build following launches in our territories outside of the United States.

Speaker #3: Lastly, Metsebi contributed $7 million as we continue to treat patients in this ultra-rare indication. Total operating expenses for the quarter were $305 million which included cost of sales of $30 million and combined R&D and SG&A expenses of $275 million.

Howard Horn: Total operating expenses for the quarter were $305 million, which included cost of sales of $30 million and combined R&D and SG&A expenses of $275 million. Total operating expenses included $30 million of non-cash stock-based compensation and $30 million of expenses related to the restructuring announced last quarter. For the quarter, net loss was $185 million or $1.84 per share. As of 31 March, we had $534 million in cash equivalents and marketable securities. Net cash used in operations for the quarter was $197 million. Recall, in the Q1 of the year, we typically use more operating cash than in each of the subsequent 3 quarters because it includes items like the payment of annual bonuses.

Speaker #3: Total operating expenses included $30 million of non-cash stock-based compensation and $30 million of expenses related to the restructuring announced last quarter. For the quarter, net loss was $185 million or $1.84 per share.

Speaker #3: As of March 31, we had $534 million in cash cash equivalents and marketable securities. Net cash used in operations for the quarter was $197 million.

Speaker #3: Recall, in the first quarter of the year, we typically use more operating cash than in each of the subsequent three quarters because it includes items like the payment of annual bonuses.

Speaker #3: In addition, the first quarter of 2026 included $38 million in payments related to UX143 manufacturing activities as well as $5 million related to severance and other payments from our recent reduction in force.

Howard Horn: In addition, Q1 2026 included $38 million in payments related to UX143 manufacturing activities, as well as $5 million related to severance and other payments from our recent reduction in force. Net cash used in operations are expected to decrease in the remaining quarters of this year as we continue on our pathway to profitability in 2027. Shifting now to guidance for 2026, we are reaffirming the revenue guidance we provided in February. Total revenue in 2026 is expected to be between $730 to 760 million, which represents 8% to 13% growth over 2025 and excludes potential revenue from new product launches. Crysvita revenue is expected to be between $500 to 520 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx.

Speaker #3: Net cash used in operations are expected to decrease in the remaining quarters of this year as we continue on our pathway to profitability in 2027.

Speaker #3: Shifting now to guidance for 2026, we are reaffirming the revenue guidance we provided in February. Total revenue in 2026 is expected to be between $730 million and $760 million.

Speaker #3: Which represents 8 to 13% growth over 2025 and excludes potential revenue from new product launches. Crisfida revenue is expected to be between $500 and $520 million, which includes all regions and all forms of Crisfida revenue to Ultragenyx.

Speaker #3: This range reflects growing underlying global demand partially offset by expected timing of ordering patterns in Brazil that we anticipate will normalize in 2027. Dojovi revenue is expected to be between $100 and $110 million.

Howard Horn: This range reflects growing underlying global demand, partially offset by expected timing of ordering patterns in Brazil that we anticipate will normalize in 2027. DOJOLVI revenue is expected to be between $100 to 110 million. We are also reaffirming the R&D and SG&A guidance we provided on our last call. Specifically, we expect 2026 combined R&D and SG&A expenses to be flat to down low single digits versus 2025. We also continue to expect 2027 combined R&D and SG&A expenses to decrease at least 15% in 2027 versus 2025. With that, I'll turn the call to our Chief Medical Officer, Eric Crombez.

Speaker #3: We are also reaffirming the R&D and SG&A guidance we provided on our last call. Specifically, we expect 2026 combined R&D and SG&A expenses to be flat to down low single digits versus 2025.

Speaker #3: We also continue to expect 2027 combined R&D and SG&A expenses to decrease at least 15% in 2027 versus 2025. With that, I'll turn the call to our chief medical officer, Eric Crombez.

Speaker #4: Thank you, Howard, and good afternoon, everyone. As Amel mentioned in the opening, I'll focus on the clinically meaningful phase one two data that we have generated with GTX102, our anti-sense oligonucleotide for the treatment of Angelman syndrome.

Eric Crombez: Thank you, Howard, and good afternoon, everyone. As Emil mentioned in the opening, I'll focus on the clinically meaningful phase I/II data that we have generated with GTX-102, our antisense oligonucleotide for the treatment of Angelman syndrome. This data is from our phase I/II open label single-arm studies, which inform the design of the phase III double-blind sham-controlled ASPIRE study. Given the differences in study design, these phase I/II results are not necessarily predictive of phase III outcomes. In our press release earlier today, we highlighted that a total of 74 patients have been treated with GTX-102 as part of our phase I/II program. This is one of our largest phase I/II studies we have conducted and was designed to inform the dose regimen, and endpoints for our phase III studies.

Speaker #4: This data is from our phase one two open label open label single arm studies which inform the design of the phase three double-blind sham control despire study.

Speaker #4: Given the differences in study design, these phase 1/2 results are not necessarily predictive of phase 3 outcomes. In our press release earlier today, we highlighted that a total of 74 patients have been treated with GTX-102 as part of our phase 1/2 program.

Speaker #4: This is one of our largest phase one two studies we have conducted and was designed to inform the dose, dose regimen, and endpoints for our phase three studies.

Speaker #4: There are now 66 patients in the long-term extension study, with patients generally receiving the 14-milligram quarterly intrathecal maintenance dose. These patients have now been on continuous therapy for an average of three years, and some patients are now in their fifth year of treatment.

Eric Crombez: There are now 66 patients in long-term extension study, with patients generally receiving the 14-milligram quarterly intrathecal m-maintenance dose. These patients have now been on continuous therapy for an average of 3 years, and some patients are now in their 5th year of treatment. These patients continue to demonstrate improvement across multiple developmental domains, with no new cases of transient lower extremity weakness. We took a cut of this data in March of this year to be able to highlight the long-term safety and efficacy of GTX-102 in a forthcoming manuscript. I wanted to share a high-level summary today. Starting with the Bayley-IV cognitive raw score, there are 53 patients in the phase 1 2 study with a Bayley-IV cognitive raw score at month 12.

Speaker #4: These patients continue to demonstrate improvement across multiple developmental domains with no new cases of transient lower extremity weakness. We took a cut of the data in March of this year to be able to highlight the long-term safety and efficacy of GTX102 and a forthcoming manuscript and I wanted to share a high-level summary today.

Speaker #4: Starting with the Bailey IV cognitive raw score, there are 53 patients in the phase one two study with a Bailey IV cognitive raw score at month 12.

Speaker #4: At this time point, they were approaching a mean change from baseline of 10 points, exceeding the meaningful score difference of six points, and with longer-term follow-up, we see continuing and improving benefits in cognition.

Eric Crombez: At this time point, they were approaching a mean change from baseline of 10 points, exceeding the meaningful score difference of 6 points, and with longer-term follow-up, we see continuing and improving benefits in cognition. Turning to the Multidomain Responder Index, or MDRI, that uses clinically meaningful score differences consistent with FDA guidance as opposed to statistically driven changes to determine a positive or negative response across 5 different developmental domains. In the Phase 1 2 data set, we now have MDRI data at month 12, 24, and 36 that evaluates response across cognition, communication, behavior, sleep, and gross motor. When comparing response to baseline, the P value across all three time points is less than 0.0001. Not only is this a very powerful statistical assessment of 5 different measures, it is consistent with doctors' and families' broader view of neurologic diseases like Angelman.

Speaker #4: Turning to the Multi-Domain Responder Index, or MDRI, that uses clinically meaningful score differences, consistent with FDA guidance, as opposed to statistically driven changes, to determine a positive or negative response across five different developmental domains.

Speaker #4: In the phase one two data set, we now have MDRI data at month 12, 24, and 36 that evaluates response across cognition, communication, behavior, sleep, and gross motor.

Speaker #4: When comparing response to baseline, the p-value across all three time points is less than 0.0001. Not only is this a very powerful statistical assessment of five different measures, it is consistent with doctors and families' broader view of neurologic diseases like Angelman.

Speaker #4: It is the intersection of all of these developmental changes that reflect how individual patients truly respond to a treatment in a holistic way. In the 48-week ESPIRE phase three study, we have primary statistical alpha split between the Bailey IV cognitive raw score and the MDRI.

Eric Crombez: It is the intersection of all of these developmental changes that reflect how individual patients truly respond to a treatment in a holistic way. In the 48-week ASPIRE Phase 3 study, we had primary statistical alpha split between the Bayley-IV cognitive raw score and the MDRI. This is not a hierarchical evaluation, meaning that both of these endpoints will be tested in parallel. If the Bayley cognition hits less than 0.04 or if MDRI hits less than 0.01, we will have a statistically successful Phase 3 study. We also took a look at expressive communication in our Phase 1/2 study assessed by the Bayley-IV. Similar to cognition, we saw meaningful improvements in expressive communication that continued and improved in longer-term follow-up.

Speaker #4: This is not a hierarchical evaluation. Meaning that both of these endpoints will be tested in parallel. If the Bailey cognition hits less than 0.04 or if MDRI hits less than 0.01, we will have a statistically successful phase three study.

Speaker #4: We also took a look at expressive communication in our Phase 1/2 study, assessed by the Bayley IV. Similar to cognition, we saw meaningful improvements in expressive communication that continued and improved in longer-term follow-up.

Speaker #4: Based on the totality of data generated in our phase one two program, I remain confident that the developmental progress and continued learning of new skills in these patients supports a meaningful benefit of using this ASO to provide UBE3A from the paternal allele.

Eric Crombez: Based on the totality of data generated in our Phase 1/2 program, I remain confident that the developmental progress and continued learning of new skills in these patients supports the meaningful benefit of using this ASO to provide UBE3A from the paternal allele. I'm looking forward to seeing the results from our Phase 3 studies and the potential to replicate these results in larger controlled studies. I'll now turn the call back to Emil to provide a reminder of our catalyst for 2026 and some closing remarks.

Speaker #4: I'm looking forward to seeing the results from our phase three studies and the potential to replicate these results in larger controlled studies. I'll now turn the call back to Amel to provide a reminder of our catalyst for 2026 and some closing remarks.

Speaker #4: Thank you, Eric. I'll close with a few of the catalysts we have later this year. A full list can be seen in the corporate deck posted to our website.

Emil Kakkis: Thank you, Eric. I'll close with a few of the catalysts we have later this year. A full list can be seen in the corporate deck posted to our website. Starting with DTX-401 for the treatment of Glycogen Storage Disease Type 1a, we continue to work well with the FDA and look forward to our PDUFA action date of 23 August. The FDA has also informed us an ad com is not planned. Next, for UX-111 for the treatment of Sanfilippo syndrome, the BLA that was resubmitted early this year is being reviewed with a PDUFA action date of 19 September. Lastly, GTX-102 for the treatment of Angelman syndrome is on track to read out top-line Phase 3 data from the ASPIRE study in H2 of the year.

Speaker #4: Starting with GTX401 for the treatment of glycogen surge disease type 1A, we continue to work well with the FDA and look forward to our PDUPA action date of August 23rd.

Speaker #4: The FDA is also informed us that an ADCOM is not planned. Next, for UX111 for the treatment of Sanfilippo syndrome, the BLA that was resubmitted earlier this year is being reviewed with the PDUPA action date of September 19th.

Speaker #4: Lastly, GTX102 for the treatment of Angelman syndrome, is on track to read out top-line phase three data from the ESPIRE study in the second half of the year.

Speaker #4: Ultragenyx has been one of the most productive companies in rare disease companies in the industry and taking programs from early research to approved therapies for patients who have no other options.

Emil Kakkis: Ultragenyx has been one of the most productive rare disease companies in the industry and taking programs from early research to approved therapies for patients who have no other options. We've done it across multiple modalities, multiple therapeutic areas, and we look forward to bringing the next set of first-ever treatments to the patients who need them. The surge in late-stage programs in the last 2 years has challenged us like it would anyone, but the benefit is once we turn the corner of these programs into approved products, we have the potential for a significant acceleration in our growth that will be a special moment in the history of Ultragenyx. With that, let's move on to your questions. Operator, please provide the Q&A instructions.

Speaker #4: We've done it across multiple modalities, multiple therapeutic areas, and we look forward to bringing the next set of first-ever treatments to the patient's needs and the surgeon late-stage programs in the last two years has challenged us like it would anyone.

Speaker #4: But the benefit is that once we turn the corner of these programs into approved products, we have the potential for a significant acceleration in our growth that will be a special moment in the history of Ultragenyx.

Speaker #4: With that, let's move on to your questions, operator. Please provide the Q&A instructions.

Speaker #3: Thank you. At this time, we'll be conducting a question-and-answer session. If you'd like to ask a question, please press star one on your telephone keypad.

Operator: Thank you. Our first question comes from Tazeen Ahmad with Bank of America. Your line is now live.

Speaker #3: Confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue.

Speaker #3: As a reminder, we ask that you please limit to one question and one follow-up. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys.

Speaker #3: One moment, please, while we poll for questions. My first question comes from Taseen Ahmad, with Bank of America. Your line is now live.

Speaker #5: Hey, guys. This is Daniel on for Taseen. Thank you for taking our question. the new update for Angelman's. What level of consistency are you seeing for patients improving on the Bailey IV and the MDRI?

[Analyst] (Bank of America): Hey, guys. This is Daniel on for Tazeen. Thank you for taking our question. I was just wondering if you could comment on the new update for Angelman. Like, what level of consistency are you seeing for patients improving on the Bayley-IV and the MDRI? You know, how, kinda how we should think about variability between the two endpoints for the phase 3? Thank you.

Speaker #5: And kind of how we should think about variability between the two endpoints for the phase three. Thank you.

Emil Kakkis: I'll touch on it. Maybe Eric can add some more. I think the Bayley that we're conducting is being done with primarily with an outside firm that's coming and doing the test at the site. We're running a very high-quality operation in terms of how we'll measure the test to help reduce variability. I think the consistency is something we can't comment on at this point in a Phase 3 study, but we can talk about how it's looked in Phase 2. I think it should be expected to be similar to what we've seen before, and I think the MDRI has been a very robust and consistent measure just in its nature because of its multiple domains that we've seen strong results, and I think Eric just talked about them. Eric, what do you think about the Bayley-IV consistency?

Speaker #4: I'll touch on it. Maybe Eric can add some more. I think the Bailey that we're conducting is being done with primarily with an outside firm that's coming and doing the test at the site.

Speaker #4: So this is—we're running a very high-quality operation in terms of how we'll measure the test to help reduce variability. I think the consistency is something we can't comment on at this point in a Phase 3 study, but we can talk about how it's looked in Phase 2.

Speaker #4: I think it should be expected to be similar to what we've seen before. And I think the MDRI has been a very robust and consistent measure just in its nature, because it has multiple domains.

Speaker #4: That we've seen strong results. And I think Eric just talked about them. So, Eric, what do you think about the Bailey IV consistency?

Speaker #6: Yeah. So I think looking at the results from phase one, two, and varying multiplied to how we design phase three, the most important thing we did was include patients with full deletions.

Eric Crombez: Yeah. I think, you know, looking at the results from Phase 1/2 and very much applied to how we designed Phase 3, the most important thing we did was include patients with full deletions. This means they're expressing no UBE3A and gives you a very consistent patient population, driving those consistent results we saw in Phase 2 and what we think will be replicated there. Then again, as a reminder, bringing patients with other mutations that add variability into our second Phase 3 study, AURORA.

Speaker #6: This means they're expressing no UBE3A and gives you a very consistent patient population driving those consistent results we saw in phase two and what we think will be replicated there.

Speaker #6: And then again, as a reminder, bringing patients with other mutations that, as variability, into our second phase three study Aurora.

Speaker #5: Yeah, that's a very good point, Eric. Yeah. Consistent genetic type will definitely help us get consistency particularly consistency in what the placebo or the untreated the sham will do because without treatment, patients with Angelman do not gain on the Bailey IV.

Emil Kakkis: Yeah, that's a very good point, Eric. Yeah. Consistent genotype will definitely help us get consistency, particularly consistency in what the placebo or the untreated, the sham will do because without treatment, patients with Angelman do not gain on the Bayley-IV significantly. Let's move on to the next question.

Speaker #5: Significantly. Let's move on to the next question.

Operator: Our next question comes from Joseph Schwartz with Leerink Partners. Your line is now live.

Speaker #3: Our next question comes from Joseph Schwartz with Lorinck Partners. Your line is now live.

Speaker #4: Great, thanks very much. So, a couple of questions on GTX102. In ESPIRE, are you stratifying randomization or prespecifying subgroups by any baseline factors? It seems like in rare pediatric trials, even modest imbalances in baseline severity could be important.

Joseph Schwartz: Great. Thanks very much. A couple questions on GTX-102. In ASPIRE, are you stratifying randomization or pre-specifying subgroups by any baseline factors? It seems like in rare pediatric trials, even modest imbalances in baseline severity could be important, and there's some literature in Angelman that this could influence variability. I'm just wondering how confident you are that ASPIRE is protected against any potential baseline imbalances.

Speaker #4: And there's some literature in Angelman that this could influence variability. I'm just wondering how confident you are that ESPIRE is protected against any potential baseline imbalances.

Emil Kakkis: Well, thanks, Joe. I'll let Eric answer specific. In general, for all of our programs, we are very aware of this whole skewing issue on the randomization. We will always, for primary endpoints, we'll stratify our primary endpoint, do our best we can. However, nothing is perfect. What are we doing for Angelman?

Speaker #5: Well, thank you. I'll let Eric answer specifically. In general, for all of our programs, we are very aware of this whole skewing issue on the randomization.

Speaker #5: So we will always, for primary endpoints, we'll stratify our primary endpoint. Do our best we can. However, nothing is perfect. So what are we doing for Angelman?

Eric Crombez: Yeah. Specifically for ASPIRE, we stratify both by age and cognitive raw score. That being our primary endpoint, we want to make sure we have consistent balance there.

Speaker #6: Yeah. So specifically for ESPIRE, we stratify both by age and cognitive raw score. That being our primary endpoint. We want to make sure we have consistent balance there.

Speaker #4: Okay. And then we noticed that you haven't narrowed the timing for ESPIRE top-line data yet. Do you have any sense when during the second half of '26 you might report the data?

Joseph Schwartz: Okay. We noticed that you haven't narrowed the timing for ASPIRE top-line data yet. Do you have any sense when, during H2 2026 you might report the data? Is late Q3 a good assumption since you finished enrollment in late July last year?

Speaker #4: Is late third quarter a good assumption since you finished enrollment in late July last year?

Speaker #5: It's fine, isn't it? Keeping you in the dark about exactly when it's happening. Yes. I think you probably can guess based on the timing of things.

Emil Kakkis: It's fun, isn't it? Keeping you in the dark about exactly when it's happening. Yes. I think you probably can guess based on the timing of things. The question is that when you close out an international study, a lot of endpoints, you do want to do it carefully. We're not being precise on that only because we want to give ourselves time to get everything straight before we do unblinding. We've said the H2, but you can tell by when last patient in was, you know, roughly when the trial should have the last patient out. The timing it takes to finish up a study with sham, there's EEG, there's a lot of things in there that will take a little time. We, you know, give it a phase.

Speaker #5: The question is that when you close out an international study, a lot of endpoints you do want to do it carefully. And so we're not being precise on that only because we want to give ourselves time to get everything straight before we do unblinding.

Speaker #5: We've said the second half, but you can tell by when last patient in was roughly when the trial should have the last patient out.

Speaker #5: But the timing it takes to finish up a study with sham, there’s EEGs, there’s a lot of things in there that will take a little time.

Speaker #5: So we give it a phase three program. We're going to take the time to make sure we're being a little unspecific now. But it's all on track.

Emil Kakkis: We probably want to take the time to make sure we're being a little nonspecific now, but it's all on track.

Speaker #4: Thank you.

Joseph Schwartz: Thank you.

Speaker #3: Our next question comes from Maury Raycroft with Jefferies. Your line is now live.

Operator: Our next question comes from Maury Raycroft with Jefferies. Your line is now live.

Maury Raycroft: Hi, thanks for taking my questions and congrats on the progress. The phase 1/2 longer-term commentary is helpful. Just clarifying, could we see the detailed phase 1/2 data ahead of the phase 3 top line? It seems like you're seeing a clearer stat sig signal on MDRI in the phase 1/2. Based on the point improvement you mentioned for cognition, I'm wondering if you're seeing a stat sig p-value for cognition versus the natural history study data set.

Speaker #7: Hi. Thanks for taking my questions and congrats on the progress. The phase one, two longer-term commentary is helpful. Just clarifying could we see the detailed phase one, two data ahead of the phase three top line?

Speaker #7: And it seems like you're seeing a clearer static signal on MDRI in the phase one, two and based on the point improvement you mentioned for cognition.

Speaker #7: I'm wondering if you're seeing a static p-value for cognition versus your versus the natural history study data set.

Speaker #4: Well, I think we've commented on the primary endpoint natural history comparison before in our powering analyses. I think we've said that, that we would be well-powered.

Emil Kakkis: Well, I think we've commented on the primary endpoint natural history comparison before in our powering analyses. I think we've said that we would be well-powered. I think that that's already sort of an analysis. The MDRI is just extremely powerful method. I think it's the way forward for neurologic diseases. Your question you asked, will you see the detailed data? Probably not. I think we haven't set which science meeting the data will come out yet. I would assume be later in the year. We have often presented things at the FAST conference, but we haven't set at this point a plan for the phase 2 data. It's not necessarily ahead of phase 3 at this point.

Speaker #4: So I think that that's already sort of an analysis. The MDRI is just extremely powerful method. I think it's a way forward for neurologic diseases.

Speaker #4: Your question you asked, will you see the detailed data? Probably not. I think we haven't set which science meeting the data will come out yet.

Speaker #4: I would assume it'd be later in the year. We have often presented things at the FAST conference, but we haven't set at this point a plan for the phase two data.

Speaker #4: But it's not necessarily ahead of phase three at this point. But we wanted to put out a little bit of data now just to give people confidence about what's going on and just give you a sense of the magnitude and outcome and the fact that we're confident about how the drug looks and that it's continues to show good safety and the kind of cognitive benefit and MDRI benefit that gives us confidence in the design and what we're conducting in phase three.

Emil Kakkis: We wanted to put out a little bit of data now just to give people confidence about what's going on and just give you a sense of the magnitude and outcome and the fact that we're confident about how the drug looks and that it continues to show good safety and the kind of cognitive benefit and MDRI benefit that gives us confidence in the design and what we're conducting in phase 3.

Speaker #7: Got it. That's helpful. Maybe one other question. Just wondering if prior to the database lock-in stats plan, do you have to have any discussions with FDA on magnitude of improvement on the primary endpoints or is it just showing a static benefit?

Maury Raycroft: Got it. That's helpful. Maybe one other question. It is just wondering if prior to the database lock and stats plan, do you have to have any discussions with FDA on magnitude of improvement on the primary endpoints, or is it just showing a stat sig benefit? Is that sufficient?

Speaker #7: Is that sufficient?

Speaker #4: Yeah. There's no regulatory step between us and unblinding at this point. We're all agreed. And there is no defined required minimally change for the Bailey.

Emil Kakkis: There's no regulatory step between us and unblinding at this point. We're all agreed, and there is no defined required minimally important change for the Bayley. I think that is something that we don't need in the design. It's a continuous variable. However, we will always have what is known as a critically, you know, clinically important change of 5 points. We'll always look at data that way, but the powering of the primary endpoint for Bayley cognition is based on a continuous analysis, which is really the appropriate thing to do. If you look at the numbers we just told you, 10, that is, you know, almost twice the MI, minimally important difference already. I think we're at a pretty good place.

Speaker #4: I think that is something that we don't need in the design. It's a continuous variable. However, we will always have what is known as a critical clinically important change of five points.

Speaker #4: We'll always look at data that way. But the powering of the primary endpoint for Bailey cognition is based on a continuous analysis, which is really the appropriate thing to do.

Speaker #4: But if you look at the numbers we just told you, 10, that is almost twice the minimally important difference already. So I think we're at a pretty good place.

Speaker #7: Got it. Thanks for taking my questions.

Maury Raycroft: Got it. Thanks for taking my questions.

Speaker #3: Our next question comes from New Palm Rama with JPMorgan. Your line is now live.

Operator: Our next question comes from Anupam Rama with JPMorgan. Your line is now live.

[Analyst] (J.P. Morgan): Hey, guys, this is Joy on for Anupam. Thanks for taking our question. Maybe just one on the two upcoming gene therapy launches, DTX401 and UX-111 in H2. Could you just discuss where you are in terms of commercial manufacturing and product scale-up and just your overall readiness from a CMC launch perspective? Thanks so much.

[Analyst] (JPMorgan): Hey, guys, this is Joy on for Anupam. Thanks for taking our question. Maybe just one on the two upcoming gene therapy launches, DTX401 and UX-111 in H2. Could you just discuss where you are in terms of commercial manufacturing and product scale-up and just your overall readiness from a CMC launch perspective? Thanks so much.

Speaker #8: Hey, guys. This is Joyce on for Unapom. Thanks for taking our question. Maybe just one on the two upcoming gene therapy launches, GTX401 and UX111 in the back half of the year.

Speaker #8: Could you just discuss where you are in terms of commercial manufacturing and product scale-up and just your overall readiness from a launch perspective from a CMC launch perspective?

Speaker #8: Thanks so much.

Speaker #4: Yeah, no, good question. I think we've been manufacturing, actually, since last year. And for GTX401, the drug substance and drug product are both made at the plant.

Emil Kakkis: Yeah, no, good question. I think we've been manufacturing actually since last year. For DTX401, the drug substance, drug product are both made at the plant in Bedford. For UX-111, we have a contract manufacturer that's making drug substance in Ohio, and we're finishing the fill finish in our Bedford plant. We've been running runs last year and this year, and that's part of our expenses that we're spending money on is actually building inventory, and that's been going well. We're building inventory and feel like we should be a reasonable position at the time of launch at this point. I think we're ready. I think the launch teams have been working on their work. I think the two PDUFA dates are quite close to each other, but the doctors we're going to are actually the same doctors.

Speaker #4: And in Bedford. And then for UX111, we have a contract manufacturer that's making drug substance in Ohio. And we're making or finishing the full finish in our Bedford plant.

Speaker #4: We've been running runs last year. And this year, I think that's part of our expenses that we're spending money on is actually building inventory.

Speaker #4: And that's been going well. And we're building inventory and feel like we should be in a reasonable position at the time of launch. At this point.

Speaker #4: So I think we're ready. I think the launch teams have been working on their work. I think the two PDUFA dates are quite close to each other.

Speaker #4: But the doctors were going to our actually the same doctors. And there's certain synergy that will happen by having the same quality most of the centers will be doing both products.

Emil Kakkis: There's certain synergy that will happen by having the same quality. Most of the centers will be doing both products. Some may do one or the other, but the qualified treatment centers are getting set up, contracts in place. I think the synergy with having two of them will be real, and we're excited about the possibility. Of course, we still need to get approval, but at this point, from both manufacturing and commercial standpoint, we're set up and moving forward and excited about the prospects of launching two gene therapy products.

Speaker #4: I'm going to do one or the other. But the qualified treatment centers are getting set up. Contracts in place. And I think the synergy with having two of them will be real.

Speaker #4: And we're excited about the possibility. Of course, we still need to get approval. But at this point, from both manufacturing and commercial standpoint, we're set up and moving forward and excited about the prospects of launching two gene therapy products.

Speaker #8: Great. Thank you.

Luca Issi: Great. Thank you.

[Analyst] (JPMorgan): Great. Thank you.

Speaker #3: Our next question is from Ellie Merrill with Barclays Bank. Your line is now live.

Operator: Our next question is from Ellie Merrill with Barclays Bank. Your line is now live.

Speaker #8: I think I was saying so much for taking my question. Just can you give us any more color on how we should think about the timelines for getting data from the Aurora study?

Ellie Merrill: Hey, guys. Thanks so much for taking the question. Just can you give us any more color on how we should think about the timelines for getting data from the AURORA study? If the data are positive in the phase 3 ASPIRE trial, how are you thinking about what your base case will be for the ages in a potential Angelman label, and if this will include adults? Thanks so much.

Ellie Merle: Hey, guys. Thanks so much for taking the question. Just can you give us any more color on how we should think about the timelines for getting data from the AURORA study? If the data are positive in the phase 3 ASPIRE trial, how are you thinking about what your base case will be for the ages in a potential Angelman label, and if this will include adults? Thanks so much.

Speaker #8: And if the data are positive in the phase three ASPIRE trial, how are you thinking about what your base case will be for the ages in a potential Angelman label?

Speaker #8: And if this will include adults? Thanks so much.

Speaker #4: Thank you. So Aurora is how we're going to expand the label to other indication-type genotypes and ages. So the main ASPIRE study is four to 17, all deletion.

Emil Kakkis: Thank you. AURORA is how we're going to expand the label to other indication type genotypes and ages. The main ASPIRE study is 4 to 17, all deletion. We have a younger group, the older group, and the other genotypes involved in AURORA. The study is still continuing to enroll and enrolling well, but it's also an international study, and we'll continue to collect data. We'll have some data at that time. We haven't really said through anything about how we'd approach our filing launch at this point in time. We're going to wait and see what the data look like and put together our plans. The study with AURORA, though, is still more enrollment to do.

Speaker #4: And so we have a younger group. The older group and the other genotypes involved in Aurora. The study is still continuing to enroll. And enrolling well.

Speaker #4: But it's also an international study, and we'll continue to collect data, so we'll have some data at that time. We haven't really said anything about how we'd approach our filing launch at this point in time.

Speaker #4: We're going to wait and see what the data look like. And our put together our plans. The study with Aurora, though, is still more enrollment to do.

Speaker #8: Great. Thanks.

Ellie Merrill: Great. Thanks.

Ellie Merle: Great. Thanks.

Speaker #3: Our next question comes from Yvonne Warber with TD Securities. Your line is now live.

Operator: Our next question comes from Jeroen Roober with Truist Securities. Your line is now live.

Speaker #7: Hi, everyone. This is Stephen on for your own. Thanks for taking my question. And really appreciate the color on Angelman. You mentioned the 14-mig.

[Analyst] (Truist Securities): Hi, everyone. This is Steven on for Jeroen. Thanks for taking my question, and really appreciate the color on Angelman. You mentioned the 14 mg was generally the maintenance dose being used. Can you give us some color on, you know, whether there might be more than one dose being used, why that might be happening, and whether there could be more than one maintenance dose in the label? Secondly, in terms of profitability projections, given that PRVs are selling for, you know, substantially over $100 million at this point, any color on what you're modeling in terms of PRV monetization and whether we can expect that full year 2027 profitability to be sustainable? Thanks.

[Analyst] (TD Securities): Hi, everyone. This is Steven on for Jeroen. Thanks for taking my question, and really appreciate the color on Angelman. You mentioned the 14 mg was generally the maintenance dose being used. Can you give us some color on, you know, whether there might be more than one dose being used, why that might be happening, and whether there could be more than one maintenance dose in the label? Secondly, in terms of profitability projections, given that PRVs are selling for, you know, substantially over $100 million at this point, any color on what you're modeling in terms of PRV monetization and whether we can expect that full year 2027 profitability to be sustainable? Thanks.

Speaker #7: Was generally the maintenance dose being used? Can you give us some color on whether there might be more than one dose being used? Why that might be happening?

Speaker #7: And whether there could be more than one maintenance dose in the label? And secondly, in terms of profitability projections, given that PRVs are selling for substantially over 100 million at this point, any color on what you're modeling in terms of PRV monetization and whether we can expect that full year 27 profitability to be sustainable?

Speaker #7: Thanks.

Speaker #4: Okay. Well, I'll touch on the dose high level. I don't know if Eric has anything more to add. But then I'll let Howard deal with the PRVs and profitability question.

Emil Kakkis: Okay. Well, I'll touch on the dose of high level. I don't know if Eric Crombez has anything more to add, but then I'll let Howard Horn deal with the PRVs and profitability question. The vast majority of patients are 14, and from the main trial, the protocol actually in ASPIRE brings them to 14 in terms of how it's done. There are some patients that certainly been on drug for longer periods of time in various regimens. I don't know if there's anything else to add. I think it's a very high fraction around 14.

Speaker #4: So the vast majority of patients are 14. And from the main trial, the protocol actually in ASPIRE brings them to 14 in terms of how it's done.

Speaker #4: There are some patients that certainly have been on drug for longer periods of time in various regimens. So I don't know if there's anything else to add.

Speaker #4: I think it's a very high fraction that are on 14.

Speaker #9: Yeah. And that is what we expect to label on. So we expect our maintenance dose of 14 milligrams every three months. Once we get into commercialized setting, we have our DMP.

Howard Horn: Yeah. That is what we expect to label on. We expect, you know, our maintenance dose of 14 milligrams every 3 months. You know, once we get into commercialized setting, we have our DMP, we can explore, you know, potentially different dosing. You know, maybe some patients would benefit from every 2 months, some could benefit from a higher dose there too. Our plan is to, after discussions with the FDA with a 14 milligram maintenance dose.

Eric Crombez: Yeah. That is what we expect to label on. We expect, you know, our maintenance dose of 14 milligrams every 3 months. You know, once we get into commercialized setting, we have our DMP, we can explore, you know, potentially different dosing. You know, maybe some patients would benefit from every 2 months, some could benefit from a higher dose there too. Our plan is to, after discussions with the FDA with a 14 milligram maintenance dose.

Speaker #9: We can explore potentially a different dosing maybe some patients would benefit from every two months. Some could benefit from a higher dose there too.

Speaker #9: But our plan is to proceed after discussions with the FDA with a 14-milligram maintenance dose.

Emil Kakkis: That's really the main source of what's you're going to see. Howard?

Speaker #4: That's really the main source of what you're going to see. So Howard, so with regard to the PRV, we watched this with interest to see how they've been selling.

Howard Horn: With regard to the PRV, we, you know, we watch this with interest to see how they've been selling. As part of our plans, we have two PRVs we plan to monetize, one for UX111 and one for DTX401. You know, I think we've stated in the past that we've baked it into our model at a little over $100 million each. Anything above that would be upside. Of course, there's also an opportunity for a PRV with GTX-102, which would also be upside to our model. That's how we're thinking about monetization. I think you'd also asked the question about sustainability of profitability post-2027. You know, our plan is to not just hang out at the razor's edge, but to continue to grow profitability.

Speaker #4: As part of our plans, we have two PRVs we plan to monetize, one for 111 and one for 401. I think we've stated in the past that we've baked it into our model at a little over 100 million each.

Speaker #4: So anything above that would be upside. Of course, there's also an opportunity for a PRV with 102, which would also be upside to our model.

Speaker #4: So that's how we're thinking about monetization. And I think you'd also asked the question about sustainability of profitability post-27. Our plan is to not just hang out at the razor's edge, but to continue to grow profitability.

Speaker #4: And depending on the launches we have and their success, we'll figure out how much we can reinvest back into the pipeline versus drop to the bottom line.

Howard Horn: Depending on the launches we have and their success, we'll figure out how much we can reinvest back into the pipeline versus drop to the bottom line. That'll be a fun conversation to have in due course.

Speaker #4: But that'll be a fun conversation to have and do course.

[Analyst] (Truist Securities): Sounds like it. Thanks very much.

[Analyst] (TD Securities): Sounds like it. Thanks very much.

Speaker #7: Sounds like it. Thanks very much.

Speaker #3: Our next question comes from Selveen Richter with Goldman Sachs. Your line is now live.

Operator: Our next question comes from Salvene Richter with Goldman Sachs. Your line is now live.

Speaker #10: Good afternoon. Thanks for taking my question. Ahead of the Phase 3 Angelman's data in the second half, can you speak to the path forward and the event that MDRI hits that Bailey Ford doesn't?

Salvene Richter: Good afternoon. Thanks for taking my question. Ahead of the phase 3 Angelman's data in the H2, can you speak to the path forward in the event that MDRI hits, but Bayley-IV doesn't? Thank you.

Salveen Richter: Good afternoon. Thanks for taking my question. Ahead of the phase 3 Angelman's data in the H2, can you speak to the path forward in the event that MDRI hits, but Bayley-IV doesn't? Thank you.

Speaker #10: Thank you.

Speaker #4: I think as Eric noted today in the script, is that we still consider that a positive study. That is, we have essentially two ways to succeed that Bailey Cog can succeed.

Emil Kakkis: I think as Eric noted today in the script is that we still consider that a positive study. That is we have essentially two ways to succeed, that Bayley Cog can succeed and the MDRI is provides maybe a more robust option. We negotiated this position with the FDA. I think while their tendency is to stick with single primary endpoints as their approach, we think the MDRI is actually a smarter and better way to go for neurologic disease. This is an opportunity to move in that direction. Our expectation is, as Eric had said, that a missed Bayley-IV but a positive MDRI is still a demonstration of efficacy in the program. Obviously, that would assume that, let's say, Bayley Cognition just missed. MDRI hit. You know, that would be one potential scenario.

Speaker #4: And the MDRI is provides maybe a more robust option. We negotiate this position with the FDA. I think while there are tendencies to stick with single primary endpoints as their approach, we think the MDRI is actually a smarter and better way to go for neurologic disease.

Speaker #4: And this is an opportunity to move in that direction. Our expectation is, as Eric had said, that a missed Bailey 4, but a positive MDRI is still a demonstration of efficacy in the program.

Speaker #4: Obviously, that would assume that let's say Bailey Cognition just missed and then MDRI hit. That would be a one potential scenario. We would not expect, for example, Bailey Cognition to go negative and then have an MDRI positive and have that work out.

Emil Kakkis: We would not expect, for example, Bayley Cognition to go negative and then have an MDRI positive and have that work out. The question really be could Bayley miss for some reason, and MDRI provides an insurance policy and support for efficacy in the product that's broader than just cognition. We feel like there's ways it's two ways to win for the program and we're actually expecting both to hit. As you know, we can always miss with our best intentions in a randomized controlled trial. I think the combination of both gives us a higher chance of being positive regardless of what happens in the patients.

Speaker #4: So the question really would be could Bailey miss for some reason and MDRI provides then insurance policy and support for efficacy in the product as broader than just Cognition.

Speaker #4: So we feel like there's ways it's two ways to win for the program. And we're actually expecting both to hit, but as you know, we can always miss in our best intentions in a randomized controlled trial.

Speaker #4: But I think the combination of both gives us a higher chance of being positive regardless of what happens in the patient's body.

Speaker #3: Thanks. Let's move on to the next question. Our next question is from Kristen Clusta with Cantor Fitzgerald. Your line is now live.

Joshua Higa: Thanks. Let's move on to the next question.

Operator: Our next question is from Kristin Klooster with Cantor Fitzgerald. Your line is now live.

Kristin Klooster: Hi, good afternoon. For this latest Angelman cut that you looked at for the phase 1-2 data, can you tell us how the 1-year plus data is stacking for cohorts A and B relative to what you saw across different measures for cohorts 4 and Z, and whether that's further strengthened your position of the dosing regimen and techniques you took forward in phase III?

Kristen Klooster: Hi, good afternoon. For this latest Angelman cut that you looked at for the phase 1-2 data, can you tell us how the 1-year plus data is stacking for cohorts A and B relative to what you saw across different measures for cohorts 4 and Z, and whether that's further strengthened your position of the dosing regimen and techniques you took forward in phase III?

Speaker #8: Hi. Good afternoon. For this latest Angelman cut that you looked at for the phase one two data, can you tell us how the one-year-plus data is stacking for cohorts A and B relative to what you saw across different measures for cohorts four and Z and whether that's further strengthened your position of the dosing regimen and techniques you took forward in phase three?

Speaker #4: Okay. Yeah. So we've shown the cohort A and B before. I think the cohort A and B is continuing to behave. And I would say remember, that's the most of the patients.

Emil Kakkis: Okay. Yeah. We've, we've shown the cohort A and B before. I think the cohort A and B is continuing to behave. I would say is that, remember, that's the most of the patients. C and D is relatively few patients. It's really mostly A and B. I think what we're talking about is cohort A and B extending now to the full year, and that's the data that we're talking about. It's really driven off of A and B. That A and B is, we think, is pretty comparable to what you're seeing in the phase 3 because the A and B was in all the international sites. That included the 7 or 8 countries that were also doing studies, including a high overlap with the sites that we're actually using.

Speaker #4: C and D is relatively few patients. It's really mostly A and B. So I think what we're talking about is cohort A and B extending now to the full year.

Speaker #4: And that's the data we're talking about. So it's really driven off of A and B. That A and B, as we think, is pretty comparable to what you're seeing in the Phase 3, because the A and B was in all the international sites.

Speaker #4: So that included the seven or eight countries that were also doing studies, including Ohio overlap with the sites that were actually using it. So I think that the A and B cohort, which is the primary driver of the data we heard about today, is very replicable with regard to what we're doing in phase three, both from a site, countries, and patient type.

Emil Kakkis: I think that the A and B cohort, which is the primary driver of the data we heard about today, is very replicable with regard to what we're doing in phase 3, both from a sites, countries, and patient type. I think it is a good model. I think the data should be in line with what we expect in phase 3.

Speaker #4: So I think it is a good model. I think the data should be in line with what we expect in phase three.

Speaker #3: Thanks. Let's move on to the next question. Our next question comes from Maxwell Score with Morgan Stanley. Your line is now live.

Joshua Higa: Thanks. Let's move on to the next question.

Operator: Our next question comes from Max Loscor with Morgan Stanley. Your line is now live.

[Analyst] (Morgan Stanley): Hello, this is Selena on for Max. On Angelman, could you describe the contribution of caregiver input to Bayley-IV cognition in the phase 1-2 and how that changes over time with the longer follow-up data? Thank you.

Speaker #8: Hello, this is Selena on from Max. On Angelman, could you describe the contribution of caregiver input to Bailey 4 Cognition in the phase one, two, and how that changes over time with the longer follow-up data?

Speaker #8: Thank you.

Speaker #4: Well, thank you for that very technical, detailed question. I'm not sure everyone knew about caregiver input. But just to be clear, in the raw scores that we're using for the Bailey 4, the FDA does not want us to include caregiver input.

Emil Kakkis: Well, thank you for that very technical detailed question. I'm not sure everyone knew about caregiver input, just to be clear, in the raw scores that we're using for the Bayley-IV, the FDA does not want us to include caregiver input. All right? All the analysis has to be done by the psychologist tester. We are not including any caregiver input in the Bayley-IV primary endpoint per FDA request. Now, out of the, I'm forgetting the number, is it 20 or 30 items or something? There's, like, a couple items where caregiver input 2 or 3 that can have an effect. When we look at raw scores with or without caregiver input, we don't think for Bayley-IV cognition there's significant issue.

Speaker #4: All right? So all the analysis has to be done by the psychologist tester. And so we are not including any caregiver input in the Bailey 4 primary endpoint per FDA request.

Speaker #4: Now, out of the I'm getting the number. Is it 20 or 30 items or something? There's like a couple items where caregiver input came in two or three that can have an effect.

Speaker #4: So when we look at raw scores with or without caregiver input, we don't think for Bailey 4 Cognition, there's significant issue. If you're doing the expressive Bailey, there's actually a lot more caregiver input potential.

Emil Kakkis: If you're doing the expressive Bayley, there's actually a lot more caregiver input potential, and so it might have more effect on the I'm sorry, expressive communication than on cognition. It's only a couple, two or three things we haven't seen have an impact, but we are doing it without caregiver input in the phase 3 trial.

Speaker #4: And so it might have more effect on the receptive I'm sorry, expressive communication than on cognition. So it's only a couple, two or three things.

Speaker #4: We haven't seen it have an impact, but we are doing it without caregiver input in the phase three trial.

Speaker #3: And Emil and Eric, I think the question was maybe more around the phase one two data that we've talked about. If we were able to look at that without the caregiver input, and I don't think that's how the phase one two was run.

Joshua Higa: Emil and Eric, I think the question was maybe more around the phase 1-2 data that we've talked about, if we were able to look at that without the caregiver input, and I don't think that's how the phase 1-2 was run.

Speaker #11: Yes. That's correct. For phase one two, we did use caregiver input. And it was part of the conversation designing phase three that the FDA made that request.

Eric Crombez: Yes, that's correct. For phase 1-2, we did use caregiver input, and it was, you know, part of the conversation designing phase 3 that the FDA made that request. We actually performed the test both ways in phase 3, but the primary endpoint does not use caregiver input.

Speaker #11: We actually performed the test both ways in Phase 3, but the primary endpoint does not use caregiver input. And that's important to eliminate bias.

Emil Kakkis: Right.

Eric Crombez: That's important to eliminate bias, that's true for both your actively treated and your control group. It's a reasonable request.

Speaker #11: And that's true for both your actively treated and your controlled group. So it's a reasonable request.

Emil Kakkis: We can analyze without those items. They will not have a meaningful impact. That's what I said, that if we drop them out, they do not impact it because there's only a couple items out of a very large number where it might be impact them, right? Okay. The situation is those 2 or 3 items, if the caregiver says that they think they're developing, but the doctor doesn't see it, the psychiatrist don't see it, they could score a point or 2. We're saying if you drop those out, it's still, it's fine in cognition. Our point would be that what we see in phase 1-2 would be consistent with or without caregiver input, right? Does that answer the question, Josh? We're good? All right. Boy, we're getting deep on COAs.

Speaker #4: But we can analyze without those items. And they will not have a meaningful impact. That's what I said. If we drop them out, they do not impact it because there's only a couple items out of a very large number where it might be an impact them, right?

Speaker #4: Okay. So the situation is there's two or three items that the caregiver says that they think they're developing, but it's doctor to see it.

Speaker #4: They've got a doctor to see it. They could score a point or two. But we're saying if you drop those out, it's fine. In cognition.

Speaker #4: So our point would be that we see in phase one two is would be consistent with or without cog caregiver input, right? Does that answer the question, Josh?

Speaker #4: We did? All right. Boy, we're getting deep on COA. So let's go on to the next question.

Emil Kakkis: Let's go on to the next question.

Speaker #3: Our next question is from Jack Allen with Baird. Your line is now live.

Operator: Our next question is from Jack Allen with Baird. Your line is now live.

Jack Allen: Taking the questions, congrats on the progress. I wanted to ask about what your expectations are as it relates to the sham performance in the ASPIRE study. I know there was a limited data set from Angelman, but are there any other surrogate neurodevelopmental indications that you've looked at as it relates to sham performance? My other follow-up was on the profitability. Any comments you can make as it relates to what you need as it relates to success from the gene therapy programs in Angelman that's baked in for assumptions for profitability. Do you account for those in the profitability guidance, or is it just the current base business?

Speaker #12: Taking the questions and congrats on the progress. So I wanted to ask about what your expectations are as it relates to the SHAM performance in the ASPIRE study.

Speaker #12: I know there's a limited data set from Angelman, but are there any other surrogate neurodevelopmental indications that you've looked at as it relates to SHAM performance?

Speaker #12: And then my other follow-up was on the profitability and any comments you can make as it relates to what you need as it relates to success from the gene therapy programs in Angelman that's baked in for assumptions for profitability.

Speaker #12: Do you account for those in the profitability guidance or is it just the current-based business?

Speaker #4: Well, I'll let Howard deal with the profitability question. But let me deal with the SHAM performance. Well, obviously, we would not expect SHAM to have an effect.

Emil Kakkis: Well, I'll let Howard deal with the profitability question, but let me deal with the sham performance. Well, obviously we would not expect sham to have an effect. We haven't looked at all possible studies, but certainly in our own, in Angelman, in the control studies we've seen, we haven't seen much change. I would say to you that when you're talking about the performance of development, these kids are not gonna have a placebo effect exactly, right? They're not thinking, Hey, I'm getting a treatment, I should be better. They're not gonna think this way. They're not, they're not developmentally changing. By not having caregiver input, which is maybe why the FDA doesn't want it allows there to be a more objective assessment of what's happening. We're really saying, could they get better on their own without anything happening?

Speaker #4: And we haven't looked at all possible studies, but certainly in our own in Angelman and the control studies, we've seen we haven't seen much change.

Speaker #4: I would say to you that when you're talking about the performance of development, these kids are not going to have a placebo effect exactly, right?

Speaker #4: Because they're not thinking, "Hey, I'm getting a treatment. I should be better." They're not going to think this way. They're not developmentally changing. By not having caregiver input, which is maybe why the FDA doesn't want it, it allows there to be a more objective assessment of what's happening.

Speaker #4: So we're really saying, "Could they get better on their own without anything happening?" What we're saying is that the deletion patients just don't. So we're pretty comfortable with the SHAM forms will not be important.

Emil Kakkis: What we're saying is that the deletion patients just don't. We're pretty comfortable the sham forms will not be important. I don't know that there's other developmental disorders that are comparable, maybe Rett syndrome or other types like that. At this point, we don't feel that the sham should be any different from an natural history, and the deletion patients are pretty stable in terms of their Bayley cognition scoring. They do not change much, and we're talking about less than a point a year, whether it's a randomized trial or even an natural history. At this point, we're comfortable with it, but I understand your point. Right now we seem comfortable with it, and we have adequate power. Even if there was a higher background signal, we should have adequate power to overcome that with the treatment effect we expect.

Speaker #4: I don't know that there's other developmental disorders that are comparable, maybe Rett syndrome or other types like that. But at this point, we don't feel that the SHAM should be any different from a natural history.

Speaker #4: And the deletion patients are pretty stable in terms of their Bailey cognition scoring. They do not change much. And we're talking about less than a point a year.

Speaker #4: So whether it's a randomized trial or even a natural history. So at this point, we're comfortable with it. But I understand your point. Right now, we seem comfortable with it.

Speaker #4: And we have adequate power even if there was a higher background signal. We should have adequate power to overcome that with the treatment effect we expect.

Howard Horn: Jack, regarding profitability and launch success assumptions, right now what we've said for top line is that we assume continued double-digit growth from our current products, plus contribution from upcoming launches, which could include UX111, DTX-401, GTX-102. We haven't said much more than that, but maybe what I can say is that it certainly doesn't require all of them to be successful for us to get to profitability. We have different levers we can pull to make sure we can live up to our promise of 2027 path to profitability.

Speaker #12: And Jack, regarding profitability and launch success assumptions, right now, what we've said for Topline is that we assume continued double-digit growth from our current products.

Speaker #12: Plus contribution from upcoming launches, which could include 111, 401, 102. We haven't said much more than that. But maybe what I can say is that it certainly doesn't require all of them, to be successful for us to get the profitability.

Speaker #12: And we have different levers we can pull to make sure we can live up to our promise of 2027 at the profitability. Great. Thanks so much for the color.

Jack Allen: Great. Thanks so much for the color.

Speaker #3: Our next question comes from Ben Burnett with Wells Fargo. Your line is now live.

Operator: Our next question comes from Ben Burnett with Wells Fargo. Your line is now live.

Speaker #12: Great. Thanks very much. I wanted to ask about the GTX 102 program. And great to hear about the long-term data. I think you mentioned there was 66 patients in the long-term extension.

Ben Burnett: Great. Thanks very much. I wanted to ask about the GTX-102 program, and great to hear about the long-term data. I think you mentioned there were 66 patients in the long-term extension. Could you comment on sort of the reasons for discontinuations? Then I have a follow-up.

Speaker #12: Could you comment on sort of the reasons for discontinuations? And then I have a follow-up.

Emil Kakkis: Sure. Yeah, we can do that. It's actually been a little here, a little there, but it's mostly often in the beginning. Maybe you can comment on that, Eric, for them.

Speaker #4: Sure. Yeah, we can do that. It's actually been a little bit here, a little there. But it's mostly, often in the beginning. Maybe you can comment on that, Eric, for them?

Speaker #12: Yeah, so very consistently, it was all due to burned-up study participation. I mean, we do need to remember that some of these patients are very far away from treatment sites, and it does become a burden for these families.

Eric Crombez: Yeah. Very consistently, it was all due to burden of study participation. I mean, we do need to remember that some of these patients live very far away from treatment sites, and it does become a burden for these families. That was across the board the reason for those discontinuations, study burden.

Speaker #12: So, that was, across the board, the reason for those discontinuations—study burden.

Speaker #4: It sometimes happens kind of early too because some people realize they just couldn't do it. But yeah. So it wasn't safety-related.

Emil Kakkis: It sometimes happened kind of early too, 'cause some people realized they just couldn't do it. Yeah, it wasn't safety related.

Speaker #12: Okay. Okay. And then the other question I just want to ask is just around Chris Vita. So I appreciate kind of the commentary you gave on the call just around some of the variability around sort of ordering patterns.

Ben Burnett: Okay. Okay.

Emil Kakkis: Thank you.

Ben Burnett: The other question I just wanna ask is just around Crysvita. Appreciate kind of the commentary you gave on the call just around some of the variability around sort of ordering patterns. I guess the question is, is sort of what visibility do you have kind of going forward through the next couple of months and sort of what gives you sort of the confidence in kind of the yearly guidance number for Crysvita?

Speaker #12: But I guess the question is, sort of what visibility do you have kind of going forward through the next couple of months? And sort of what gives you sort of the confidence and kind of the yearly guidance number for Chris Vita?

Speaker #4: Yeah. Well, I'll let Eric comment a little bit because Eric's very close to the team at Karen on what's going on. But I think one of the elements of this is that every year, we're going to have one other factor, which is the way the royalty is in the first part of the year, it's a little bit lower, then it's across the threshold and it goes up.

Emil Kakkis: Yeah. I'll let Eric comment a little bit 'cause Eric's very close to the team at Kyowa Kirin Co. on what's going on. I think one other element of this is that every year we're gonna have one other factor, which is the way the royalty is in the first part of the year is a little bit lower, then it crosses a threshold and it goes up. Whatever revenue is coming, our percentage goes up as the year goes on, and that's why the quarterly revenue goes up as well. It's just an ordering pattern thing, and there's gonna be this continuous ramp-up of our percent in the royalty stream. It's just gonna reset every year and crawl back up. Eric, what gives you confidence in Crysvita going forward in the North American territory?

Speaker #4: So whatever revenue is coming, our percentage goes up as the year goes on. And that's why the quarterly revenue goes up as well. So it's an ordering pattern thing.

Speaker #4: And there's going to be this continuous ramp-up of our percent in the royalty stream. So it's just going to reset every year and crawl back up.

Speaker #4: Eric, what gives you confidence? And Chris, Vita going forward in the North American territory?

Speaker #13: Yeah. No, it's quite simple. We're very confident in the underlying demand that we continue to see with finding patients and patients wanting to get treated.

Erik Harris: Yeah, no, it's quite simple. We're very confident in the underlying demand that we continue to see with finding patients and patients wanting to get treated across our regions, which is why we reaffirmed our guidance. Consistent with prior years, we expect the same sawtooth pattern that we've seen previously with lower Q1 and a rebound in Q2 and softer Q3 and a strong Q4. We expect, as we have in previous years, to continue to deliver on our commitment to the street.

Speaker #13: Across our regions, which is why we reaffirmed our guidance. And consistent with prior years, we expect the same sawtooth pattern that we've seen previously with lower Q1 and a rebound in Q2 and softer Q3 and a strong Q4.

Speaker #13: So we expect as we have in previous years to continue to deliver on our commitment to the street.

Speaker #4: Yeah. I think the thing that we would see in Q1, though, is the STAR forms. What's the STAR? That's the demand you talked about.

Emil Kakkis: Yeah. I think the thing that we would see in Q1 though is like the start forms. What's the start? That's the demand you talked about. So and continuations and so forth. Demand is strong in Crysvita. It's a great product. People stay on it when they get on it, and they continue to grow it, and we're here to support them and do our own work where we're commercializing. Crysvita continues to grow and do well, and we just have to understand there's always this quarterly plan that's gonna have moments the same every year. We feel comfortable how the year will go.

Speaker #4: And continuations and so forth. So demand is strong in Chris Vita. It's a great product. People stay on it when they get on it.

Speaker #4: And they continue to grow it. And we're here to support them and do our own work where we're commercializing. But Chris Vita continues to grow and do well.

Speaker #4: And we just have to understand there's always this quarterly plan that's going to happen almost the same every year. So we feel comfortable how the year will go.

Speaker #12: Okay. Thank you for the color.

Ben Burnett: Okay. Thank you for the color.

Speaker #3: Our next question comes from Iago Nachimosis with Citigroup. Please, your line is now live.

Operator: Our next question comes from Miguel Nachamosis with Citi.

Speaker #12: Hi. Great. Thanks for taking the question. I was curious about the long-term extension data. And you mentioned that you've seen the positive improvements in multiple domains.

Miguel Nachamosis: Hi, great. Thanks for taking the question. I was curious about the long-term extension data, and you mentioned that you've seen the positive improvements in multiple domains and patients are continuing to improve developmentally. I'm just wondering how you assess those metrics with respect to sufficient powering on the endpoint for the ASPIRE trial for the Bayley-IV cognition. Do those observations in the long-term extension study on development improvement give you confidence that the powering on the Bayley-IV is sufficient for the ASPIRE trial. What would be the clinically meaningful delta that you'd wanna see on Bayley-IV?

Yigal Nochomovitz: Hi, great. Thanks for taking the question. I was curious about the long-term extension data, and you mentioned that you've seen the positive improvements in multiple domains and patients are continuing to improve developmentally. I'm just wondering how you assess those metrics with respect to sufficient powering on the endpoint for the ASPIRE trial for the Bayley-IV cognition. Do those observations in the long-term extension study on development improvement give you confidence that the powering on the Bayley-IV is sufficient for the ASPIRE trial. What would be the clinically meaningful delta that you'd wanna see on Bayley-IV?

Speaker #12: And patients are continuing to improve. Developmentally, I'm just wondering how you assess those metrics with respect to sufficient powering on the endpoint for the Aspire trial for the Bailey 4 cognition.

Speaker #12: Do those observations in the long-term extension study on development improvement give you confidence that the powering on the Bailey 4 is sufficient for the Aspire trial?

Speaker #12: And what would be the clinically meaningful delta that you'd want to see on Bailey 4?

Speaker #4: Yeah. So you've got thanks for the question. I think, look, I think Eric just talked about hitting around 10 points, let's say, in the one-year timeframe.

Emil Kakkis: Yes, Miguel, thanks for the question. Eric just talked about hitting around 10 points, let's say, in the 1-year timeframe. That's the part of the A and B cohort and the others together that have, you know, gotten to the 1-year mark. Some people are at the 3 to 5-year mark. What we're saying is that 1 year they're hitting a number which is pretty close to what we've been expecting the whole time, and that size shows we're radically powered, and it's well above the MID at 1 year. We're feeling comfortable at that size.

Speaker #4: So that's the part of the A&D cohort and the others together that has gotten to the one-year mark. So some people are at the three-to-five-year mark.

Speaker #4: What we're saying is that one year, they're hitting a number which is pretty close to what we've been expecting the whole time. And that size gives us, shows a radically powered.

Speaker #4: And it's well above the MID at one year. So we're feeling comfortable at that size. And by the way, most people that know that test are shocked at how much change there is because it usually doesn't move at all for most people who are experts, including Kim Goodspeed, who's our physician with a developmental specialist.

Emil Kakkis: By the way, most people that know that, just that test are shocked at how much change there is because it usually doesn't move at all for most people who are expert, including Kimberly Goodspeed, who's our physician, who's a developmental specialist. She says you just don't see this thing move. 10 points is a big number. What we are saying and the way Eric put forth is that when you continue to follow these kids over the longer haul, they continue to go up in Bayley cognition. That kinda tells us that the patients are having a sustained benefit of the ASO on their function in their brain, and it just continue to gain ground. That, to me, is really important, and that's what the long-term is telling you.

Speaker #4: He says, "You just don't see this thing move." So 10 points is a big number. What we are saying and what Eric put forth is that when you continue to follow these kids over the longer haul, they continue to go up in Bailey cognition.

Speaker #4: And so that kind of tells us that the patients are having a sustained benefit of the ASL on their function in their brain, and they're continuing to gain ground.

Speaker #4: That, to me, is really important. And that's what the long-term is telling you. I think you phase three, of course, is very important. We're getting follow-up approval.

Emil Kakkis: I think Phase III, of course, is very important for getting final approval. What is the commercial potential of a product? I think the long-term safety and chronic treatment, and it continue to gain ground, tells you this is a treatment that has the ability to help kids over long periods of time in the post-market setting. With Phase III in hand, being able to get to a commercial setting, I think this gives us more confidence that the potential of the drug to be a long-term benefit for patients with Angelman syndrome.

Speaker #4: But what does the commercial potential of a product? I think the long-term safety and chronic treatment and continuing to gain ground tells you this is the treatment that has the ability to help kids over a long period of time in the post-market setting.

Speaker #4: And so with phase three in hand, being able to get to a commercial setting, I think this gives us more confidence that the potential of the drug to be a long-term benefit for patients with ancient syndrome.

Speaker #12: Okay, thanks. And then, one on UX111. Since the resubmission, have you had any other requests for information since the acceptance in April, or any other inspection requirements post-acceptance of the BLA?

Miguel Nachamosis: Okay, thanks. One on UX-111. Since the resubmission, have you had any other requests for information since the acceptance in April or any other inspection requirements, post acceptance of the BLA?

Yigal Nochomovitz: Okay, thanks. One on UX-111. Since the resubmission, have you had any other requests for information since the acceptance in April or any other inspection requirements, post acceptance of the BLA?

Speaker #4: Yeah. Well, we're having what I would call routine discussion with the HC. We normally don't discuss the details of those. We've had what I would call routine discussions on the BLA.

Emil Kakkis: Yeah. Well, we're having what I would call routine discussion with the agency. We normally don't discuss the details of those. We've had what I would call routine discussions on the BLA, and those continue. At this point, we feel that business is normal moving forward. We won't really comment in detail about it until something, a decision gets made.

Speaker #4: And those continue. And at this point, we feel that business is normal moving forward. And we won't really comment in detail about it until something a decision gets made.

Speaker #4: We're excited about the potential of that program, and we are planning for a launch, assuming we get approval.

Miguel Nachamosis: Okay.

Yigal Nochomovitz: Okay.

Emil Kakkis: We're excited about the potential of that program and are planning for a launch, assuming we get approval.

Speaker #12: Thanks.

Miguel Nachamosis: Thanks.

Yigal Nochomovitz: Thanks.

Speaker #3: Our next question comes from Gavin Clark with Evercore. Your line is now live.

Operator: Our next question comes from Gavin Clark with Evercore. Your line is now live.

Yilun Chen: Hello, this is Yilun Chen for Gavin Clark. Thanks for taking our question. Two from us. One is for Angelman MDRI endpoint. Just for clarification for the stat analysis. What is the delta versus the sham control is actually defined? Is the difference in the medium net response between the two arms or the difference in the proportion of the patients that are achieving a net response in at least one domain? Secondly, we have a question about UX-106 in GNE myopathy, which we saw recently got IND clearance. Wondering what is the key difference between this new molecule versus previous one that looks like also run through the same indication but failed in the phase 3. What are some key takeaways we can learn from that history study to inform the current trial design? Thank you.

[Analyst] (Evercore): Hello, this is Yilun Chen for Gavin Clark. Thanks for taking our question. Two from us. One is for Angelman MDRI endpoint. Just for clarification for the stat analysis. What is the delta versus the sham control is actually defined? Is the difference in the medium net response between the two arms or the difference in the proportion of the patients that are achieving a net response in at least one domain? Secondly, we have a question about UX-106 in GNE myopathy, which we saw recently got IND clearance. Wondering what is the key difference between this new molecule versus previous one that looks like also run through the same indication but failed in the phase 3. What are some key takeaways we can learn from that history study to inform the current trial design? Thank you.

Speaker #14: Hello, this is Isiom for Gavin. Thanks for taking our question. So, two from us. One is for the Angelman MDRI endpoint. Just for clarification for the stat analysis, how is the delta versus the sham control actually defined?

Speaker #14: Is the difference in the median net response between the two arms, or the difference in the proportion of the patients that are achieving a net response in at least one domain?

Speaker #14: And secondly, we have a question about 106 in GNE myopsy, which we saw recently got IND clearance. So wondering what is the key difference between this new molecule versus previous one that looks like also runs through the same indication but failed in the phase three?

Speaker #14: So what are some key takeaways we can learn from that history study to inform the current trial design? Thank you.

Speaker #4: Sure. Thanks. So for the MDRI, what you're looking at is net domain improvement. So each patient will have a number of domains that they hit, right?

Emil Kakkis: Sure. Thanks. For the MDRI, what you're looking at is net no domain improvement. Each patient will have a number of domains that they hit, right? We look at net domain improvement comparing the distribution curve of the treated patients to the distribution curve of the control patients, right? It's a net domain improvement. How many positive wins per patient do you see? We've shown before that we had often two domains or more on average per patient around that, in that range. Those domains can be variable. There can be various combinations. There are some patients that had as many as four or five domains for improvement. We'll look at those distribution curves for the net domains per patient. All right? That's the statistical comparison.

Speaker #4: And we look at net domain improvement comparing the distribution curve of the treated patients to the distribution curve of the control patients, right? So it's a net domain improvement.

Speaker #4: How many positive wins per patient do you see? And we've shown before that we had often two domains or more on average per patient around that in that range.

Speaker #4: But those domains can be variable. They can be various combinations. There are some patients that had as many as four or five domains of improvement.

Speaker #4: So, we'll look at those distribution curves for the net domains per patient. All right? That's the statistical comparison. For the GNE myopathy, I've been involved with that program from the very beginning.

Emil Kakkis: For the GNE myopathy, I've been involved with that program from the very beginning. It's a horrible muscle disease. We think maybe around 10,000 patients out there, and we think it's a very chronic and terrible disease. The original molecule of sialic acid replacement didn't work as well because the sialic acid just didn't penetrate. What the new drug is a prodrug, one that we designed it that has enhanced hydrophobicity that helps target uptake into muscle and gets released and transported by the sialic acid transporter. It allows it to get taken up into the lysosome and cleared across the lysosomal membrane into the muscle.

Speaker #4: It's a horrible muscle disease. We think maybe around 10,000 patients out there. And we think it's very chronic and terrible disease. The original molecule, salicylic acid, replacement didn't work as well because the salicylic acid just didn't penetrate what the new drug is a prodrug, one that we designed that has an enhanced hydroviscosity that helps target uptake into muscle and gets released and transported by the salicylic acid transporter.

Speaker #4: So it allows it to get taken up into the lysome and cleared across the lysomal membrane into the muscle. And that improved hydroviscosity mechanism will allow us to, in the animals or in dogs, to deliver large amounts of salicylic acid to the cells substantially better than the other molecule, like many, many fold better.

Emil Kakkis: That improved hydrophobicity mechanism will allow us to, in the animals or in dogs, to deliver large amounts of sialic acid to the cells substantially better than the other molecule, many fold better. We think the potency is just dramatically better, and that puts us in a better position to actually achieve the replacement therapy that's required. We know from the prior work, and particularly the biopsy work, that these patients have an 85% depletion of sialic acid in their muscle. This drug should take us back to complete replacement, if not, above replacement levels of sialic acid. We have greater hope this can be an effective drug for GNE myopathy.

Speaker #4: So we think the potency is just dramatically better. And that puts us in a better position to actually achieve the replacement therapy that's required.

Speaker #4: And we know from the prior work, and particularly the biopsy work, that these patients have an 85% depletion of salicylic acid in their muscle.

Speaker #4: This drug should take us back to complete replacement, if not above replacement, levels of salicylic acid. So we have greater hope this can be an effective drug for GNE myopathy.

Speaker #4: It's a program I should point out is funded through a venture philanthropy agreement with the patient group. And who are very interested in the product moving forward.

Emil Kakkis: It's a program I should point out, it's funded through a venture philanthropy agreement with the patient group who are very interested in the product moving forward. We were able to do that even under our financial constraints with the fact that they were funding it. They're funding us through the phase 2 proof of concept, which is allowing this program to move forward at this point in time.

Speaker #4: And we were able to do that even under our financial constraints, with the fact that they were funding it. So, they're funding us through the Phase 2 proof of concept, which is allowing this program to move forward at this point in time.

Speaker #14: Thank you.

Yilun Chen: Thank you.

[Analyst] (Evercore): Thank you.

Speaker #3: Our next question comes from Luca Izzi with RBC Capital Markets. Your line is now live.

Operator: Our next question comes from Luca Issi with RBC Capital Markets. Your line is now live.

Speaker #15: Oh, great. Yeah, thanks so much for taking my question. Congrats on the progress. Maybe Emil and Eric, circling back on a couple of prior questions.

Luca Issi: Oh, great. Yeah, thanks so much. Thanks for my question. Congrats on the progress. Maybe Emil and Eric circling back on a couple prior questions. What is your relative level of conviction on Bayley score cognition versus MDRI? It feels to me that during the call, you came across as incrementally more positive on MDRI versus Bayley score cognition. 1, would that be fair? 2, if so, can you still amend the protocol to potentially reallocate more alpha to the MDRI versus the Bayley score cognition? Again, any call there, much appreciated. Then maybe super quickly, on OI, I did not see anything in the press release or in the remarks. Should we assume that you have discontinued that program? Thanks so much.

Speaker #15: What is the relative level of conviction on Bailey's four cognition versus MDRI? It feels to me that during the call, you came across as incrementally more positive on MDRI versus Bailey's four cognition.

Speaker #15: One, would that be fair? And two, if so, can you still amend the protocol to potentially reallocate more alpha to the MDRI versus the Bailey's four cognition?

Speaker #15: Again, any color there, much appreciated. And then maybe, super quickly, on OI—I do not see anything in the press release or in the prepared remarks.

Speaker #15: So should we assume that you have discontinued that program? Thanks so much.

Emil Kakkis: That we've discontinued OI. Oh, I see. Missed it. The MDRI is a more powerful measure. It has 5 endpoints in it. They gain power from all those endpoints. It is a very powerful way. We've been promoting it. We used it in our MEPSEVII program. It's just new for regulators. At this point, in our agreement with regulators, we've put 80% of the power into the Bayley-IV, which is actually where you need the power because it's, there's a sort of a smaller magnitude effect. The MDRI hits various rounds of statistical significance. You don't really need more alpha assigned MDRI, even if you have higher confidence in it, because it's tremendous amount of power in it. I think what we've done is the appropriate proportion, and we don't really need to shift it more.

Speaker #16: That we've discontinued OI. Oh, I see. Missed it. So the MDRI is a more powerful measure. It has five endpoints in it. The game power from all those endpoints.

Speaker #16: It is a very powerful way. We've been promoting it. We used it in our MEP70 program. It's just new for regulators. And so, at this point, in our agreement with regulators, we've put 80% of the power into the Bailey four, which is actually where you need the power, because there's sort of a smaller magnitude effect.

Speaker #16: The MDRI hits very strong statistical significance. So you don't really need more alpha up to sign MDRI, even if you have higher confidence in it because it's tremendous amount of power.

Speaker #16: And so I think what we've done is the appropriate proportionment, and we don't really need to shift it more. The OI, we've continued to do evaluations and discussion.

Emil Kakkis: The OI, we continue to do evaluations and discussion. We put a little bit in the release on this. We'll inform the street when we have a decision what we're doing, but we did not discontinue the program. It continues at the moment until we complete and get answers to key questions and make a determination.

Speaker #16: We put a little bit in the release on this. We'll inform the Street when we have a decision on what we're doing. But we did not discontinue the program.

Speaker #16: It continues at the moment. And until we complete and get answers to key questions and make a determination.

Speaker #15: Got it. Thanks so much.

Luca Issi: Got it. Thanks so much.

Speaker #3: Our last question comes from Raghuram Selvasi with HC Wainwright. Your line is now live.

Operator: Our last question comes from Raghuram Selvaraju with H.C. Wainwright. Your line is now live.

Speaker #17: Hi. Thank you for taking our question. This is a MEP4ROM. I just have a question about the PDUFA dates coming up in the second half of 2026.

Ahmed Faruqi: Hey, thank you for taking our question. This is Ahmed Faruqi. Just have a question about the PDUFA dates coming up in H2 2026. Can you frame the cadence of the commercial rollout and when to expect a meaningful revenue from both UX111 and DTX401? The second question is on the GTX-102 in Angelman. You mentioned discontinuation rates due to non-safety burden. Are you preparing any way to reduce discontinuation rates in a commercial setting, or do you not foresee that being an issue? Thank you.

[Analyst] (H.C. Wainwright): Hey, thank you for taking our question. This is Ahmed for Rom. Just have a question about the PDUFA dates coming up in H2 2026. Can you frame the cadence of the commercial rollout and when to expect a meaningful revenue from both UX111 and DTX401? The second question is on the GTX-102 in Angelman. You mentioned discontinuation rates due to non-safety burden. Are you preparing any way to reduce discontinuation rates in a commercial setting, or do you not foresee that being an issue? Thank you.

Speaker #17: Can you frame the cadence of the commercial rollout? And when to expect a meaningful revenue from both UX111 and DTX401? And then a second question is on the GTX102 and Angelman.

Speaker #17: You mentioned discontinuation rates due to non-safety burden. Are you preparing in any way to reduce discontinuation rates in the commercial setting, or do you not foresee that being an issue?

Speaker #17: Thank you.

Speaker #18: Sure. So obviously, we launched for gene therapy is complicated. The reimbursement part of it and so forth. We are not guiding on any revenue.

Emil Kakkis: Sure. Obviously, launch of gene therapy is complicated, the reimbursement part of it and so forth. We're not guiding on any revenue, what the revenue would be for this year, but we're certainly planning to move forward on getting the launch together. I'm sure Eric could go through this in great detail. I'll just summarize for you, Eric. It's that there'll be obviously various policies at launch we'll have to manage, but eventually we were talking to payers in appropriate meetings now to help lay pipe for the planning process for that. The reimbursement will be some of the process, and then we'll have to work through and get patients treated. Our expectation is that there will be some time from PDUFA date to be able to get things going.

Speaker #18: What the revenue would be for this year, but we're certainly planning to move forward on getting launched together. I'm sure Eric could go through this in great detail.

Speaker #18: I'll just summarize for you, Eric. There will be, obviously, various policies at launch that we'll have to manage. But eventually, we were talking to payers and appropriate meetings.

Speaker #18: Now, to help lay pipe forward the planning process for that. But the reimbursement will be some of the process. And then we'll have to work through and get patients treated.

Speaker #18: So our expectation is that there will be some time from PDUFA date to be able to get things going. We're trying to work as hard to get it going within the few weeks.

Emil Kakkis: We're trying to work as hard to get it going within a few weeks and to see how we can get it going. We expect to have product available, and it's more a question of getting the commercial process going. I think the team's been working aggressively on getting all the pieces in place it would take. I've been participating with them on some of the payer meetings that look at what the plan is, what the policies were, and how to navigate the process to get the best outcome for patients. For discontinuation rates, we actually find the discontinuation rate very limited, actually. It's really small, it's a handful.

Speaker #18: And to see how we can get it going, we expect to have product available. And it's more a question of getting the commercial process going.

Speaker #18: But I think the team's been working aggressively on getting all the pieces in place that would take and I've been participating with them on some of the payer meetings that look at what the plan is, what the policies were, and how to navigate the process to get the best outcome for patients.

Speaker #18: For discontinuation rates, we're actually finding the discontinuation rate very limited. Actually, it's really small, a handful. And usually, the treatment effect that patients start seeing is so meaningful that that's something that patients have been looking for, their whole families are looking for, their whole lives.

Emil Kakkis: Usually, the treatment effect the patients start seeing is so meaningful that, you know, that's something that patient families are looking for their whole lives. We don't expect a big discontinuation rate. As we move forward in it, we will clearly need to manage the accessibility and convenience. This may involve, you know, bringing in a device to help make lumbar punctures easier. We're gonna do our best to make sure this is as burdenless as possible. I would say, too, that a randomized trial or any kind of clinical trial has way more burden than getting something clinically in terms of what you have to do. I think the amount of tests and stuff is a lot, and I think for an Angelman family, that was probably more of a factor.

Speaker #18: So we don't expect a big discontinuation rate. But as we move forward in it, we will clearly need to manage the accessibility and convenience and this may involve bringing in a device to help make lumbar punctures easier.

Speaker #18: But we're going to do our best to make sure this is as burdenless as possible. And I would say, too, that a randomized trial or any kind of clinical trial has way more burden than getting something clinically, in terms of what you have to do.

Speaker #18: So I think the amount of tests and stuff isn't a lot. And I think for an Angelman family, that was probably more of a factor.

Speaker #18: So at this point, based on what we've seen, we're not expecting discontinuation to be a big deal. But we are also going to do our best to take care of patients before there's an issue and give them the best patient experience we can in terms of convenience for our treatment that involves an intrathecal delivery of an ASL.

Emil Kakkis: At this point, based on what we've seen, and we're not expecting discontinuation to be a big deal, but we are also gonna do our best to take care of patients before there's an issue and give them the best patient experience we can in terms of a convenience for a treatment that involves an intrathecal delivery of an ASO.

Speaker #3: Thank you. We have reached the end of the question and answer session. I would now like to turn the call back to Joshua Higa for closing remarks.

Ahmed Faruqi: Thank you.

[Analyst] (H.C. Wainwright): Thank you.

Operator: We have reached the end of the question and answer session. I would now like to turn the call back to Joshua Higa for closing remarks.

Speaker #18: 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 us.

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 us.

Operator: This concludes today's conference. You may disconnect your lines at this time, and we thank you for your participation.