Q1 2024 Ultragenyx Pharmaceutical Inc Earnings Call

Operator: Good afternoon, and welcome to the Ultragenyx first quarter 2024 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 turn the call over to Joshua Higa, Vice President of Investor Relations. You may begin.

Joshua Higa: 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, Erik Harris, Chief Commercial Officer, Howard Horn, Chief Financial Officer, and Erik 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.

Okay.

Speaker Change: Good afternoon, I'll walk you through the oxygen expert first quarter 'twenty to 'twenty four financial results conference call.

Speaker Change: At this time all participants are in a listen only mode.

Speaker Change: At the end of the prepared remarks, you'll have an opportunity to ask questions. During the Q&A portion of the call.

Speaker Change: It is now my pleasure to turn the call to Joshua Hagen, Vice President of Investor Relations you may begin.

Joshua Higa: Thank you.

Joshua Higa: A press release detailing our financial results, which you can find on our website at ultra GATX dotcom.

Joshua Higa: Please refer to the risk factors discussed in our latest SEC filing. I'll now turn the call over to Josh. Thanks, Josh, and good afternoon, everyone. This is the year that we're harvesting the exciting results of multiple years of focused execution across our key clinical programs, and we've shared a lot of meaningful data already this year. For example, at the World Symposium meeting in February, we presented positive biomarker and long-term cognition data from our U.S. 1-11 gene therapy in Sanfilippo syndrome.

Joshua Higa: Joining me on this call are chemo package, Chief Executive Officer, and President, Eric Harris, Chief Commercial Officer, Howard Hard Chief Financial Officer, and aircraft as 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 act.

Speaker Change: Results may differ materially please refer to the risk factors discussed in our latest SEC filings I'll now turn the call over to him.

Joshua Higa: The data show the treatment resulted in a rapid and sustained reduction of CSF, pepper, and sulfate, and the distance correlated with improved long-term cognitive development. We also participated in a workshop on the heparin sulfate biomarker hosted by the Reagan-Udall Foundation.

Eric Harris: Thanks, Josh and good afternoon, everyone.

Eric Harris: This is a year that we're harvesting the exciting result of multiple years of focused execution across our key clinical programs.

Emil D. Kakkis: This workshop brought together FDA representatives, patient advocates, scientists, and industry leaders to discuss the overwhelming body of data supporting the use of CSF heparan sulfate as a biomarker to enable accelerated approval for neuropathic MPS diseases. In support of Peter Marks and the FDA, recognizing this biomarker as a surrogate endpoint in support of steroid approval would be a profound benefit for the MPS communities and companies working on knee disease, and really all companies working on gene therapies and other types of precision medicine.

Speaker Change: We've shared a lot of meaningful data already this year.

Speaker Change: At the World Symposium meeting in February we presented positive biomarker and long term cognition data from our U X 111 gene therapy in Sanfilippo syndrome.

Eric Harris: The data showed the treatment resulted in rapid and sustained reduction of CSF heparin sulfate and that this was correlated with improved long term cognitive development.

Eric Harris: We are also participating in a workshop on the heparin sulfate biomarker hosted by the Reagan eat All foundation.

Eric Harris: Workshops brought together FTA representatives patient advocates scientist and industry leaders to discuss the overwhelming body of data supporting use of CSF heparin sulfate.

Emil D. Kakkis: Stripping away to Satuzumab, just this week, we announced that we had completed our enrollment in our Phase 2-3 Orbit Study and our Phase 3 Cosmic Study in Osteogenesis Imperfecta. The FACES data presented late last year was clearly compelling for the study of best years and led to accelerated interest and enrollment in the program.

Eric Harris: As a biomarker to enable accelerated approval and Dorado Pathic M. P S diseases.

Eric Harris: The sport of Peter Mark than the F D a and recognizing this biomarker as a surrogate endpoint to support accelerated approval would be a profound benefit for the M. P. S communities and companies working on these diseases and really to all companies working on gene therapies or other type of precision medicines.

Emil D. Kakkis: Two weeks ago, we announced strong, positive interim data from the Phase I-II study of GTIPS-102 and Angelin syndrome. The interim data we shared confirmed in a larger body of data that GTIPS-102 could fundamentally change the development trajectory of Angelin patients. Importantly, the magnitude of the effect across all domains in the expansion cohort was found to be similar or greater than what we observed previously with the dose escalation cohort. Ongoing treatment of GCA-CoA2 resulted in continuous and sustained improvement in these patients, as evidenced by the long-term data in the dose escalation cohort, and we've demonstrated the safety profile can be successfully managed.

Eric Harris: Shifting just to choose a mab just this week, we announced that we've completed enrollment in our phase two three orbit study and our phase III Cosmic studies osteogenesis imperfecta.

Eric Harris: The phase two data presented late last year was clearly compelling for the study investigators and led to accelerated interest and enrollment in the program.

Eric Harris: Two weeks ago, we announced strong positive interim data from the phase one two study of G takes one or two in Angelman syndrome.

Eric Harris: The interim data, we shared confirmed in a larger body of data that gtx, one or two can fundamentally change the development trajectory of Angelman patients.

Emil D. Kakkis: This is based on two studies out of the most severe Angelin Syndrome patients, those with genetic deletions, where there's typically no improvement on the Bayley scale. This has been observed in both natural history and placebo-controlled studies.

Eric Harris: Importantly, the magnitude of effect across all domains in the expansion cohorts was found to be similar or greater than what we observed previously with the dose escalation cohorts.

Emil D. Kakkis: For example, in our recent ANGEM clinical study, after one year, the placebo group showed only a 0.8 point improvement in the Bayley-3 cognition score. What we saw in our study was a 5 point improvement in the Bayley-4 score, beginning as early as day 170 in the dose expansion cohorts and almost double that at one year in the dose escalation cohorts. We also saw that this improvement continued through day 758 in the dose escalation cohorts.

Eric Harris: Ongoing treatment Gtx, what two resulted in continuous and sustained improvement in these patients as evidenced by the long term data in the dose escalation cohorts.

Eric Harris: We have demonstrated the safety profile can be successfully managed.

Eric Harris: This phase one two studies value the most severe AIDS the angelman syndrome patients those with genetic deletion deletions, whether that typically no improvement on the Bayley scale.

Emil D. Kakkis: The magnitude of the change we observed with the family was further supported by multiple other assessments, including the age of severity assessments and the aberrant behavior checklist. The improvements in the domain of sleep and behavior or hyperactivity at day 170 were better than what we saw after a year or more in the prior cohort. Families also talk about their kids being calmer, more attentive, and more aware of the world around them. This allows greater independence across multiple facets of development like eating, sleeping, and mobility.

Eric Harris: This has been observed in both natural history and placebo controlled studies for example, our recent and current clinical study after one year. The placebo group showed only a 0.8 point improvement in Bayley three cognition score what we saw in that study was a five point improvement the Bayley four score beginning as early as day, one Saturday in the dose expansion cohorts.

Eric Harris: And almost double that at one year in the dose escalation cohorts. We also saw that this improvement continued today 758 in the dose escalation cohorts.

Eric Harris: The magnitude of change we observed with the Bayley with further supported.

Emil D. Kakkis: The improvements in cognition and motor function really came across in the videos that we showed on April 15th call. The patient was able to solve puzzles and navigate more challenging walking paths, which provided a small, real-world sample of the significant changes we're seeing in the charts and graphs. The combination of improvements across cognition, receptive communication, and motor function provides a real sense of the potentially transformative nature of this therapy. The multidomain Respondrinix, or MDRI, also resonated with physicians and families.

Eric Harris: In multiple other assessments, including Haynesville severity assessments and the aberrant behavior checklist.

Eric Harris: Premises and domain of sleeping behavior or hyperactivity. They want 70 were better than what we saw after a year or more than the prior cohorts.

Eric Harris: Families also talked about their kids being calmer more attentive more aware of the world around them.

Eric Harris: Got greater independents across multiple fastest development like eating sleeping and mobility.

Eric Harris: Improvements in cognition and motor function really came across in the videos that we showed in April 15th call.

Emil D. Kakkis: The MDRI brings all the domains of movement across the study population together and is a great way to look at changes across individual patients for a heterogeneous patient group. MDRI analysis across the four domains of cognition, receptive communication, behavior, and sleep resulted in a statistically significant median improvement across all cohorts at this early time point of day 170. Furthermore, the majority of the patients in the expansion cohort achieved improvements in at least two, and up to, all four domains.

Eric Harris: Patient was able to solve puzzles and navigate more challenging walking path, which provide a small real world samples significant changes, we're seeing in the charts and graphs.

Eric Harris: Combination of improvements across cognition receptor communication and motor function provide a real sense of the potentially transformative nature of this therapy.

Eric Harris: The multi main responder next our M. D. R. I also resonate with physicians and families. The Android brings all the domain of movement across the study population together and it's a great way to look at changes across the individual patients for a heterogeneous patient group.

Emil D. Kakkis: Importantly, the data representatives show the GTX 1200 has a tolerable safety profile. Lower extremity weakness is now a rare, well-deserved transient that occurred in 2 out of 53 patients in the extension cortex who had completed the loading phase.

Eric Harris: And right now so it's across the board a means of cognition.

Eric Harris: His communication behavior asleep resulted in a statistically significant medium premium of two domains across all cohorts at this early time point of day 170.

Emil D. Kakkis: Both patients were in cohort A and B, and no events were observed in cohort C through E. The events were classified as mild and moderate, and all resolved quickly with the patient remaining in the study. Six earlier patients with this safety issue from the beginning of the study are all on chronic dosing and received multiple doses without any issues. Given our understanding of this issue and recent feedback from regulators, we are comfortable that the current safety profile is accessible and manageable and will continue providing routine safety updates, although only with RFC updates.

Eric Harris: Further the majority of the patients in the Spanish courts achieved improvements in at least two and up to.

Eric Harris: All four domains.

Eric Harris: Importantly, the data we presented show that Gtx why don't you have a tolerable safety profile.

Eric Harris: Lower extremity weakness is now a rare well understood trends event that occurred in two out of 53 patients in exchange of course had completed the loading phase.

Eric Harris: Well patients, where the cohort a and b and no events observed in cohort C Thru E D.

Emil D. Kakkis: We've heard strong enthusiasm from KOLs over the past couple of weeks, including those reviewed by our analysts; some of you might be on the call. These treating physicians expressed comfort with the safety profile and the route administration of these patient populations and the broad agreement that treatment GHGs 1 and 2 resulted in clearly meaningful efficacy in these patients, but we just don't typically see any improvement. With all this put together, we have a strong product candidate and plan for Phase 3 development.

Gtx: Yeah, Vance were classified as mild and moderate and.

Gtx: And all resolved quickly with patients remaining in the study.

Eric Harris: Earlier patients with this safety issue from the beginning of the study are all on chronic dosing I received multiple doses without any issues.

Eric Harris: Given our understanding of this issue and recent feedback from regulators, we're comfortable with the current safety profile is acceptable and manageable and will continue to providing routine safety updates only with our efficacy updates.

Emil D. Kakkis: We're confident this product candidate has the potential to be a transformative treatment for patients with Angelman Syndrome. Now I'll turn the call over to our Chief Commercial Officer, Erik Harris, to provide an update on our commercial efforts that led to another successful quarter. Thank you, Emil, and good afternoon everyone. I'll start with Chris Peters' performance in North America.

Eric Harris: We've heard strong enthusiasm kols over the past couple of weeks, including those reviewed by our analysts some of you might be on the call. The treating physician expressed comfort with a safety profile and their administration. These patient population and the broad agreement that treat with GH checks wanted two resulted in clearly meaningful efficacy in these patients.

Eric Harris: You just don't typically see any improvements.

Erik Harris: I want to remind everyone that Chiara Caron has been responsible for driving contributed revenue in North America since the transition in April of last year. We will continue to augment their efforts through additional field support to ensure a smooth transition, maintain patient continuity, and help them generate additional SAR. Demand for Clifida in the U.S. remains strong in Q1 2024. Approximately 60% of the star forms came from adult patients.

Eric Harris: With all of US put together, we have a strong product candidate and plan for phase III development. We're confident this product candidate has the potential to patriots wide of treatment for patients with Angelman syndrome.

Eric Harris: Now I'll turn the call over to our Chief Commercial Officer Officer, Erik Harris to provide an update on our commercial efforts that led to another successful quarter.

Erik Harris: I want to remind everyone that key our care and he has been responsible for driving per suite as revenue in North America since the transition in April of last year.

Erik Harris: All rights reserved. resulting in nearly 70 new prescribers in the quarter. This is encouraging if an adult penetration is in the low 20s, and this implies Procedure has ample room to continue growing. As is typical, this quarter had some seasonality as patients worked through the reauthorization process with their insurance providers at the beginning of the year. However, we are confident in our full-year U.S. revenue projections given the strength of the underlying demand.

Erik Harris: To augment their efforts through additional support to ensure a smooth transition maintain patient continuity and help them generate additional start forms.

Erik Harris: The demand for Chris Vita in the U S remained strong in Q1 2020 for approximately 60% of the stock loans came from adult patients.

Eric Harris: By community physicians, resulting in nearly 70, new prescribers in the quarter.

Erik Harris: Moving to Portugal and Latin America, where we lead commercialization, our team delivered another successful quarter, and Lycan by adding approximately 50 new patients. Thank you, Christina, totaling over 550 patients on reimbursed therapy since launch. While Brazil drove more than 60% of Perseverance's last-hand revenue in Q1 2024, we also saw a significant uptick in Argentina and Mexico. We are particularly excited about Mexico, the second largest market in LATAM, which recently cleared all pediatrics and adult reimbursement hurdles. IMSS, Mexico's largest payer, approved the procedure for pediatric patients in about two years versus the three to five years it usually takes for such approval.

Eric Harris: This is encouraging given adult penetration is in the low twenties and this implies per theater has ample room to continue growing.

Eric Harris: As is typical this quarter had some seasonality as patients work through the reauthorization process with our insurance providers at the beginning of the year.

Eric Harris: We are confident in our full year U S revenue projections given the.

Eric Harris: The strength of the underlying demand.

Eric Harris: Shifting to Christina in Latin America, where we lead commercialization.

Christina: Our team delivered another successful quarter.

Christina: In Latam by adding approximately 50 new patients.

Christina: This leader totaling over 550 patients on reimbursed therapy since launch.

Christina: While Brazil drove more than 60% of Chris meters Latam revenue in Q1 2024, we also saw a significant uptick from Argentina and Mexico.

Erik Harris: This recognizes the value they see for Christie's on a pediatric patient. The team is now busy getting procedural and local hospital formularies to expedite reimbursement. [inaudible] As I mentioned on previous earnings calls, we expect quarter-to-quarter variability in LICAM revenue driven by uneven ordering patterns but remain confident in Underlying Demand Growth for our product. Moving on to DeJovia, growth of new star forms remains strong.

Christina: We are particularly excited about Mexico, the second largest market in Latam, which recently cleared all pediatric and adult reimbursement hurdles.

Christina: IMS S. Mexico's largest payer approved for speed for pediatric patients and about two years versus the three to five years, usually takes for such approval.

Christina: This recognizes the value they see for Chris Reed, our pediatric patients. Our team is now basically getting Christina on local hospital formularies.

Erik Harris: In the U.S., we added over 30 star forms and 15 patients on reimbursed therapy, resulting in over 485 reimbursed patients since launch, with approximately a 65 to 35 split between pediatric and adult patients. The number of new prescribers continues to grow, adding approximately 10 new prescribers in Q1 2024. As you know, Joby has not yet been approved by the European Medicines Agency. So across Europe and the MENA region, sales are driven by named patient sales requests. Approximately 200 patients are treated under MGS across 12 countries as of the first quarter. The majority of demand is from France, but we are receiving increasing requests from other countries within the Amina region.

Christina: Expedite reimbursement for these patients.

Christina: As I mentioned on previous earnings calls, we expect quarter to quarter variability in Latam revenue driven by uneven ordering patterns, but remain confident in the underlying demand growth for our products.

Christina: Moving on to the jewelry growth of New Star forms remains strong in the U S. We added over 30 start forms and 15 patients on reimbursed therapy, resulting in over 485 reimbursed patients since launch with.

Christina: With approximately a 35% to 65% to 35 split between pediatric and adult patients.

Christina: The number of new prescribers continues to grow.

Christina: Adding approximately 10, new prescribers in Q1 2024.

Erik Harris: 2024 is an important launch year for FTE. As of Q1 2024, we are treating nearly 100 patients in EMEA through MTS and regular reimbursement processes where we have been approved. We expect to launch Akiva and more in these countries in 2024. In Canada, we started enrolling patients in our hub after Health Canada's approval last year. Our next step is to secure reimbursement agreements with public payer authorities in late 2024 or early 2025.

Christina: As you know did you all we have not yet been approved by the European Medicines Agency.

Christina: So across Europe, and the Mena region did you always driven by named patient sales request.

Christina: Approximately 200 patients are treated under MTS across 12 countries as of the first quarter the.

Christina: The majority of demand is from France, but we are receiving increasing requests from other countries within the EMEA region.

Christina: Yes.

Christina: 'twenty 'twenty four is an important launch year for <unk>.

Christina: As of Q1 2024, we're treating nearly 100 patients in EMEA through NPS and regular reimbursement processes, where we have approval.

Erik Harris: The team is also working closely with private payers to secure reimbursement in 2024 for enrolled patients who have insurance through these private plans. In Japan, we received regulatory approval in January and pricing and reimbursement approval in April. The launch is underway, and the HOSH physician and patient community in Japan is very excited about FPV. We're excited to receive StarForms in our hub, and we expect a robust launch in 2024 as we continue to educate physicians and patients on the benefits of the FQs and label for appropriate patients.

Christina: We expect to launch our pizza and more EMEA countries in 2024.

Christina: In Canada, we started enrolling patients in our hub after health Canada's approval last year. Our next step is to secure reimbursement agreements with public payer authorities in late 2024 or early 2025 and the team is also working closely with private payers to secure reimbursement in 2020.

Christina: For all enrolled patients who have insurance through these private players.

Erik Harris: Overall, Q1 2024 was a strong quarter for Ultragenyx, generating $109 million dollars in revenue. Given the strong underlying demand for our four commercial products across all regions and the upcoming FQ2 launches, we remain confident in delivering our 2024 revenue guidance. With that, I'll turn the call over to Howard to share more details on our financial results for the court. Thanks, Eric, and good afternoon, everyone. I'll briefly summarize our financials that were reported in our press release earlier today. As Eric noted, we reported this.

Christina: In Japan, we received regulatory approval in January and pricing and reimbursement approval in April the launch is underway.

Christina: <unk> H physician and patient community in Japan is very excited about ftes there.

Christina: <unk> started to receive stock forms in our hub and we expect a robust launch in 2024 as we continue to educate physicians and patients on the benefits of the FTE as a label for appropriate patients.

Christina: Overall, Q1, 2024 was a strong quarter for <unk> generating $109 million in revenue.

Howard Horn: $109 million in total revenue for the first quarter of 2024 Chris Vita contributed $83 million, including $40 million from North America, $36 million from Latin America and Turkey, and $6 million from Europe.

Christina: Given the strong underlying demand for our four commercial products of course across all regions and the upcoming <unk> launches, we remain confident in delivering our 2020 for revenue guidance with that I'll turn the call to Howard to share more details on our financial results for the quarter.

Howard Horn: Chris Vita Net Sales and underlying patient demand continue to grow meaningfully compared to the prior year, including in North America.

Maurice Thomas Raycroft: Thanks, Eric and good afternoon, everyone I'll briefly summarize our financials that we reported in our press release earlier today.

Howard Horn: As a reminder, since the transition of North American Commercial Responsibility,

Howard Horn: Responsibilities to KKC in April 2023 and going forward. Our revenue in the region shifted from a profit share to loyalty. This is calculated using annual revenue tiers based on net sales, with royalties ranging from the mid-twenties up to 30%.

Maurice Thomas Raycroft: As Eric noted, we reported $109 million in total revenue for the first quarter of 2024.

Maurice Thomas Raycroft: Chris Vida contributed $83 million, including $40 million from North America, $36 million from Latin America, and Turkey, and $6 million from Europe.

Maurice Thomas Raycroft: Chris Vita net sales and underlying patient demand continued to grow meaningfully compared to the prior year, including in North America.

Howard Horn: As a result, our first quarter revenue was on the low end.

Maurice Thomas Raycroft: As a reminder, since the transition of North American commercial responsibilities to <unk> in April 2023, and going forward our revenue in the region shifted from a profit share to a royalty.

Howard Horn: With the increasing royalty rate and growing underlying demand, we expect North American Crispida quarterly revenue to meaningfully increase throughout the year. Jolvi revenue in the first quarter was $16 million, and Metsevi revenue in the first quarter was $4.4 million.

Maurice Thomas Raycroft: This is calculated using annual revenue tiers based on net sales with royalties ranging from the mid twenties up to 30%.

Howard Horn: Our total operating expenses in the first quarter were $274 million, which included R&D expenses of $178 million and ST&A expenses.

Maurice Thomas Raycroft: As a result, our first quarter revenue started to the low end of the royalty range and we expect the blended rate for the full year to be at the upper end of the range.

Howard Horn: 78 million, and cost of sales of $18,000. Operating expenses included an on-cash, stock-based compensation of $37 million. In the first quarter, the net loss was $171 million, or $2.03 per share. As of March 31st, 2024, we had $569 million in cash, cash equivalents, and marketable securities. In the first quarter, net cash used in operations was $191 million. The first quarter of the year is typically a larger use of cash than the others reported.

Maurice Thomas Raycroft: With the increasing royalty rate and growing underlying demand, we expect north American crisp <unk> quarterly revenue to meaningfully increase throughout the year.

Maurice Thomas Raycroft: The jewelry revenue in the first quarter was $16 million.

Maurice Thomas Raycroft: <unk> revenue in the first quarter was $7 million.

Maurice Thomas Raycroft: Our total operating expenses in the first quarter were 240, excuse me 274 million, which included R&D expenses of $178 million SG&A expenses of 78 million and.

Maurice Thomas Raycroft: And cost of sales of $18 million.

Maurice Thomas Raycroft: Operating expenses included noncash stock based compensation of $37 million.

Howard Horn: It includes items like the payment of annual bonuses. This quarter also ended with a relative.

Maurice Thomas Raycroft: In the first quarter net loss was $171 million or $2 <unk> per share.

Howard Horn: with a relatively high accounts receivable balance due to the timing of receipts from our commercial activities. Importantly, our guidance for 2024 net cash use and operations remains unchanged from what we provided last quarter and is expected to be less than $400 million for the year. We are also reaffirming our 2024 revenue guidance ranges.

Maurice Thomas Raycroft: As of March 31, 2024, we had $569 million in cash cash equivalents and marketable securities.

Maurice Thomas Raycroft: In the first quarter net cash used in operations was $191 million.

Maurice Thomas Raycroft: The first quarter of the year is typically a larger use of cash than the other three quarters because it includes items like the payment of annual bonuses.

Howard Horn: Total revenue is expected to be between $500,000 and $530,000.

Howard Horn: which represents 15 to 22 percent growth versus 2023. CrossFeeder Revenue is

Maurice Thomas Raycroft: This quarter also ended with a relatively high accounts receivable balance due to the timing of receipts from our commercial activity.

Howard Horn: is expected to be between $375 and $400 million, which includes all regions and all forms of revenue to Ultragenyx. Specifically, it includes Crispida product revenue from Latin America and Turkey, and cash and non-cash royalties from North America and Europe. Our Casita guidance range represents 14 to

Maurice Thomas Raycroft: Importantly, our guidance for 2024 net cash used in operations remains unchanged from what we provided last quarter and is expected to be less than $400 million for the year.

Maurice Thomas Raycroft: We are also reaffirming our 2020 for revenue guidance ranges.

Maurice Thomas Raycroft: Total revenue is expected to be between 500 $530 million, which represents 15% to 22% growth versus 2023.

Howard Horn: to 22% growth versus 2023. Jolvi revenue is expected to be between $75 and $80 million.

Howard Horn: This represents 6 to 13 percent growth versus 23.

Maurice Thomas Raycroft: Chris feeder revenue is expected to be between 375 and $400 million, which includes all regions and all forms of crispy to revenue to ultra <unk>.

Howard Horn: Our Djolby projections represent a blend of faster growth in countries where we commercialize and lower growth in countries where we respond to named patient requests.

Maurice Thomas Raycroft: Specifically and includes Chris speed up product revenue from Latin America, and Turkey, and the cash and noncash royalties from North America and Europe.

Eric Crombez: With that, I'll turn the call over to our CMO, Erik Crombez, who will provide an update on our upcoming clinical data release.

Maurice Thomas Raycroft: Our <unk> guidance range represents 14% to 22% growth versus 2023.

Eric Crombez: Clinical Theater Leader Thank you, Howard, and good afternoon, everyone. Emil has already gone through the exciting GTX-102 data that we shared last month, so I will focus most of my comments on some of our other programs. I would, however, like to reiterate the enthusiasm that we are hearing from patient advocacy organizations and the treating community, who all feel that GTX-102 has the potential to be a transformative treatment for patients with Angelman Syndrome. We are at an important inflection point for the GTX-102 program.

Eric Crombez: We have clear and clinically meaningful efficacy, and we are transitioning to phase 3 study startup. The phase 3 will be a global, randomized, placebo-controlled study that is expected to enroll approximately 100 to 120 patients. We expect to finalize these plans, including endpoints and study duration, in an end-of-Phase 2 meeting that has been scheduled with the FDA in May 2024. We plan to initiate Phase 3 around the end of the year. Moving to DTX-401, our investigational gene therapy for the treatment of glycogen storage disease type 1.

Maurice Thomas Raycroft: <unk> revenue is expected to be between $75 million to $80 million.

Maurice Thomas Raycroft: Which represents 6% to 13% growth versus 'twenty three.

Maurice Thomas Raycroft: Our to Dolby projections represent a blend of faster growth in countries, where we commercialized and lower growth in countries, where we respond to named patient requests.

Maurice Thomas Raycroft: With that I'll turn the call to our CMO, Eric <unk>, who will provide an update on our upcoming clinical data readouts.

Eric Harris: Howard and good afternoon, everyone <unk> already went through the exciting Gtx 102 data that we shared last month. So I will focus most of my comments on some of our other programs I would however, like to reiterate the enthusiasm that we are hearing from patient advocacy organizations and the treating community who will all feel that gtx one.

Eric Harris: Two has the potential to be a transformative treatment for patients with Angelman syndrome.

Eric Harris: We are at an important inflection point for the Gtx 102 program, we have clear and clinically meaningful meaningful efficacy and we are transitioning to phase III study startup.

Eric Harris: The phase III will be a global randomized placebo.

Eric Crombez: Phase 3 data from this program, which we expect this quarter, will be the first pivotal data set from our large and late-phase gene therapy portfolio. All of the patients in the Phase 1-2 study demonstrated a clinically meaningful response to DTS-401 that has proven durable with the earliest treated patients in their fifth year of follow-up. The randomized placebo-controlled phase 3 study enrolled 49 patients, and we expect to see clinically meaningful and statistically significant reductions in daily coronary heart failure.

Maurice Thomas Raycroft: Controlled study that is expected to enroll approximately 100 to 120 patients we expect to finalize these plans, including endpoints in study duration and an end of phase II meeting that has been scheduled with the FDA in mid 2024, we plan to initiate the phase III around the end of the year.

Maurice Thomas Raycroft: Shifting to <unk> 401, our investigational gene therapy for the treatment of glycogen storage disease type one a.

Maurice Thomas Raycroft: Phase III data from this program, which we expect this quarter will be the first pivotal data set from our large and late stage gene therapy portfolio.

Eric Crombez: Our experience with the Phase I-II program helps us to better understand the importance of reducing dependence on overnight cornstarch and the great fear that all patients with GSD-1A and their families have regarding missing acorn perch doses and the resulting potential for hyperglycemia during sleep, which can be fatal, especially in children.

Maurice Thomas Raycroft: All of the patients in the phase <unk> study demonstrated a clinically meaningful response to <unk> that has proven durable with the earliest treated patients in their fifth year of follow up.

Maurice Thomas Raycroft: The randomized placebo controlled phase III study enrolled 49 patients and we expect to see clinically meaningful and statistically significant reductions in daily Cornstarch therapy.

Eric Crombez: As seen in our Phase 1-2 results, we do expect the Phase 3 to show improved glucose control during the day and, also importantly, overnight improvement. We plan to share POPLINE data within the next couple of weeks. I'll close with Struzumab, our fully human monoclonal antibody for the treatment of osteogenesis imperfecta. We recently announced completion of enrollment in our Phase III Orbit and Cosmic studies. We ended up over-enrolling, in record time, with 158 patients in Orbit and 66 patients in Cosmic. And this could not have been done without the efforts and strong support from the patient and treating community.

Maurice Thomas Raycroft: Our experience with the phase III program helped us to better understand the importance of reducing dependence on overnight corn starch and the great fear that all patients with <unk> and their families have regarding missing a corn starch dose and the resulting potential for hypoglycemia during sleep, which can.

Maurice Thomas Raycroft: Be fatal, especially in children.

Maurice Thomas Raycroft: Our phase <unk> results, we do expect the phase III to show improved glucose control during the day and also importantly overnight improvement we plan to share top line data within the next couple of months.

Eric Crombez: We expect to share additional data from the Phase 2 portion of the ORBIT study in the second half of this year. This data will include at least 12 months of follow-up and build on the data we presented last October. I'll now turn the call back to Emil for some closing remarks. Thank you, Erik.

Maurice Thomas Raycroft: I'll close with <unk>, our fully human monoclonal antibody for the treatment of osteogenesis Imperfecta, We recently announced completion of enrollment in our phase III orbit in Cosmic studies, we ended up over enrolled in record time with 158 patients in orbit in 66 patients in cosmic.

Emil D. Kakkis: In the first part of your presentation, we made significant progress advancing our clinical pipeline. I'll close by quickly summarizing our key clinical catalysts for the rest of the year. Late in this quarter, we expect to share top-line phase 3 DTH401 data from our gene therapy for GSD1A. We've scheduled the GTF-102 and the Phase II meeting of the FDA in mid-2024 that would enable initiating our Phase III around the end of the year.

Maurice Thomas Raycroft: And this could not have been done without the efforts and strong support from the patient and treating communities. We expect to share additional data from the phase II portion of the orbit study in the second half of this year. This data will include at least 12 months of follow up and build on the data. We presented last October I will now turn the call back to AML to provide some closing.

Emil D. Kakkis: The U.S. 7-01 for Wilson disease stage 1 data is expected in the second half of 2024. This will be approximately six months after the last patient was dosed in phase 3, plus some time for all the data to be collected and analyzed. On U.S. 143, we expect to share updated long-term safety data in the second half of the year. For the U.S. 143 Sting 3 portion of the ORBIT study, there are two interval analyses planned, with the first anticipated by the year-end or early 2025.

AML: Our remarks.

AML: Thank you Eric and the first part of your we made significant progress advancing our clinical pipeline and up close by quickly summarizing our key clinical catalysts for the rest of the year.

AML: Later this quarter, we expect to share top line phase III <unk> hundred one data from our gene therapy for GSD <unk>.

AML: We have scheduled the gtx, one or two end of phase two meeting with FDA in mid 2024 that would enable initiating our phase III around the end of the year.

AML: The U S 701 for Wilson disease stage, one data is expected in the second half of 2024. This will be approximately six months. After the last patient was dosed in phase III plus some time for all the data to be collected and analyzed.

Emil D. Kakkis: The first analysis will have a stringent threshold of P less than or equal to 001 if the thresholds aren't met. The second M&L will occur a few months later, followed by a final analysis at 18 months. Interim analyses will not be reported to the company by the Daily Monitoring Committee unless they are positive.

AML: <unk> three we expect to share updated long term phase II data in the second half of the year.

AML: For the U S. <unk> phase III portion of the orbit study there are two interim analyses planned with the first anticipated by year end or early 2025.

Emil D. Kakkis: In the event of a positive interim analysis, we would share that outcome, but top-line results will not be announced immediately as the study would require patients to complete a final visit and time to collect and prepare the data for a formal analysis. For those of you keeping track... We may have three products at or near readiness for BLA filings in sample-equal syndrome with UX111, GSK1A with UX401, and Oxygenic Imperfect with We are at a company-defining inflection point that builds on our strong base of growing commercial products and positions us to transform the lives of even more rare disease patients. With that said, let's move on to your questions. Operator, please provide the Q&A instructions. Thank you.

Maurice Thomas Raycroft: The first analysis will have a stringent thresholds of P less than or equal to 001.

Maurice Thomas Raycroft: If the thresholds are met.

Maurice Thomas Raycroft: A second interim analysis will occur a few months later, followed by a final analysis at 18 months.

Maurice Thomas Raycroft: Interim analysis will not reported to the company by the data monitoring committee unless they are positive.

Maurice Thomas Raycroft: In the event of a positive interim analysis, we would share that outcome, but topline result will not be announced immediately as the steady would require patients to complete a final visits and time to collect and prepare the data for a formal analysis.

Maurice Thomas Raycroft: For those of you keeping track we may have three products at or near readiness for BLA filings in Sanfilippo syndrome, with <unk> hundred 11, <unk> with U S 401, and osteogenesis imperfecta with <unk> over the next year or so.

Operator: Ladies and gentlemen, to ask a question, please press star 1-1 on your telephone and then wait to hear your name announced. To withdraw your question, please press star 11 again. We ask that you limit yourself to one question and one follow-up. Please stand by while we compile the Q&A roster. Our first question comes from the line of Yigal Nochomovitz of Citigroup. Your line is open.

Maurice Thomas Raycroft: We are at a company defining inflection point to build on our strong base of growing commercial products and positions us to transform the lives of even more rare disease patients.

Speaker Change: With that let's move on to your questions. Operator, please provide the Q&A instructions.

Emil D. Kakkis: Oh, hi, great. Thank you so much for taking the time to answer the question. I just have one on GST-1A for a program that we haven't talked about too much, but we're coming up with the typical data. Could you just remind everybody what is required in terms of the primary endpoint to reach a positive study? What are the timelines in terms of the filing strategy for this program? And then, thirdly, could you just give a little bit of perspective on the incidence and prevalence of GST-1A and how you would think about pricing this program? Thank you.

Speaker Change: Thank you.

Speaker Change: Ladies and gentlemen to ask a question. Please press star one on your telephone and wait to hear your name announced.

Speaker Change: To withdraw your question. Please press star one again.

Speaker Change: We ask that you limit yourself to one question and one follow up.

Speaker Change: Please standby, while we compile the Q&A roster.

Speaker Change: Our first question comes from the line of Eagle No Tollbooth Djokovic with Citigroup. Your line is open.

Speaker Change: Hi, great. Thank you so much for taking the question I just had one on the <unk> program.

Emil D. Kakkis: Yeah, so for the CFPY program, the primary endpoint is the continuous variable mouse, the Clark Search for Utilization, and so we'll be comparing The Decrease of Cardiovascular Febrilization for the Primary Compared to the Triary of the Febrile Group, that also requires that the patients have good glucose control for that reduction in starch. That's the primary endpoint agreed with the FDA. In terms of filing strategy, we are transitioning the manufacturing into our plant, and we plan with the data to go to FDA and have a discussion and lay that out, so we'll provide more detail in the filing timeline when we have it, but the transition of the manufacturing, and we'll need to talk with FDA about setting it, but it's on the path, assuming our data are positive.

Speaker Change: Positive study.

Speaker Change: What are the timelines in terms of the filing strategy for this program and then thirdly could you just give a little bit of perspective on the incidence and prevalence of <unk> and how you are thinking about pricing.

Speaker Change: Thank you.

Speaker Change: Yes, so for the <unk> program.

Speaker Change: Primary endpoint is a continuous variable now cornstarch.

Speaker Change: Utilization and so we will be comparing the.

Speaker Change: The decrease in <unk> utilization for the primary.

Speaker Change: Between the treated and placebo group.

Speaker Change: As also requires that the patients have good <unk> control for that reduction in starch. That's the primary endpoint agreed with the FDA.

Emil D. Kakkis: Now, the last instance of prevalence in pricing. We believe there are around 8,000 patients with GST-1 in the commercial territories, and that might be a little under 2,000 that are in the U.S. with the disease. That's an estimate. We haven't set pricing at all at this point.

Speaker Change: In terms of filing strategy, we are transitioning the manufacturing into our plant and we plan with the data to go to FDA and have a discussion and lay that out so we'll provide more detail on that filing timeline.

Emil D. Kakkis: We're thinking about it, but it is a severe disease. It is an urgent disease. Patients are on a treadmill every day trying to stay alive. And we've seen from the enrollment of studies that there is a desire. So, while probably surprising, in fact, I think the degree of urgency is what defines success in gene therapy launches to date. And I think GSD-1 is urgent. I think people want to get treated, they want to get off the treadmill, they want to, as I say, put the gun down. This point to their head every day about managing their glucose. So we're excited about the potential, but there's still obviously more work to do.

Speaker Change: We have it but the transition of the manufacturing and we'll need to talk to the FDA and setting it but its on its on path assuming our data are positive.

Speaker Change: Now the last incident prevalence and pricing.

Speaker Change: We believe there's around 8000 pace with GSE, one in the commercial territories and that might be well under 2000 that are in the U S with the disease.

Speaker Change: That's an estimate.

Speaker Change: We haven't set pricing at all at this point, we're thinking about it but.

Speaker Change: It is a severe disease. It is an urgent disease patients are on a treadmill everyday trying to stay alive and we've seen from the enrolment of this study that there is a desire so while prevalence of pricing have an impact I think the degree of urgency is what defines success in gene therapy launches to date and I think GST one is urgent I think people.

Operator: Thank you very much, everyone. Thank you. Please stand by for our next question. Our next question comes from Anupam Rama with J.P. Morgan. Your line is open.

Operator: Please stand by for our next question. Our next question comes from Anupam Rama with J.P. Morgan. The line is open. Hey guys!

Speaker Change: Wanted to get treated they want to get off the treadmill, they want to as I say put the gun down.

Speaker Change: At this point that there had every day about managing their glucose. So we're excited about the potential but there's still obviously more work to do.

Speaker Change: Okay.

Speaker Change: Thank you very much.

Speaker Change: Thank you.

Speaker Change: Please note for our next question.

Emil D. Kakkis: Well, I think that there's still difficulty appreciating the meaning of the changes in Bayley, for example, and I think what we heard from some of the KOL feedback is that they're excited about the changes, these are meaningful changes, and they know that Bayley doesn't change for a foundation. So I think that's one of the major ones.

Speaker Change: Our next question comes from the line of Omnipod Rama with Jpmorgan. Your line is open.

Anupam Rama: Hey, guys. Thanks, so much for taking the question.

Anupam Rama: And then just thinking about the Gtx 102 update last month.

Anupam Rama: Just in your discussion with the Street, what do you think are the most misunderstood or divergent points.

Emil D. Kakkis: I think there were some misconceptions about the safety and low extremity weakness that was reported. It was only one patient, one mild, it resolved quickly, but it's out of 53 patients now through the full load, so it's a relatively small thing, it's reversible, I think people are still overstating the meaningfulness, but I think if you talk to KOLs, they say it's not a deal, it's not going to change things, and the regulator says, you know, fine, it's So I think we're on the right path. I think these are the two things that need to be straightened out.

Anupam Rama: Our feedback you get relative to say the physician or Kols feedback Youre getting post day. Thanks, so much.

Anupam Rama: Well I think that there is still.

Anupam Rama: Difficulty appreciating the meaning of the changes and Bailey for example, and I think what we heard from some of the KOL feedback that Derrek Derrek cited about the changes these are meaningful changes and they know the bayley doesn't change for cognition. So I think that's one of the major ones I think there was some misconception about the same.

Anupam Rama: Ft low extremity weakness that was reported.

Anupam Rama: It was really one patient moderate one mild they resolve quickly but its out of 53 patients out through the full load. So it's a relatively small thing. It's reversible I think people are still overstating the meaningfulness, but I think if you talk to Kols. They say, it's not a deal is not going to change things and the regulators said fine it's all good.

Emil D. Kakkis: But what I'd say is imagine the data we saw, the speed and the combination of domains is quite exceptional, and I think people aren't seeing that multiple domains of improvement for one treatment in treatment areas that normally don't change. And we need to keep telling our story. And I hope that if people talk to more KOLs and see the data, understand it, that might help people understand the meaningfulness of what we're seeing and how unusual it is for this disease to see any change at all. So we're excited about it. Thank you for the question.

Anupam Rama: They didn't ask us to do anything to move ahead.

Anupam Rama: And they went ahead and accepted in the phase III schedule already so I think I think we're on path. I think these are the two things that need to be straight, but what I would say the magnet. The data we saw the speed and the combination of domains is something quite exceptional and I think people are seeing that multiple domains of improvement for one treatment.

Operator: Please stand by for our next question. Our next question comes from the line of Tazeen Ahmad with Bank of America Securities. Your line is open.

Anupam Rama: And treatment areas that normally don't change and we need to keep telling our story and I hope that if people talk to more kols that have seen the data to understand it that might help people inform what the meaningfulness of what we're seeing and how unusual it is for this disease to see any change at all so we're excited about it and thank you for the question.

Anupam Rama: Tom.

Tom: Thank you.

Speaker Change: Please standby for our next question.

Emil D. Kakkis: Well, fortunately, both studies enrolled too many patients but got to the same point almost at the same time. And I actually think the younger patients will probably, as historically true, even respond faster. So I actually think both studies will have read it out about the same time. Our expectation would be to file for the full age range based on that data. So we're actually in good shape to do that. I think it's the right thing to do.

Speaker Change: Our next question comes from the line of <unk> Ahmad with Bank of America Securities. Your line is open.

Ahmad: Hi, guys. Thanks for taking my question.

Ahmad: Just in terms of timing for the orbit in cosmic studies for ally.

Ahmad: Do you think that theyre going to readout at around this time and is it your plan to submit for the different age group as part of a single application or is it going to be scattered.

Emil D. Kakkis: I think it would be tough to submit one part of the age range and not the youngest. So with the young patient study getting enrolled puts it in play to have both studies in parallel and get them both in the filing of their plan.

Speaker Change: Well Fortunately both studies over enrolled but got to the same point almost the same time and I actually think the younger patients will probably.

Speaker Change: As historically true even respond faster so I actually think both studies will have will probably read out but at the same time and our expectation would be to file for the full age range based on that data.

Operator: Please stand by for our next question. Our next question comes from the line of Gena Wang with Barclays. Your line is open.

Emil D. Kakkis: Regarding the DCX-102, the C3 trial design is due to be finalized with FDA. So what will be the use of a single domain for the primary endpoint? Is that the daily score calculation? And also, will you use full loading doses or three loading doses? Since you also explored three loading doses in cohort C2E? And very quickly on the ORFIT trial enrollment, Emily. Did I hear correctly the first interim analysis that will still be the same before year end? Or could that be earlier than our initial assumption since you have completed enrollment ahead of expectation?

Speaker Change: So we're actually in good shape to do that I think it's the right thing I think it would be tough to submit one part of the age range and not the youngest.

Speaker Change: So with the young patient we're excited getting enroll puts it in play to have both studies in parallel and get them. Both in the filing that's our plan.

Speaker Change: Okay.

Speaker Change: Thank you.

Speaker Change: Thank you.

Speaker Change: Please standby for our next question.

Anupam Rama: Our next question comes from the line of Gena Wang with Barclays. Your line is open.

Gena Wang: Thank you.

Gena Wang: Regarding the Gtx 102.

Gena Wang: Okay.

Gena Wang: The trial design.

Gena Wang: Finalize with FTE.

Gena Wang: I'll be your single domain for primary endpoint is that the bayley for calculation and also will you use full loading doses all three loading doses since you're also exploring three loading doses in cohort two.

Emil D. Kakkis: Very good. So in G612, phase 3, the primary end point we're most likely looking at is the Bayley cognition score that we've talked about. It's an integration of multiple things that happen. And they're improving the most.

Gena Wang: And then very quickly on.

Gena Wang: The trial in women and with did I hear you correctly the timing the first interim analysis that will still be the same before year end.

Emil D. Kakkis: It proves rapidly. It's a validated tool. It's well-known. I think these are features.

Gena Wang: Earlier.

Emil D. Kakkis: The FDA is currently aware of this endpoint choice. We've had discussions about it. We'll include other domains within the secondaries.

Gena Wang: <unk>.

Gena Wang: Initial assumptions is now complete.

Gena Wang: Complete enrollment.

Gena Wang: Head of expectation.

Emil D. Kakkis: And the MDI will be, we think, one of the key secondaries. That's our expectation in the plan. But I think we've got great data on all of these and could potentially use other ones if we wanted to.

Gena Wang: Very good so on on the <unk> phase III, the primary endpoint, where it most likely looking at is the Bayley cognition, Florida that we've talked about is.

Emil D. Kakkis: But I think the FDA would have missed this most likely. With regard to three or four doses, let me be clear, the cohorts that we're testing all have the same number of doses for J170. It's just, in cohort A and B, they're actually getting four, and then there's a three-month separation. In the other cohorts, we have the fourth dose separated by a month, so there's a slight difference between the two. So it's not really three versus four, it's really six doses over about a six-month period, exactly how they're spread out.

Gena Wang: As the integration of multiple things that happen they are improving the most improved rapidly.

Gena Wang: Validated tool is well known I think these are feature of the Fda's certainly aware of this endpoint and choice. We've had discussions on it will include other domains within the secondary then the <unk> will be we think one of the key secondaries thats, our expectation and the plan, but I think we've got great data on all of these and.

Gena Wang: Good potential to use other ones that we wanted to but I think balan submissions most likely.

Emil D. Kakkis: We will make a final decision on that after the agency looks at all of our data, but I don't think there will be a material difference between the two. We're just testing them out just to see if there was any difference in how patients would behave or what safety would be like.

Gena Wang: Regard to three or four doses, let me clear the cohorts that we're testing all have the same number of doses through day 170, it's just.

Gena Wang: In the cohorts A&P Theyre actually getting for and then there's a three months separation and the other cohorts. There is we have the fourth doses separated by a month. So it's a slight difference between the two so it's not really <unk> for its really six doses over about a six month period, just exactly how theyre spread out we will make a final decision.

Emil D. Kakkis: But right now, we're still comfortable doing either. Now on the US-143, timing. We got it done here in April, essentially. The timing for the interim depends a little bit on when we think the fractures would be hit and when we think the interim will be done. Our expectation is coming toward the end of the year, possibly earlier next year. So it's around that same timeframe. It hasn't really changed.

Speaker Change: That with the agency looking at all of our data, but I.

Gena Wang: I don't think there will be a material difference to we are just testing them out just to see if there was any difference in how patients were behavior, what with safety would be like but right now we're feeling comfortable doing either.

Emil D. Kakkis: We just want to be clear that there are a lot of factors that come into doing the interim. And so it also is happening, you know, in December, let's say, December, and January. So there's a lot of other things going on, but we're not really changing that. I think it could begin; it could happen in early January before we hear. Keep in mind that the actual process may begin for sure, and then it takes time to get through it because we have to clean the data, prepare it, analyze it, DMT meeting, and then release it.

Gena Wang: Now on the EG UX 143.

Gena Wang: It's timing.

Gena Wang: We got done here in the April essentially.

Gena Wang: The timing for the interim is depends a little bit on when we think.

Gena Wang: The fractured would be hit and timing.

Gena Wang: <unk> is coming towards the end of the year.

Gena Wang: Possibly early in the next year. So it's around that same timeframe. It has not really changed we just wanted to be clear that we have to there's a lot of factors that come in and doing the interim and so.

Emil D. Kakkis: But so, our expectations, DMC, opportunity for review would be end of the year, early next year if it's positive and hits less than P-value, less than 001. Then we will hear about it. If it's not positive, then we will go on to the next one. We set that stringent standard, so it may not mean much to MIPS because I think it could be a great result, which is not quite 0.01, but... That's the time here. Hopefully, that's clear for you, you know. Yep, very clear.

Operator: Yup, very clear. Thank you.

Gena Wang: It also is happening in December let's say December January so there's a lot of other things going on but.

Gena Wang: We're not really changing that I think it could begin it could happen in early January before we would hear keep in mind that the actual process may begin for sure and then it takes time to get through it because they have to clean the data prepare it analyze it DMC meeting and then release it but so.

Gena Wang: Our expectation of the DMC.

Operator: Please stand by for our next question, which comes from the line about Dagon Hall with Stiefel.

Gena Wang: Opportunity for a review would be end of the year early next year, if it's positive and it's less than P. P value less than <unk> one.

Operator: Hey, good afternoon. Thanks for taking our questions and congrats on the progress. I'll just bundle the questions and ask two straight away. So on GTX-102, when the press release talks about other regulatory meetings in the second half, I mean, you've obviously had conversations with the FDA, but what do you think are some of the divergences or differences that they might bring up in terms of endpoints, for example, or even trial design, like enrollment and duration?

Operator: Your line is open. Hey, good afternoon. Thank you.

Gena Wang: Then we would hear about it it's not positive then it will go on to the next one we said that stringent standards. So it may not mean much to miss because I think it could be a great result, but just not quite pointed out one but.

Gena Wang: That's the timing hopefully.

Claire: Claire for you.

Gena Wang: Yes.

Claire: Thank you.

Claire: Thank you.

Speaker Change: Ladies standby for our next question.

Gena Wang: Our next question comes from the line of Dave <unk> with Stifel. Your line is open.

Operator: And then second question, just going back to the 401-GFD-1A, can you provide a little bit more color on how you're thinking about presenting euglycemia throughout the night since that's such an important aspect for KLL? Thanks so much.

Dave: Hey, good afternoon, thanks for taking our questions and congrats on the progress.

Dave: Just bundle all the questions and ask two straight away. So on the Gtx 102, when the press release talks about other regulatory meetings in the second half.

Emil D. Kakkis: Cheers. So. The other EdCurr meetings; it's just a normal habit with a product of this importance to decide that you're going to talk to the European authorities and you're going to talk to the Japanese authorities about what we're doing. The FDA review is really the dominant view that will drive decision making. We've had preliminary discussions, so it's not like we haven't had any. The design of the study is pretty standard; the expectation is likely to be a day 338 or 48 week study. So I think these are pretty standard choices.

Dave: You've obviously had conversations with the FDA, but what do you think are some of the divergences or differences that they might bring up in terms of endpoints for example, or even trial design and enrollment in duration and then second question just going earlier to the 401 <unk> can.

Dave: Can you provide a little bit more color on how youre thinking about presenting the.

Dave: Glycemia throughout the night since that's such an important aspect of our kols. Thanks, so much.

Speaker Change: Sure so the.

Speaker Change: The other AG for meetings as just normal habit with a product of this importance in size that youre going to talk to the European authorities and you talk to the Japanese authorities about.

Emil D. Kakkis: I don't expect there to be much of a problem with them, and I don't actually think there's gonna be a lot of differences. If there were some differences on endpoints or, we can, of course, customize the statistical plan for each region, which we have done in other programs when necessary. But I think the hardwired pieces, the randomized trial, 100, 120 patients... And that basic design, I think that's going to be universal. I don't think there's going to be any problems.

Speaker Change: But what we're doing with the FDA review is really the dominant view will drive the decision, making we've had preliminary discussions so it's not like we haven't had any.

Dave: The design of the study is pretty standard.

Dave: The expectation thats likely to be $3 38, or 48 week study.

Emil D. Kakkis: So the rest of it is going to be more about statistics and positioning, if anything. We're comfortable, though, that what we're proposing is pretty straightforward. I don't really think that will be a problem.

Dave: So I think these are pretty standard choices I don't expect there to be much problem with them and I don't actually think there's going to be a lot of differences. If there were some differences on endpoints or.

Emil D. Kakkis: But of course, there can be feedback. As I said, the FDA's position would dominate our choices for going forward. With regard to the [inaudible] Program. During, we've been presenting the data looking at the fraction of time between the low and the high right. That's mostly what we've been doing Eric right and, We'll likely look at nighttime on the CGM monitor, you know, where the patients will sleep, the CGM monitor, and we'll look at those tracings.

Dave: We can of course customize step the statistician plan for each region, which we have done at other programs when necessary, but I think the hard wired pieces randomized trial of 120 patients.

Dave: That basic design, I think thats going to be a universe I only illuminate problems. So the rest of it.

Dave: More about statistics positioning if anything were comfortable though that what we're proposing is pretty straightforward and I don't really think that will be a problem, but of course, there can be feedback as I said, the fda's position would dominate in our choices for going forward.

Emil D. Kakkis: When we did that during Phase 1-2, I was the most impressed with these kids who were not taking starch at night any longer, and you could watch their glucose; you could see their glucose turn the corner and stabilize, and so you knew their livers were turning on and releasing glucose. So we're going to look for that pattern that they can safely go through the night and that their livers are going to keep them safe. So we'll be able to do that easily at CGM. I wasn't sure. Do you think there's anything else, Erik?

Dave: With regard to the.

Dave: GSD <unk>.

Dave: Program.

Dave: During we've been presenting the data looking at the fraction of time between the low and the high rate Thats been mostly what we've been doing Eric right and.

Dave: We will likely look at the night time on the CGM monitor where the patients are asleep and CGM monitored and we will look at those tracings.

Emil D. Kakkis: Yeah, we are maintaining the controlled fasting challenge in the hospital setting, so we will bring them in, fast them overnight, and monitor them in a controlled setting, so that's further support from the really large amount of data we'll be getting from the CGM on a daily basis. So am I understanding it correctly, it's going to be an average graph, if you will, across the treated and untreated across the 48 weeks of what the low versus high would be on an every night basis?

Dave: When we did that during phase one two I was most impressed with your kids who were not taking starts at night any longer.

Dave: Wash your glucose you could see their glucose turning the corner and stabilize and so you knew their livers returning on in recent glucose. So we're going to look for that pattern that they can safely go through the night and that their livers are going to keep them safe.

Dave: So we'll be able to do that as you look at CGM I wasn't sure. You think there is anything else Eric Yeah, we are maintaining the controlled fasting challenge in the hospital setting. So we will bring them in past them overnight and monitor them in a controlled setting. So that's further support from a really large amount of data we will be getting from the CGM on a daily basis.

Emil D. Kakkis: Yeah, so, for each patient, there's an interval of time where we're doing intensive monitoring of their glucose levels. During those periods, we'll take that, create an average for each patient of where they are in their range, right, and set their target. We're not averaging and then doing the meter. We're taking each patient for their own control range. And then we'll do the meaning of that. And you'll see a graph which we had before, like a bar chart that shows, um, where the two groups are ranging over time between the high and the low. So, we can talk more about that, but there's a way to present this over time so you can kind of see the sense of improving control. Decreasing hyperglycemia and maintaining no hypoglycemia and tightening up over time. This is what we've been watching in our other patients. Right, right. Okay. Thank you very much.

Operator: Please stand by for our next question. Our next question comes from the line of Kristen Kluska with Panel Fixed Journal. Your line is open.

Speaker Change: So am I understanding it correctly, it's going to be on average graph. If you will across the treated and untreated across our 48 weeks of what the low versus high would be on every night basis.

Speaker Change: Yes so.

Eric Harris: For each patient there is an air of all time, we're redoing intensive monitoring of their glucose levels.

Dave: During those periods will take that created average for each patient of where they are in their range set their target, we're not averaging and then doing the mean of it we're taking each patient for their own control range.

Dave: And then we will do the mean of that and Youll see a graph, which we've had before like a bar chart that shows.

Dave: Where the two groups, how they're ranging over time between the high and the low so.

Dave: We can talk more about that but there is there is a way to present. This over time. So you can kind of see the sense of improving control.

Dave: Decreasing hyperglycemia and maintaining no hypoglycemia.

Dave: And tightening up over time, which is what we've been watching in our other patients.

Speaker Change: Right right. Okay. Thank you very much.

Speaker Change: Thank you.

Speaker Change: Please standby for our next question.

Speaker Change: Our next question comes from the line of Kristine <unk> with Cantor Fitzgerald. Your line is open.

Emil D. Kakkis: Well, you know, I think our phase two data kind of laid down what I think we're going to expect. I would expect it to be that a reduction would be very similar, but what we've seen is not better.

Kristine: Hi, good afternoon, Thanks for taking my question.

Kristine: We often get asked about setting expectations for the first interim Readouts just are choosing ups could you. Please help us frame what are some of the factors that are controllable that we can kind of help to predict in advance and then some of the items, where we're less sure about and again how to help frame the expectation. Thank you.

Emil D. Kakkis: So we said we found that with only a minimum of six months, an average of nine months exposure, 67% reduction. The patients we're enrolling are very comfortable with that. If anything... Well, patients might have a higher fracture rate, I think, and... So we would expect that reduction to be something you'd expect to see. Those are, I don't know if you consider, when you enroll patients with fractures, it's not exactly controllable; they are who they are, but because we have a threshold requirement to get in the trial.

Kristine: Well.

Speaker Change: Our phase two data kind of lay down what I think we're going to expect I would expect it to be.

Kristine: Is that a reduction would be very similar to what we've seen if not better.

Kristine: So we set we found there.

Kristine: With only a minimum of six months in average of nine months exposure 60.

Kristine: 67% reduction.

Emil D. Kakkis: We're essentially eliminating patients who would have very low fracture rates and wouldn't necessarily be able to demonstrate benefit in that period of time, I think. With the types of patients enrolled, the number of each type, I think we set those up to replicate what we saw before, and I really don't see any uncontrolled factors. I don't know, Erik, if you have anything.

Kristine: The patients were enrolling are very comparable to that if anything.

Kristine: They're all patients might have a higher fracture eight I think.

Kristine: And.

Kristine: So we would expect that that reduction to be something that you'd expect to see that.

Kristine: Our.

Kristine: Okay.

Speaker Change: I don't know if you consider.

Emil D. Kakkis: Yeah, definitely, and I think the biggest controllable factor was really enrollment rate, and the studies were fully enrolled. Yes, you know, the types of patients, and it was good to get a good mix of one, three, and four in there. I would say yes, I would agree.

Kristine: You enroll patients with fractures is not exactly controllable they are who they are but because we have.

Kristine: The threshold requirement to get in the trial.

Kristine: We're essentially eliminating patients who had a very low fracture rates it wouldn't necessarily.

Emil D. Kakkis: The uncontrollable factor may be, especially when you're a person issuing treatment in the first couple months, you may have some patients who have had fractures before, so TruSnap really takes effect there, but, you know, there is a degree of unpredictability with fractures. It's probably also the fact that some people, some of the kids feel really good, and they're being more active. People were worried maybe that it might cause more fractures, but it didn't look like that was true.

Kristine: Yes, they would be able to demonstrate benefit in that period of time.

Kristine: I think with.

Speaker Change: With the type of patients enrolled the number of which type I think we've set ourselves up to replicate what we saw before and I really don't see any uncontrolled factors I don't know Eric if you have anything yes, definitely I mean, I think the biggest controllable factor factor was really enrollment rate and the studies are fully enrolled.

Emil D. Kakkis: As long as they feel it didn't fracture, so we actually are not concerned about the fact that he might feel good and start being more active. It doesn't look like it's going to cause a problem that looks like their bones are stronger, they're doing great. The truth is, more activity probably strengthens the bones faster because the action actually puts strain on the bones, and the bones actually are strengthened by that actual action.

Eric Harris: The types of patients and it was good to get a good mix of one three and four in there.

Speaker Change: Yes, I would agree the uncontrollable factor may be especially when you're first initiating treatment in the first couple of months you may have some patients who are having fractures before us the truth Mab really takes effect there but.

Speaker Change: There is a degree of unpredictability with fractures.

Emil D. Kakkis: So, thank you for the question.

Speaker Change: Probably also the fact that some people some of the kids like feel really good therapy and more active.

Operator: Thank you. Please stand by for our next question. Unknown Speaker.

Speaker Change: We're worried me with that caused more fractured but it didnt look like that was true or is that as they felt they didn't factor. So we actually are not concerned about the fact that his might feel good and start being more active it doesn't look like it's going to cause a problem that it looks like their bones was stronger theyre doing great. So.

Emil D. Kakkis: Thanks for taking my questions. Maybe I'll ask one on Wilson's disease. Just wondering how you're sensing changes in global copper metabolism and what drives the time Employee of the Time Frame for When You Can Measure Benefit and Get Adequate Insight. Well, the two main ways we're looking at copper are how much free copper is coming out in the urine, right, the urine of copper, which is a sign of how much is sort of oozing out of the tissues and coming out with a key writer. So if you get rid of the detoxifying, if you detoxify copper through the bile, then you should have less coming out in your urine. That's the detox side of the equation.

Speaker Change: The truth is the more activity, probably strengthen the bone faster because the action actually puts strain and the bones of bones actually are strengthened by that actual action. So thank you for the question.

Speaker Change: Thank you.

Speaker Change: Thank you.

Speaker Change: Please standby for our next question.

Speaker Change: Our next question comes from the line of Maury Raycroft with Jefferies. Your line is open.

Speaker Change: Hi.

Maury Raycroft: Thanks for taking my question.

Maury Raycroft: Maybe I'll ask one on Wilson's disease I was just wondering how youre assessing changes in global copper metabolism, and what drives the time point of the endpoint at the timeframe for when you can measure benefit and get adequate insight into into benefit.

Emil D. Kakkis: On the other side of the question is... loading copper on the frutal plasma increases your fructose oxidase activity, which is a very sensitive way of looking at copper loaded correctly on the frutal plasma. So those two biomarker assays will give us a sense of the overall topography. I wasn't sure, Eric. Was there anything else to add? Yeah, we're doing a liver biopsy sub-study, so it'll be great.

Speaker Change: Well the two main ways, we're looking at copper is.

Speaker Change: How much <unk> coming out in the year and right. The tyranny of copper, which is a sign of how much is sort of moving out of the tissues in coming out with a key later so if you've got rid of the Detoxifying. If you detoxify copper through the bile then you should have less coming out in Europe.

Emil D. Kakkis: This is really the first time we've been able to do it for biopsies. We made it optimal, but the majority of patients did opt in for that. So it will be interesting to look at copper concentration and histopathology in those samples. God, that's a lot.

Speaker Change: That's the detox side of the equation.

Speaker Change: On the other side of the question is.

Speaker Change: Is loading copper onto through NUPLAZID for <unk> activity. So we will be measuring the sewer plasmoptysis activity, which is very sensitive way of looking at copper loaded correctly anthro plasm. So those two those two biomarker assays will give us a sense of.

Emil D. Kakkis: And maybe just a quick question on Khatru Zamav. We see that he's got a title at ENDO and you're guiding to, which is I think scheduled for June 1st, and you're guiding to having longer term phase 2 data in the second half of this year. Just wanted to clarify, will that presentation at ENDO be an encore, or should we expect, what should we expect in that update? Yes, that will be a pure on court presentation. Got it. Okay. Thanks for being here. We'd like to see good news again, frankly.

Speaker Change: The overall copper metabolism I wasn't sure Eric who is there anything else to add yes, we're doing a liver biopsy subsidiary so it'll be great. If this is really the first time, we've been able to do liver biopsies, we made an optional but the majority of patients to opt in for that so it will be interesting to look at copper concentration and histopathology and the Sam.

Speaker Change: <unk>.

Speaker Change: Got it maybe just a quick.

Speaker Change: And maybe just a quick question on.

Speaker Change: <unk>, we see that you've got a titled at Endo and Youre guiding to which is I think scheduled for June one and you're guiding to having the longer term phase two data in the second half of this year just wanted to clarify will that presentation at endo.

Operator: Please stand by for our next question. Our next question comes from the line of Jeff Hung with Morgan Stanley. Your line is open. Thanks for taking my questions.

Operator: Thanks for taking my questions. So, the Truth in the Aborted Study, if you go to the second... What would the bar be for stopping the study at that point? And in that scenario, would you have greater confidence in stopping the study early with a second interim? And then for the COSMIC study, what would it take for you to stop the study early in that?

Emil D. Kakkis: Yes, so, the second end, as we've planned it right now, would be at 0.01. So that's much less stringent, right? That's a 10-fold larger p-value. And then the final is 0.04. So.

Speaker Change: Non core or should we expect what should we expect in that update.

Speaker Change: Yes.

Speaker Change: It will be a pure encore presentation.

Speaker Change: Got it okay. Thanks for taking my questions.

Speaker Change: We'd like to see good news again frankly.

Speaker Change: Hey.

Speaker Change: Please standby for our next question.

Speaker Change: Our next question comes from the line of Jeff Hung with Morgan Stanley. Your line is open.

Jeff Hung: Thanks for taking my questions for the truth in that orbit study. If you go to the second interim what would the Barbie for stopping the study at that point and in that scenario would you have greater confidence for stopping the study early with a second interim.

Emil D. Kakkis: I think the reason the second is less changing is that, at that point, everyone would have at least a year of treatment, so we felt there were fewer regulatory issues there. Um, and then 18 months would be the, you know, for just sort of the backstop if we have to go that long for Cosmic. Remember, it's an open-label study, randomized, but open-label. And so we'll be looking at the activities of the DMC.

Jeff Hung: And then for the Cosmic study what would it take for you to stop the study.

Jeff Hung: The study early in that.

Speaker Change: Yes so.

Speaker Change: The second room as we've planned it right now would be 0.1.

Speaker Change: So that's much less stringent tenfold larger P value and then the final point out for so.

Emil D. Kakkis: And our DMC will be looking, since these are little kids; one of the questions will be, if there is a stark separation in the fracture rate. In that study, the DNC was probably obligated to end the study and not keep kids on an inferior treatment. And so, while we haven't set criteria for that, they will be looking at the study during the year. And if they were to hit a strong separation of the groups that they thought was unrepresentative, they could stop.

Jeff Hung: I think the reason the second is less stringent that at that point, everyone would have at least a year of treatment. So we felt there is less regulatory issue there.

Jeff Hung: And then 18 months would be the pointed out for its just sort of a backstop. If we have to go that long.

Jeff Hung: Cosmic.

Jeff Hung: Remember, it's an open label.

Jeff Hung: Steady randomized, but open label and so we will be look at the X rays of the DMC and our DMC will be looking at this either little kids. One other question will be is if there is a separation of the fracture rates.

Emil D. Kakkis: Our expectation is that the younger patients will respond faster, and since they have already finished enrollment, we think by the time the first interim of one study is done, the other study should be pretty far along. If one hits, I think the other one should be ready. So, we'll probably be pretty closely coordinated with the two, but the DMC will always have the opportunity to look at the data and determine if there's a reason to stop that study.

Jeff Hung: In that study the DMC will probably be obligated to.

Jeff Hung: To end the study and not keep kids on an inferior treatment and so while we haven't set criteria for that.

Jeff Hung: They will be looking at the study.

Jeff Hung: During the year and if they were to hit.

Emil D. Kakkis: And remember, going another year is a big deal if you're two years old and you have a bone issue, right? So, it's a lot different in that study. But fortunately, being open-label, DMC has a chance to take action each time they take a look.

Jeff Hung: Our strong separation of the groups that they felt was unethical team that could stop our expectation that the younger patient will respond faster and since they've finished enrollment we think by the time, we're doing the first interim the one study the other study should be pretty far along in the.

Jeff Hung: The one hit I think the other one will be should be ready. So we will probably be pretty closely coordinated with the two but the DMC will be all along have the opportunity to look at the data and determined as her a reason to stop that study I remember going another year is a big deal if you're two years old and you have a bone issue right. So.

Operator: Please stand by for our next question. The next question comes from the line of Joon Lee with CHOICE. Your line is open.

Operator: Thanks for the update, friends, for taking our questions. For the HMM program, are you talking to CBER or the Neurology Department? And if it's not CBER, you know, would it be possible to request UCS1 be released by CBER? And near the end of the Phase 2 meeting, how strongly would you be advocating for MDRI as an approvable endpoint, or has that shift already failed? Thank you.

Jeff Hung: It's a lot different in that study, but fortunately being open label DMC has a chance to take action.

Jeff Hung: At each time, they take a look.

Speaker Change: Great. Thank you.

Speaker Change: Thank you.

Speaker Change: Please standby for our next question.

Emil D. Kakkis: Well, we're under here, we're actually in, we said we're in the psychiatry part of the neurology sciences group. That's where we've been the whole time, so, and they're actually doing a great job, Tiffy, first of all, she's the leader of that group, and then we've had good meetings, and she's great to work with, so I'm actually, we're very happy with the setting we're in and how it's going, so they're in CETR, and there's really no purpose, it's not, it's really a well-characterized drug, so it's not really gonna fit within the CBER mantra, and there's no benefit to us to doing that at this point, so we're comfortable where we are with that one.

Speaker Change: Our next question comes from the line of Jim Lee with <unk>. Your line is open.

Joon So Lee: Hey, thanks for the updates and for taking our questions for the Angelman program are you talking to CEVA or the neurology Department and if it's not seeber.

Joon So Lee: Would it be possible to request <unk> to be reviewed by steeper and muni and the phase II meeting how strongly would you be advocating for MRI as an approvable endpoint or has that ship Rd sale. Thank you.

Speaker Change: Well, we are under theater, we're actually in we said before in the psychiatry part of of the Neurology Sciences group.

Joon So Lee: And <unk>.

Emil D. Kakkis: Regarding the MVRI... We like MDRI, but it is something very different. While we had it in our MEDCIV program, it was used and helped support the program. It's still a methodology that's new for FDA. We've had a lot of meetings. I presented at a lot of conferences.

Joon So Lee: That's where we've been the whole time, so they are actually doing a great job 50 for China as the leader of that group and we've had good meetings and chief great to work with so I am actually we're very happy with the setting we're in and how it's going.

Joon So Lee: So theyre in Cedar and Theres really no purpose its not its really well characterized drugs is not really going to fit within the <unk>.

Emil D. Kakkis: I think we'll have growing support for it if we use it. So our plan, rather than press our case, is probably to put in a single primary validated type endpoint for them and then put our MDRI in as a key secondary. That way, we get the best of both.

Joon So Lee: Mantra and there's no benefit to us doing that at this point. So we're comfortable where we are with that one.

Joon So Lee: With regard to MTI.

Joon So Lee: We like <unk>, but it is something very different while we had it in our <unk> program and it was used and had helped support the program is still a methodology. This new for FDA. We've had a lot of meetings I presented a lot of conferences.

Emil D. Kakkis: We manage what FDA may want or prefer, and at the same time, we get an MDRI in there, which allows us to support the product. I do believe, and my belief in the long run is that the NDRI will be a fundamentally new way and a better way of doing, particularly, heterogeneous neurologic disorder analysis. And once the FDA sees that in a large randomized trial, see how it performs, and understands it, I think they'll start gaining more appreciation for why it's a superior approach to analyzing clinical outcomes.

Joon So Lee: I think.

Joon So Lee: They'll be growing support with every use it so our plan rather than press. Our case is probably to put in a single primary validated type endpoint for them and then put our MDI in as key secondary that we would get the best of both we managed what FDA may want or prefer and same time, we get to MDI in there, which.

Joon So Lee: Allows us to support the product.

Operator: Please stand by for our next question. Our next question comes from the line of Joseph Schwartz with Delivery Partners. Your line is open.

Joon So Lee: I do believe and my belief in the long run is it the Andrew or I will be a fundamentally new way and better way of doing particularly heterogeneous neurological disorder analysis and once the FDA sees that in a large randomized trial see how it performs and understand it I think they will start gaining more appreciation more appreciation.

Operator: Great. Hi, all. This is Will on for Joe today.

Operator: Thanks for taking our questions and congratulations on the progress this quarter. So one for us on the DTX-401 program, we recently saw the updated data in the ASGCT abstract, which suggests that the corn starch benefit rebounded favorably as compared to the data shared last year. So just wondering if you could provide some comments on how you're thinking about the durability of this treatment and how this may change your expectations, if at all, for the corn starch production. Well, I don't think that's changed our opinion very much on that at all.

Joon So Lee: It's a superior approach to analyzing clinical outcomes.

Speaker Change: Great. Thank you.

Speaker Change: Thank you.

Speaker Change: Please standby for our next question.

Speaker Change: Our next question comes from the line of Joseph Schwartz with Leerink Partners. Your line is open.

Will: Great Hi, Al. This is will on for Joe today, and thanks for taking my questions and congrats on the progress this quarter as the one for US on the Gtx 401 program. We recently saw the updated data in the <unk> abstracts, which suggests that the cornstarch benefit rebounded favorably compared to the data shared last year.

Operator: I think what we are noting over time is that the reduction in starch happens very quickly, but to get all the way down takes time. And there are some secondary factors. It does depend a little bit in the long run on how the doctor manages the starch. They have to get the starch down and get the glucose to come down so that the gene therapy actually expresses that the expression of the gene therapy is dependent on stimulating the promoter because we're using the normal GSC-1A, a glucose-6-phosphatase promoter. So there are some interesting features of how that operates, but we're comfortable with where we are.

Will: Just wondering if you could provide some comments on how youre thinking about the durability of this treatment and how this may change your expectations at all for the cornstarch reduction that we might see in a pivotal study later this quarter.

Will: Well I don't think Thats changed our opinion very much on that at all I think the.

Will: What we are noting over time is that the.

Will: Actions charge happens very quickly.

Will: But to get all the way down takes time and there is some secondary factors it does depend a little bit in the long run on.

Emil D. Kakkis: We haven't changed our expectations for the study. We think that you know, we saw something like a 50% reduction within a short period of time. But if you look, it took a lot longer to get down. It was highly more dependent on how doctors were titrating an individual patient.

Will: How the Doctor manages the starch they have to get the starts down and get the glucose to come down so that the gene therapy actually expresses that the expression of the gene therapies dependent on stimulating the promoter because we're using the normal <unk>.

Emil D. Kakkis: But we're very comfortable with what we're seeing. We haven't, we don't have any concerns yet about durability. We think it's going to be good over the long haul.

Will: We closed six phosphatase promoter.

Will: So there are some interesting features how that operates but we're comfortable with where we are we haven't changed our expectations for the study. We think that we saw something like 50, <unk> sat reduction within a short period of time, but if you looked it took a lot longer to get down and was highly more dependent on how doctors were titrated and individual.

Operator: Please stand by for our next question comes from the line of Yaron Werber, and Yaron is voting.

Operator: Great. This is Brendan on for Yaron.

Operator: Thanks for taking the question, sir. Just a quick one from us on the gene therapy pipeline. I think you recently said that you might file for GSD-1A around the end of this year or early next year. I totally understand that this is somewhat in flux. But I guess in light of the transition to manufacturing, should we expect a similar timing between top-line data and filing for OTC, or would you expect that to potentially go more quickly after manufacturing than health? And then, kind of along the same lines on pricing, is it fair to assume that both GSD-1A and OTC would be priced similarly? And I guess if not, what might be dropping?

Will: <unk>, but.

Will: We're very comfortable with what we're seeing and we haven't.

Will: We don't have concern yet on durability, we think it's been good over the long haul.

Will: Okay.

Speaker Change: Thank you.

Will: <unk>.

Speaker Change: Please standby for our next question.

Speaker Change: Comes from the line of Juran Weber with TD Cowen Your line is open.

Speaker Change: Great. This is Brendan on for Ron Thanks for taking the question guys. Just a quick one from US on the gene therapy pipeline I think you correct me if I'm wrong I think you recently said that you might file for <unk> around the end of this your early next year.

Emil D. Kakkis: Yes, well, the BLA, I don't want to predict exactly the timing behind, we have transitioned manufacturing internally, we're running those, we'll be running those runs, and we have to meet with FDA to make sure, for example, what do they require of our manufacturing to be in the filing right at the time of filing versus can be submitted as, let's say, during the filing, so those are factors that will impact the exact timing Our expectation, though, is probably going to end up being, if it's late in the year, it would actually be more likely next year to get all the pieces early next year, but...

Speaker Change: Totally understand that this is somewhat in flux.

Brendan: But I guess in light of the transition to the manufacturing should we expect kind of similar timing between topline data and filing for OTC or would you expect that to potentially go more quickly after the manufacturing in house and then kind of along the same line.

Speaker Change: Pricing is it fair to assume that both <unk> and OTC would be priced similarly, and I guess, if not what might be driving the differences.

Speaker Change: Yes, well the BLA I don't want to predict exactly the timing filing we have transitioned manufacturing internally we're running those.

Speaker Change: We're running those runs and we have to go meet with FDA to make sure for example.

Emil D. Kakkis: Right now, we don't want to make a prediction because of some pieces we have to get straight. With regard to OTC timing... Well, that's a bit further out. I'm not sure I want to predict whether we're going to or how fast that's going to go. But I can say that if you look at everything we have, and we don't know that everything will be successful, but we have six ERA filings in front of us over the next three years or so. So something like that. So, we're going to be busy, including three, within the next year or so, right? So,

Speaker Change: What do they require of our manufacturing to be in the filing right at the time of filing versus can be submitted at let's say during the filing. So those are factors that will impact the exact timing of filing and we need to get the data and see them in a pretty related meeting and get that straight. So we'll put out a little bit more data.

Speaker Change: Our expectation, though is probably going to end up being if its late in the year. It would be actually more likely next year to get all of the pieces early next year, but.

Emil D. Kakkis: We'll be busy, and I'm sure OTC will have to be fit in once the pay sweep's out. With regard to pricing... I don't think there's a big difference in how we price UC1-OTC. They have very similar population sizes and severity of diseases. OTC happens to have very expensive drugs like Revictine, which a lot of patients use. They probably could justify pricing easier with regard to the cost of production, you know, assuming patients were getting off their other drugs. But right now, we haven't put any stakes around regarding pricing. We're listening and watching what's going on, and we'll come up with a plan when we get closer.

Speaker Change: Right now, we don't want to make a prediction because of some pieces, we have to get to eight regard to OTC timing.

Speaker Change: Well, it's a bit further out I am not sure I want to predict whether we're going to how fast that's going to go but I can say is that if you look at everything we have and we don't know that everything will be successful, but we have in front of us six BLA filings over the next three years or so so something like that so.

Speaker Change: We're going to be busy including three within the next year or so right. So.

Speaker Change: We will be busy and I'm sure OTC will have to be fit in.

Speaker Change: Once the phase III with regard to pricing.

Speaker Change: I don't think Theres, a big difference in how we price GSD, one OTC theyre very similar population sizes and severity of diseases.

Operator: Please stand by for our next question. Our next question comes from Alarm Salveen Richter with Goldman Sachs. The line is open. Hi, this is Lydia on behalf of Salveen.

Speaker Change: OTC happens to have very expensive drug like <unk>, which a lot of patients you probably could justify pricing easier with regard to the cost.

Speaker Change: Production, assuming patients were getting off there other drugs, but.

Speaker Change: Right now we haven't put a stake in the ground regarding pricing, we are listening and watching what's going on and we'll come up with the plan we get closer in.

Speaker Change: Yeah.

Speaker Change: Alright, great. Thank you.

Speaker Change: Please standby for our next question.

Operator: I think part of the outcome is essentially finalizing the end point, the palette of end points, and the statistical approach we're taking. As well as what, you know, the ability to put that forth and get it approved. That would be the idea. So, while we already have agreement on basic studies, I want to give some comfort on the duration, as well as, you know, the drug-testing regimen, and Dan Boynton.

Goldman Sachs: Our next question comes from the line in solving which there with Goldman Sachs. Your line is open.

Speaker Change: Okay.

Speaker Change: Hi, This is <unk> on for Shelby and thanks, So much for taking my question and congrats on the progress.

Speaker Change: Just another on the end of phase two meeting with the FDA for Angelman, what would you view as a positive outcome here and could you just remind us how you plan to message to the Street post this meeting and what details you plan to disclose thanks, so much.

Speaker Change: So.

Emil D. Kakkis: I think the majority of the issue will be finalizing endpoints for them, and that's what people are most interested in. Regarding the messaging, if we complete the meeting and have a very clear solution, we'll put out a notice on the street about that fact. Sometimes a meeting can be pretty clear, but there's still a couple pieces to solve, in which case we'd finish that discussion until there is a final agreement between FDA and us, and then we would only announce it at that point in time.

Speaker Change: I think pause the outcome is essentially finalize the endpoint palette of endpoints and statistical approach we're taking.

Speaker Change: As well as what.

Speaker Change: What.

Speaker Change: The ability to put that forth and get a file for approval that would be the idea. So while we already have agreement on basic studies I want to set some comfort on the duration.

Speaker Change: As well as.

Speaker Change: The dose dosing regimen.

Speaker Change: And the endpoints, but I think the majority issue, we'll be finalizing endpoints with them and Thats what people are most interested in.

Operator: Please stand by for our next question. Our next question comes from the line of Jack Allen with Baird. The line is open.

Speaker Change: With regard to messaging.

Speaker Change: We complete the meeting and have a very clear.

Speaker Change: <unk> solution will we'll put out a notice.

Operator: Thanks so much for doing the question and congratulations to the team on the progress made over the course of the quarter. I know a few people have spoken out on this idea, but what are you thinking about as it relates to expectations for the annual fracture rate in the placebo out of orbit? And I also wanted to ask, are you matching patients based on their seasonal involvement in the study? I recently did some work with the KLO, and they mentioned that seasonality can affect fracture rates as well. Any context you provide there would be very helpful. Yeah, well, we don't have any way to control the seasons, but if we did...

Speaker Change: On the street on that fact.

Speaker Change: Sometimes I mean, it can be pretty clear, but theres still a couple of pieces to solve in which case, we'd finish that discussion until there's a final agreement between FDA and US and then we would only announce at that point in time.

Speaker Change: Yes.

Speaker Change: Thanks, so much.

Speaker Change: Thank you.

Speaker Change: Please standby for our next question.

Speaker Change: Our next question comes from the line of Jack Allen with Baird. Your line is open.

Jack Allen: Alright, thanks, very much for taking my question and congratulations to the team on the progress made over the course of the quarter.

Emil D. Kakkis: So, there are a lot of things that affect fracture rates, and one thing I'll tell you is actually coming into the trial will increase the fracture rate, simply coming into the trial because they're transporting, getting out of cars, and in fact, in the Phase 2 study, 25% of the fractures occurred between screening in the beginning, like a lot of fractures in the last year were actually part of the process of coming into a trial. So I would think that there are fractures and fractures that are, you know, are harder to predict.

Jack Allen: A few people have talked around this idea, but what are you thinking about as it relates to expectations for the annual fracture rate in the placebo arm of orbit and I also wanted to ask are you matching patients based on their seasonal enrollment in the study recently did some work with the Kols I mentioned that seasonality can affect fracture rates as well any context you can provide.

Jack Allen: There would be very helpful.

Speaker Change: Yeah, well, we don't have any way to control the seasons, but if we did.

Speaker Change: So there's a lot of things affect fracture eight and one thing I'll tell you is actually coming into a trial will increase the fracture rate simply coming into the trial, because they're transporting getting out of cards.

Emil D. Kakkis: What we have assumed right now, I think, is about 0.67 factor. The threshold to be in the study is one fracture per year, but we're assuming, and people ask me why you're assuming that, well, you don't want to assume the middle ground of what you expect; you always assume the boundary, you know, you want to pick a safe boundary. Our expectation is that it should be higher than.67. How much higher will be somewhat dependent on who's enrolled. What happens to them, you know, how far they travel, how many potential risks are there, and the type of OI they have.

Speaker Change: And.

Speaker Change: In fact in the phase II study, 25% of the fractured occurred between screening and the beginning of like a lot of the fracture than they were last year, we're actually part of the process.

Speaker Change: Coming to a trial so I would say to you there is factors in fracture that are.

Speaker Change: Are harder to predict.

Speaker Change: What we have assumed right now I think is about six seven fractures.

Emil D. Kakkis: But at the boundary of 0.67 and the 50% reduction, you know, we had ample power for the study. And if the fracture rate is higher and the reduction is higher, you synergize those two, we could have substantially more power than required. So I think we're in a good place in what we're positioning, but we said 0.67 with a criteria for entry, though, of having at least one a year, got it got it that's great color i guess just as it was a seasonality component i understand the global study or the patient's going to be um you know distributed and matched across the geography Yeah, they will be remember, they're always going to be in small, you randomize a little block, right?

Speaker Change: The threshold to be in the studies, one fracture per year, but we are assuming and people ask me why it would be assuming that well you don't want to assume the middle ground of what you expect you always assume on the boundary you want to pick a safe boundary. Our expectation is it should be higher than <unk> 67, how much higher will be somewhat dependent on who is enrolled.

Speaker Change: What happens to them how far they traveling how many potential risks are there and the type of Oi they have but.

Speaker Change: At the boundary of <unk>, seven and Fisher cent reduction.

Speaker Change: Have ample power for the study.

Emil D. Kakkis: So within any period of time, the blocks are small enough that you should be. Creating evenness will also be stratifying based on fracture rate, right, so the patient's high fracture or low fractures are even, are even numbers between the two groups. I will also point out to you the way the trial unfolded, it actually unfolded. The majority of the patients are all between November and March, right? Probably. So they're all really in a pretty tight window, I would say as tinkerously enrolled as we've seen in terms of the number of patients.

Speaker Change: Refresh rates higher than the reductions higher if since synergize. Those two we could have substantially more power than required. So I think we're in a good place and what we're positioning but we've said six to seven.

Speaker Change: The criteria for entry of having at least one a year.

Speaker Change: Got it got it that's great color I guess just a.

Speaker Change: Seasonality component I understand it's a global study or the patient is going to be.

Speaker Change: Distributed and matched across the geographies.

Speaker Change: They will be but remember there are always going to be in small.

Speaker Change: You randomize, a little blocks right. So within any period of time the blocks are.

Speaker Change: Our small enough that you should be.

Emil D. Kakkis: Yeah, and the randomization should help with seasonality too, because you know, you're not random, you're not randomizing exactly one to one, but you are trying to keep that balance through randomization. So that could help there as well. Got it. Thanks for watching again.

Speaker Change: Creating even if it will also be stratified based on fracture rate right. So patients high fracture load factors or even or even number of between the two groups.

Speaker Change: I'll also point out to you the way the trial enrolled it actually enrolled the.

Operator: Please stand by for our next question. Our next question comes from the line of Luca Ussa with RBC Capital. Your line is open.

Speaker Change: The majority of the patients are all between November.

Speaker Change: And March probably so theyre, all really in a pretty tight window I would say as synchronously enrolled as we've seen in terms of number of patients and the randomization should help us seasonality too because you are not random youre not randomize I can exactly one to one but you are trying to keep that balance through randomization, so that that could help there as well.

Operator: Oh great, thanks so much for taking my question; congrats on the progress. Maybe circling back to the prior questions and the first interim look for COSMIC, maybe just ask a slightly different thing. In a scenario where the Phase 2 data is replicated, and the 57% reduction in fracture is actually recapitulated in phase 3, would that be sufficient to hit the stats by year-end, or would you need to see something better in order to hit the stats by year-end? So that's question number one.

Speaker Change: Got it thanks, so much for the color.

Speaker Change: Thank you.

Speaker Change: Please standby for our next question.

Speaker Change: Our next question comes from the line of Luca Asa with RBC capital. Your line is open.

Emil D. Kakkis: And question number two on ORI, can you just remind us the latest thinking on the competitive landscape? It looks like Angin is actually running a Phase 3 trial versus Biphosphonate in 5 versus 17 years of age, whereas you're obviously running a Phase 3 trial versus placebo in 5 to 25 years of age. How should we reconcile that difference? Why is the FDA asking them to run a trial versus Biphosphonate in 5 and older versus you running a trial versus placebo? Any thoughts there? It would be much appreciated. Thanks so much.

Luca Asa: Oh, great. Thanks, so much for taking my question Congrats on the progress maybe circling back on the prior questions on the first interim look for cosmic maybe just asked slightly differently.

Luca Asa: Scenario, where the phase II data is replicated in the 67% reduction in fracture is actually Rick stipulated in the phase III would that be sufficient to hit the SaaS by year end or do you need to see something better in order to meet the status by year end. So that's question number one question number two can you just remind.

Emil D. Kakkis: I'd agree that ours is better, but that would be the simple answer. Our trial will be 5-25 against placebo, but we're also running 2-7 against bisphosphonate, so you'll be able to look at both sides of the story. But I feel confident that we're in a good position.

Speaker Change: Find us the latest thinking that the competitive landscape. It looks like Amgen is actually running a trial phase III versus by fast five versus 17 year stage versus you're obviously running in phase II versus placebo. These last two.

Speaker Change: Five years of age how should we reconcile that difference why is the FDA asking them to run a trial versus buy phosphate five and older versus youre running a trial versus placebo any thoughts there much appreciate it. Thanks so much.

Emil D. Kakkis: The data that Enzin put out on BMD was about half what we achieved, and that was at their highest dose that they tested in their dosing study. So right now, our data will look stronger than theirs just based on that. So so far, we're not, right now, we're not concerned. With regard to the cosmic, 60% is one of the factors.

Speaker Change: Sure well I'd reconcile that ours is better.

Speaker Change: That would be the simple answer.

Speaker Change: Our trial will be 525 against placebo level. We're also running two to seven.

Speaker Change: The phosphate so youll be able to look at both sides of the story, but I feel confident that we're in good position.

Emil D. Kakkis: The other important factor is how many fractures we really are doing. For example, if it was one and a half fractures, that would greatly help the ability of the control group to hit the end point. If it's 0.67 or less, then it might take more time.

Speaker Change: The data that Amgen put out in BMD.

Speaker Change: At six months.

Speaker Change: It's about half what we achieved that was at our highest dose that they tested in their dosing study. So right now our data will look stronger than theirs, just based on that so so far we're not right now we're not concerned with regard to the <unk>.

Emil D. Kakkis: So, 6-10-7 is enough to hit it, but you need to have enough fractures, so that's the other, those two variables are synergistic and how they impact things. So we couldn't say for sure. I think trying to indicate whether the first one's gonna hit is stringent. I think it's a relatively lower possibility of hitting.

Speaker Change: Cosmic <unk>.

Speaker Change: <unk> is one of the factors the real other important factors. How many factors really are going for example is one and a half fracture that would greatly help the ability and the control group.

Emil D. Kakkis: But we wanted to open the door in case fractures were high and the reduction was high, and we were already off scale. We wouldn't keep going with those kids on placebo. And you can imagine, these are people's children. So continuing placebo when you're already a long way past what's required is smart, and better for them, and the right thing to do.

Speaker Change: Hit the endpoint, if it's six seven or less than it might take more time.

Speaker Change: So six 7% is enough to hit it but you need to have enough fractured so thats. The other those two variables are synergistic and how they impact things.

Speaker Change: So we couldn't say for sure I think trying to handicap, whether it first of all is going to hit its stringent I think it's.

Speaker Change: Our relatively low our possibility of hitting but we wanted to open the door and case fractures were high and the reduction was high and we are already off scale, they wouldn't keep going with those kids on.

Operator: I'm showing no further questions in the queue. I would now like to turn the call back over to Joshua for closing remarks.

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

Speaker Change: On.

Speaker Change: Placebo.

Speaker Change: And you can imagine theres people children, so continuing placebo when there when you've already gone way past, what's required I think thats smart, so and better for them the right thing to do.

Operator: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Speaker Change: Thank you.

Speaker Change: Thanks, so much.

Speaker Change: Thank you.

Speaker Change: I'm showing no further questions in the queue I would now like to turn the call back over to Joshua for closing remarks.

Joshua: Thank you. This concludes today's call for additional questions. Please contact us by phone or at IR at <unk> Dot com. Thank you for joining us.

Speaker Change: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation you may now disconnect.

Speaker Change: Okay.

Speaker Change: [music].

Speaker Change: Okay.

Speaker Change: Yes.